Paraneoplastic pemphigus associated with neoplasms.
\r\n\tThis book aims to introduce general concepts about clock synchronization describing clock generation techniques and the properties of oscillators, phase-locked loops and in general of frequency synthesizers. Also welcome are topics that describe clock synchronization for digital ICs and the pertaining low-latency clock domain crossing techniques based on clock phase adjustment and standards for clock synchronization, such as the IEEE1588 and the Precision Time Protocol. Moreover, the book aims to describe the issues of sub-nanosecond synchronization in distributed systems on scales from a few tens of meters to a few tens of kilometers.
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He has spent most of his scientific career in the field of research and development of electronics for data acquisition and processing in Nuclear and Subnuclear Physics experiments, including ATLAS, RD51, Belle2 and SuperB. He is the author of 371 papers on well-recognized scientific international peer-reviewed journals, including IEEE TNS, NIM-A, and JINST. His H-index is higher than 63 and the total number of citations is around 20k. He gave numerous contributions to international conferences (including 15 oral, 2 invited oral). He is the inventor of granted patents in the field of digitally controlled oscillators and methods for radiation hardening of SRAM-based FPGAs.',institutionString:"University of Naples Federico II",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Naples Federico II",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:[{id:"70233",title:"Design and Analysis of Analog to Digital Converter System Clock Source Using Direct Digital Synthesizer",slug:"design-and-analysis-of-analog-to-digital-converter-system-clock-source-using-direct-digital-synthesi",totalDownloads:10,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67359",title:"Paraneoplastic Pemphigus Is a Life-Threatening Disease",doi:"10.5772/intechopen.84956",slug:"paraneoplastic-pemphigus-is-a-life-threatening-disease",body:'\nParaneoplastic pemphigus (PNP) was first described in 1990 by Anhalt et al. as a rare autoimmune disease that causes ulcerated lesions and vesicular eruptions in the mucocutaneous regions [1]. In 2001, the researcher Nguyen et al. introduced the term multiorganic autoimmune paraneoplastic syndrome, since it is a systemic disease that can affect the kidneys, bladder, and smooth and striated muscles [2]. PNP is a disease triggered mainly by B-cell lymphomas and malignant hematological diseases [3]. Other neoplasms also demonstrate the onset of this disease, as well as carcinoma of the stomach, lung, and colon [3]. The patients with PNP present high mortality rates, being around 90% of the cases, besides presenting an extremely complex and difficult diagnosis, since it resembles several other diseases [4, 5]. The treatment and management of this disease are often ineffective, as it is an extremely aggressive and lethal disease.
\nIn this chapter, we will address the epidemiological aspects, the main triggers, pathophysiology, main manifestations, diagnosis, differential diagnoses, treatments used, prognosis, and the quality of life of patients affected by PNP.
\nBecause PNP is an extremely rare disease, there is still no data on the incidence of this disease in the world population [3]. To date, about 500 cases have been reported in the literature, with PNP representing 3–5% of all cases of pemphigus in the population [6, 7, 8]. The vast majority of affected patients demonstrate lymphoproliferative disorders (LPD) [9]. Although this disease can affect children and adolescents, the most common age group is between 45 and 70 years of age and is not correlated with place of origin, race, and sex [7, 10, 11, 12, 13, 14].
\nPNP can be triggered by several types of neoplasias; however, about 84% of all patients present neoplasias or hematological disorders [3, 7, 15]. Non-Hodgkin’s lymphoma is the most common disorder with 38.6% of cases, followed by chronic lymphocytic leukemia and Castleman disease with 18.4% each (Table 1). Among the non-hematological neoplasms, sarcomas present approximately 8.6% of the cases, such as leiomyosarcoma, malignant nerve sheath tumor, poorly differentiated sarcoma, reticular cell sarcoma, dendritic cell sarcoma, liposarcoma, and inflammatory myofibroblastoma [15, 16, 17]. Other less common diseases described in the literature that provide PNP are malignant thymoma, squamous cell carcinoma of the esophagus, colon carcinoma, CD8+ T-cell lymphoma, retroperitoneal Kaposi’s sarcoma, and lymphoepithelioma-like carcinoma [18, 19, 20, 21, 22, 23]. Although the PNP is triggered by several neoplasias, the manifestations of this disease may precede the hematological disorders and other malignancies, thus requiring the frequent and continuous follow-up of these patients [15]. In addition, there are reports of the occurrence of PNP without a detecting the cause [24, 25].
\nNeoplasms | \nFrequencies (%) | \n
---|---|
Non-Hodgkin’s lymphoma | \n38.6 | \n
Chronic lymphocytic leukemia | \n18.4 | \n
Castleman disease | \n18.4 | \n
Sarcoma | \n8.6 | \n
Others | \n16 | \n
Paraneoplastic pemphigus associated with neoplasms.
It is known that the major histocompatibility complex (MHC) has important relationships in increasing the susceptibility of autoimmune diseases. Although there are few papers that analyze the relationship between PNP and genetics, some studies in the Caucasian and Chinese population showed the relationships of the HLA class II alleles DRB1*03 and HLA-Cw*14 in the PNP’s trigger [26, 27]. HLA-Cw* 14 proved to be a more specific allele type of PNP. Its importance has been associated with PNP, regardless of whether it is a Castleman disease or other tumors, in addition to Castleman disease. [26]. However, to date, these studies are preliminary studies that suggest the association between genetic factors and PNP. To better understand this relationship, it is important to conduct studies with larger numbers of patients and that are affected by different tumors, as well as the realization of this association in different populations.
\nPNP even being a disease not yet known at the present time, it is known that both autoantibodies, as cell-mediated immunity, are involved [28]. Certainly, it deduces that the immune system is paramount in the pathophysiology of this disease.
\nPNP triggers immune changes with the production of autoantibodies capable of acting on various proteins in the body. The major target proteins of the autoantibodies are desmoglein 1 (DSG-1) and desmoglein 3 (DSG-3); desmocollins 1, 2, and 3; desmoplakins 1 and 2; BP230; BP130; and envoplakin, in addition to several other epitopes affected by autoantigens found in the individual [29]. These characteristics demonstrate the immunological complexity of the disease.
\nProteins of the plakin family, such as desmoplakins 1 and 2, envoplakin, periplakin, plectin and BP230, demonstrate the major targets of autoantibodies [30]. In contrast, the proteins of the cadherin family are the second most affected, with proteins such as DSG-1 and DSG-3 and desmocollin [31]. It is known that the presence of autoantibodies to some proteins are not related to the clinical practice of the patients, although there is a study that has mentioned DSG-3 relation with genital involvement [32].
\nOther autoantibodies such as alpha-2 macroglobulin-like 1 (A2ML1), a broad-range protease inhibitor, have been shown to be important in some patients. This protein has been shown to increase in the oral mucosa, intestine, esophagus, and muscles. However, its true function in the epithelium is unknown [33, 34].
\nPNP studies with tumor resection demonstrate that tumors have the capacity to secrete autoantibodies capable of affecting the proteins of the epidermal region [35]. While knowing that most PNPs are involved in neoplastic and LPD diseases, triggering by solid tumors is still poorly understood and demonstrates other mechanisms involved in the production of autoantibodies to plakin proteins.
\nThe involvement of the humoral immunity of PNP presents the desmoplakins 1 and 2, envoplakin, periplakin, BP230, A2ML1, and DSG-1 and DSG-3 as the main proteins of concern [1]. However, 16% of all affected do not demonstrate the presence of these autoantibodies, and this makes, in some cases, the accomplishment of the early diagnosis difficult. A study conducted in patients with PNP and who developed muscle weakness demonstrated autoantibodies against neuromuscular junction proteins and muscle tissue. These muscle-associated proteins were autoantibodies to anti-acetylcholinesterase receptors and anti-titin and anti-ryanodine receptor [36].
\nCellular immunity has evidenced important roles in the immunophenotyping of PNP. Pathological analyses have demonstrated inflammatory infiltrates with the presence of CD8+ T cells, CD68+ monocytes, and non-major histocompatibility complex-restricted CD56+ in the subepidermal region [2, 37]. Besides that, in the places of affection, the increase in tumor necrosis factor, as well as interferon gamma, was evidenced [38]. These findings show the importance of cellular immunity in the pathogenesis of the disease, since they present abundantly in the sites of PNP involvement.
\nPNP presents several symptoms and clinical evolutions. The first symptoms as well as the progression of the disease are very varied from one patient to another. However, there are more frequent clinical features of these individuals.
\nThe oral mucosa is often affected in patients with PNP [3, 39, 40]. Oral symptoms may be the first symptoms in these patients, even before skin lesions [41]. The most common symptoms are oral and labial erosions with bleeding that may be associated with blisters, macules, papules, vesicles, and erythema (Figure 1). In addition, these patients may present a positive Nikolsky sign [41].
\nSevere erosive mucositis with hematic crusting on the lips and oral mucosa.
PNP lesions may be similar to oral manifestations of other diseases. Pemphigus vulgaris is a disease that initially triggers blisters and ulcers in the oral mucosa (especially on the cheeks) and may even reach the body. Erythema multiforme also affects the region of the oral mucosa with the appearance of erythema, edema, and some superficial erosions with formation of pseudomembrane. Lichen planus causes erythematous lesions where Wickham striae are present and may in rare cases develop erosions. In most cases of oral lichen planus, these are asymptomatic manifestations with few complications. Even though these diseases show some similarity to PNP, they are less aggressive, lethal, painful, and incapacitating, with less ability to spread to all mucosal and other body sites when compared to PNP [28, 42, 43].
\nLesions can also affect regions such as the oropharynx, esophagus, stomach, duodenum, large intestine, conjunctiva, and anogenital region [2, 3, 7, 39, 41, 44, 45]. The involvement of the oropharynx and esophagus commonly triggers painful sensations and dysphagia [4]. The anogenital lesions demonstrate red-violet erythema in the glans or its surroundings (Figure 2). In some cases, lichen planus presents a possible differential diagnosis. However, unlike red-violet lesions, lichen planus forms linear white streaks that may arise in the glans, scrotum, and vulva, in addition to the presence of dyspareunia and pruritus [43]. In these patients, both necrosis and loss of epidermis are absent, unlike patients with PNP who present this clinical [43].
\nRed-violet lesion in the genital organ.
About 70% of the patients present conjunctival lesions such as bilateral bulbar conjunctival hyperemia, diffuse papillary tarsal conjunctival reactions, conjunctival epithelium desquamation, forniceal shortening, painful ocular irritation, poor vision, conjunctival and corneal erosions, and pseudomembranous conjunctivitis [2, 46, 47].
\nSkin lesions usually appear soon after the onset of mucosal involvement [48]. The most affected sites are the dorsal region (Figure 3), head, and neck (Figure 4), in addition to the nearby extremities [4, 39, 49]. Patients with PNP started the study in very different ways, with the first signs being erythema, bullous and vesicular lesions, papules, skin scaling with Nikolsky sign, exfoliative erythema, and ulcers with hematic crust. Often, the first clinical sign on the skin is erythema that may progress with bullous and ulcerated lesions [24, 50]. Unlike adults, PNP in the skin of children appears in the form of lichenoid lesions, rather than bullous lesions.
\nExtensive erosions and blisters in the dorsal region.
Confluent erosions with hematic crusts in the head and neck region.
Similar to PNP, bullous pemphigoid (BP) provides blistering with erythematous base or normal skin. However, BP lesions occur more frequently in the lower abdomen and lower limbs, and in most individuals, mucosal lesions are not affected [51]. In addition, pruritus is present in the vast majority of these patients, unlike PNP, which show painful and disseminated lesions mainly in the upper body and mucosal regions [28, 51].
\nAlready erythema multiforme shows prodromal symptoms such as fever and myalgia before the appearance of lesions on the mucosal and skin. Their skin lesions change in feature according to the course of the disease and resemble insect bites or hives that result in the well-known targetoid lesions that are common in this disease. Although cases of necrosis and blisters occur in the center of the lesions, this disease shows less aggression and fewer blisters and ulcers with hematic crusts than the patients affected by PNP [42].
\nLichen planus affects flexor surfaces of the wrists, forearm, and legs. These lesions have round reticular white lines such as Wickham striae. They may arise in places that suffer trauma (Koebner’s phenomenon), in addition to making the site pigmented after inflation, thus demonstrating clinical differences in cutaneous erosions seen in the course of PNP progression [43].
\nThe graft versus host disease causes rash and maculopapular rash that present itching and can spread to the entire body, less in the scalp. In very severe cases, there may be some sites with necrosis at the base of epidermal rete pegs [52]. Generally, these severe cases are differentiated from the PNP both by the patient’s clinical history and by skin biopsy that demonstrate distinct histopathological characteristics.
\nApproximately 92.8% of the cases described in the literature show pulmonary involvement [3]. The pulmonary clinical signs of PNP are dyspnea, obstructive pulmonary disease, and bronchiolitis obliterans. The resolution of pulmonary problems is of extreme importance, since it is the main cause of death in individuals with PNP [53]. The patients with the greatest pulmonary involvement are Chinese children and patients with Castleman disease [53]. Studies show that 71% of the patients had bronchiolitis obliterans organizing pneumonia, and they give worse prognosis even if treatment of the neoplasia occurs [12, 54].
\nThe pathological analyses demonstrate many varied aspects, since they show them peculiar characteristics according to the evaluated lesions [55]. When analyzing the biopsy of blisters, we found acantholysis with inflammatory infiltrates (Figure 5) [55]. However, when it presents inflammatory maculopapular lesions, the most common findings are lichenoid interface dermatitis [55]. In the presence of lesions with the presence of blisters and maculopapular lesions, mixed characteristics of each type of lesion may occur in the pathology. The findings with dyskeratosis and suprabasal acantholysis are one of the most important characteristics that lead to the definitive diagnosis of PNP [6]. Dyskeratosis is an abnormal formation of epidermal keratinization, whereas acantholysis is the loss of adhesion between skin cells [28]. These findings may help in the diagnosis even when there is no possibility of performing direct immunofluorescence (DIF) or when they are negative [39, 55]. DIF is a laboratory technique capable of detecting the deposition of autoantibodies and immune cells in the sites affected by the disease. The use of DIF demonstrates an extremely important technique for the diagnosis of PNP, since it can analyze both specific autoantibodies and cytotoxic cells of the human immune system, such as CD8+ T cells that act by attacking several layers with keratin and demonstrating intracellular staining of cementum and/or marking of epidermal dermal junctions in band [28, 55].
\nHistopathological examination of the biopsy specimen showing keratinocyte apoptosis and acantholysis (hematoxylin and eosin, original magnification × 100).
The use of DIF demonstrates great importance in the diagnosis of PNP even though approximately 50% of the cases show negative [3]. This technique shows a staining in IgG deposition intracellular chicken wire pattern (linear formation of autoantibodies deposition) along the dermoepidermal junction in both the linear form, as granulate [15]. The presence of IgG deposition in the dermoepidermal region is very characteristic of the PNP; however, only 25% presents this pattern [56].
\nThe use of indirect immunofluorescence (IIF) shows involvement of the epidermis by the deposition of IgG in the intercellular regions. Other techniques used as cytoplasmic fluorescence (intracellular staining) demonstrate a prominent basal staining. IIF marking is extremely strong in the layers of the epithelium, and this, alerting to PNP investigation, since it shows high specificity [56].
\nOther serological methods may also be used, such as immunoprecipitation, immunoblot and anti-EP enzyme-linked immunosorbent assay (ELISA) [57, 58, 59]. Studies evidenced 95 and 100% sensitivity in radioactive and nonradioactive immunoprecipitation techniques, respectively, and this demonstrates that immunoprecipitation is the most serologically sensitive test for PNP diagnosis [57, 60, 61]. Currently the immunoprecipitation is considered gold standard in the diagnosis of PNP, that is, the main criterion to diagnose [62, 63].
\nThe criteria for diagnosis according to Anhalt et al. in 1990 are based on five criteria, such as clinical characteristics, histopathological analysis, direct and indirect immunofluorescence, and immunoprecipitation [1]. These criteria have been modified and adapted. In 1993, researchers included to perform the diagnosis the presence of three main criteria or two major and two minor [63]. Already in 2002, Mimouni et al. reviewed the Anhalt criteria and considered four minimum criteria of high confidence in diagnosis (Table 2) [12]. DIF is a nonessential criterion because of its low sensitivity. As for IIF on rat bladder epithelia and monkey esophagus, they were considered useful for tracking and detecting PNP [57, 64]. Negative IIF cannot exclude PNP, and other techniques such as immunoblotting and immunoprecipitation should be used to confirm or rule out a diagnosis.
\n1. Clinical features of severe and protracted mucosal involvement and polymorphic cutaneous eruptions | \n
2. Histologic features of acantholysis or lichenoid or interface dermatitis | \n
3. Demonstration of antiplakin autoantibodies | \n
4. The presence of an underlying neoplasm, especially lymphoproliferative tumors | \n
Minimum criteria for diagnosis.
The diagnosis of PNP can be complex and difficult to perform because there are several similar diseases (Table 3). PNP and pemphigus vulgaris (PV) are very similar clinically, but some details differentiate them. PNP develops with inflammatory papules or macules that progress to blisters, while PV presents bullous lesions with a reddish background. Molecularly, the PNP presents some antibodies specific for this disease, such as the presence of anti-A2ML1, anti-envoplakin, and anti-periplakin, and demonstrates patterns of IgG deposition on cell surfaces with accumulation in the basement membrane zone [57, 64, 65, 66]. Even though bullous autoimmune diseases resemble each other, PNP differentiates it by the presence of antibody that stains the mouse bladder. In bullous pemphigoid (PB), BP230 and BP180 can be found, as well as in PNP. However, the use of DIF differentiates them by the IgG deposition patterns found in the PNP. The involvement by morbilliform-like erythema, toxic epidermal necrolysis, and Stevens-Johnson syndrome can also be confused with PNP. However, the detection of antibodies, pathological analysis of the lesions, and the patient’s clinic can differentiate these diseases [1, 10, 39, 57, 64, 65, 66].
\nDisease | \nCausers | \nPathophysiology | \n
---|---|---|
Pemphigus vulgaris | \nAutoimmune reaction | \nAutoantigens anti-desmoglein 1,3 | \n
Bullous pemphigoid | \nAutoimmune reaction | \nAutoantigens anti-BP180 and anti-BP230 | \n
Lichen planus | \nAutoimmune reaction | \nAutoantigens anti-keratinocyte and antinuclear | \n
Erythema multiforme | \nhypersensitivity by infection, viruses and drugs | \nInfiltration of cytotoxic T cell and increased tumor necrosis factor-α | \n
Toxic epidermal necrolysis | \nDrug reaction that affects more than 30% of the body | \nInfiltration of cytotoxic T cell, natural killer, and increased granulysin | \n
Stevens-Johnson syndrome | \nDrug reaction that affects less than 10% of the body | \nInfiltration of cytotoxic T cell, natural killer, and increased granulysin | \n
Drug eruption | \nDrug reaction | \nPerivascular infiltration by lymphocytes, eosinophils, and increased histamine and leukotrienes | \n
Differential diagnosis.
Despite some cases that both clinically and histologically resemble each other, it is important to perform other techniques to rule out differential diagnoses. The use of otorhinolaryngological examination is very important to differentiate the diseases that affect the mucous membranes. Well-done physical examination of the oral cavity, histopathological analysis characteristics, cutaneous involvement, and the presence of IIF strongly suggest for the diagnosis of PNP [40, 44, 67].
\nEffective treatment for PNP is still a major puzzle because of its rarity. Although several drugs are used in the literature, PNP has shown great resistance when compared to other forms of pemphigus [50, 68]. When there is suspicion or evidence of PNP, the performance of the six steps described on 2011 by Frew et al. may provide better management of individuals (Table 4) [69]. Stabilization of patients, according to the first step, is the most important step, since it is the major cause of death in patients [69].
\n1. Stabilization of vital parameters | \n
2. Assessment of any underlying malignancy | \n
3. Diagnosis of PNP | \n
4. Removal and therapy for the triggering tumor | \n
5. Treatment of PNP | \n
Management of the patient with suspected PNP.
Currently, the first-line treatment for PNP is still high doses of corticosteroids [70]. This treatment improves the cutaneous lesions, but the mucosal involvement is little altered. The use of other drugs also shows little efficacy in the lesions of the mucosa, this resistance being the characteristic of the disease [69, 71].
\nSeveral studies have shown that the combination of drugs has been effective and safe. These associations were prednisolone used with other therapies, such as mycophenolate mofetil, cyclosporine A, azathioprine, plasmapheresis, and intravenous immunoglobulin [72, 73, 74, 75, 76, 77]. Even though treatment is more effective, mucosal involvement is still resistant to such combined therapies [71].
\nThe use of monoclonal antibody has been effective in the treatment of PNP in some case reports described in the literature. Administration of rituximab, an anti-CD20, has shown good PNP therapy due to B-cell lymphoma [78, 79]. This therapy is based on an infusion of 375 mg/m2 weekly for 4 weeks followed by eight weekly infusions for 4 weeks of corticosteroid and administration of other immunosuppressive drugs such as cyclosporine A [69].
\nThe use of alemtuzumab, a humanized monoclonal antibody that binds to CD52, has been reported. Reported in the treatment of PNP remission in patients whose presence of chronic lymphoid leukemia [80]. Alemtuzumab has been used in a patient with resistance to other drugs such as corticosteroids, intravenous immunoglobulin, and cyclosporine A. In this patient, intravenous 30 mg was infused three times a week for 3 months. Even though there was improvement in both skin and mucosal lesions, the patient continued maintenance treatment with 500 mg of mycophenolate mofetil and 5 mg of prednisone [80]. Although there are several treatment alternatives, new therapies that reduce the resistance of PNP to drugs are still fundamental. Daclizumab, a monoclonal antibody against T-cell interleukin-2, has been shown to be a promising therapy [81].
\nIt is known that in order to avoid large amounts of autoantibodies released into the bloodstream during tumor excision surgery, it is necessary to block blood flow and prevent compression of neoplastic tissue. In addition, the use of intravenous immunoglobulin before and during operations has demonstrated a significant reduction in mortality caused by bronchiolitis obliterans. Even after complete tumor resolution, immunoglobulin administration is required until 2 years to provide remission of autoimmunity triggered by PNP [82, 83].
\nIn addition to the treatment of neoplasia and PNP, other ducts must be performed. When there is loss of skin integrity or immunosuppression, antimicrobial therapy is recommended early to prevent sepsis. Medications for pain control are also useful, since patients have pain in regions with ulceration and erosions [50].
\nAlthough there are several treatments stipulated in the literature, there are still no known drugs that reduce the mortality of patients, since the PNP proves highly resistant to more aggressive therapies. However, it is known that management, diagnosis, and early treatment are indispensable methods for a better response of the patients in the prescribed procedures.
\nThe prognosis of PNP is extremely poor. Mortality can reach 90% of the cases in the first year, 41% of mortality in the second year, and 38% of death in the third year with the disease [84]. Commonly, death is triggered by systemic complications such as bronchiolitis obliterans, sepsis, and bleeding in the gastrointestinal tract [6, 50]. It is known that regardless of the cure or control of the neoplasia, the PNP progresses, demonstrating itself autonomous to the triggering factor [6, 10, 11, 13, 50]. Patients who exhibit morbilliform erythema and necrosis of skin biopsy keratinocytes demonstrate a worse overall survival [84]. In some cases, the removal of Castleman disease and benign thymoma has shown better results than other underlying diseases [84, 85].
\nEven with a high mortality rate, the prognosis depends very much on the proper management of the patient, such as monitoring of vital signs, control of oral and skin lesions, treatment of the triggering disease, and prevention of sepsis and bronchitis obliterans. For this, it is essential to follow the patient closely and treat the disease aggressively [50].
\nStudies have mentioned severe losses in the quality of life of patients with pemphigus. The main criteria that impair the quality of life were the greater severity of the disease, anxiety, and depression. However, there was no clear measurement of gender, age, type of pemphigus, duration of disease, skin involvement, disease activity, itching, burning sensation in the skin, or treatment in use [86]. There is still a great need in the standardization and validation of PNP-specific questionnaires, as this proves to be extremely important in order to know and enable actions at key points by multidisciplinary teams.
\nPNP demonstrates a great challenge for physicians, since it presents several clinical aspects and varied degrees of bodily involvement. Early diagnosis, management of the patient, treatment of the underlying neoplasia, and aggressive treatment for PNP are of paramount importance for the best prognosis of the patient, since it is an extremely lethal disease. For this, more studies are needed to better understand the disease and cooperation between multidisciplinary teams involving dermatologists, oncologists, hematologists, otorhinolaryngologists, surgeons, ophthalmologists, immunologists, psychologists, nurses, and social workers.
\nThe author would like to acknowledge the help of Dr. Paulo Prata and the School of Health Sciences Barretos, São Paulo, Brazil.
\nThe author has declared no conflicts of interest.
\n\n alpha-2 macroglobulin-like 1 bullous pemphigoid direct immunofluorescence desmoglein indirect immunofluorescence lymphoproliferative disorders paraneoplastic pemphigus
The circulating cellular elements of blood consist of erythrocytes (red blood cells; RBC), leukocytes (white blood cells; WBC) and platelets. The hemorheology of these blood cells is unique in that these cells exist in a fluid phase subjected to variable, and often extreme, rheological shear stress, viscosity changes and biomechanical obstacles (e.g., capillaries and splenic filtration). Hemodynamically, shear stress is induced by the highly variable flow rate of blood within the ~100,000 kilometers of the human vasculature bed which encompasses both large arteries and veins to the capillary beds (Figure 1A) [1]. With an average resting cardiac output of approximately 5 L/min, blood flow in the largest artery (i.e., aorta) is approximately 50 cm/s while flow rates drop to only about 0.03 cm/s in the smallest capillaries and return to about 15–40 cm/s in the largest veins (e.g., superior and inferior vena cava) [1, 2]. In high flow conditions, RBC reside in the fast flowing central axial column of the vessel while WBC (and platelets) are located more peripherally and prone to mechanical interaction with the endothelial cells lining the blood vessels. WBC also have adhesion molecules on their membrane and, if appropriate signals (e.g., inflammation) are present, they actively roll on the endothelial cells prior to attachment and extravasation (Figure 1A,B). Moreover, the viscosity of blood is also variable and is a function of, primarily, red blood cell (RBC) number and flow rate. At high RBC counts and high flow rates, blood is highly viscous while at low RBC counts and low flow rates (capillaries), blood viscosity is greatly reduced. Moreover, as shown in Figure 1C, the rheological stress is further exacerbated by the biomechanical stresses induced by the extreme disparity in the size of RBC (~8 μm) and WBC (10–25 μm) to the minimum diameter of the vascular capillary beds (4–5 μm) and splenic interendothelial clefts (0.5–1.0 μm) [3, 4]. Hence, consequent to both the shear forces, viscosity and biomechanical stresses placed on blood cells, a key biologic/physiologic requirement of both RBC and WBC within the vascular space is rheological deformability. Biomechanically, the intracellular viscosity and membrane rigidity of the RBC and WBC are the key factors in imparting their vascular rheological deformability.
\nThe physiology and morphology of the vascular bed and blood cells imparts unique rheological stress on circulating blood cells. Panel A: the vascular bed is composed of blood vessels of various sizes which create significant disparity in blood (fluid and cellular) velocity consequent to vessel diameter. The fluid flow induces rheological sheer stress while the vessel size can create biomechanical deformation of cellular elements. Panel B: shown are the general physical parameters of human RBC and WBC. Note that the biconcave RBC is a anuclear while within the WBC, the nucleus:cytoplasm (N:C) ratio of monocytes and lymphocytes are quite divergent. RBC cytoplasmic viscosity is primarily defined by hemoglobin while in WBC, in addition to the nucleus, the presence of granules and vacuoles also impact intracellular viscosity and the aggregate cellular deformability. Panel C: blood cell deformability is crucial during vascular flow due to the size disparity between red blood cells and various leukocytes (e.g., monocytes and lymphocytes) and the capillary (4–58 μm) and splenic interendothelial clefts (0.5 μm). Panels B,C are drawn approximately to scale.
For the anuclear RBC, intracellular viscosity is primarily determined by hemoglobin content (both absolute content and hemoglobin structure (Figure 1B)). RBC membrane deformability/flexibility is primarily imparted by the cytoskeletal structure of the cells and, to a lesser extent, the composition of the bilayer itself (lipid species, protein content, integral versus peripheral membrane proteins, and carbohydrates). For normal RBC the intra- and inter-individual variability of both intracellular viscosity is relatively invariant; however, genetic mutations affecting hemoglobin structure (e.g., HbS, α and β thalassemia, HbE mutations) will dramatically affect both hemoglobin content and the viscosity of the hemoglobin itself. Similarly, the cytoskeletal structure of normal red blood cells is both well characterized and consistent within humans. But, as with hemoglobin variants, mutations in any component of the cytoskeleton can dramatically affect the discoid shape of the RBC and result in size changes and/or altered rigidity or stability of the cytoskeleton and cell itself. Indeed, numerous studies have documented that changes in either the hemoglobin content or structure (the major determinant of viscosity) or mutations to cytoskeletal components (the major determinant of membrane rigidity) can exert significant effects on RBC deformability, biologic function and in vivo circulation. In evidence of this, both biological conditions and pharmacologic agents that affect hemoglobin content and/or viscosity or the RBC cytoskeleton alter cellular deformability and have profound in vivo and in vitro effects on RBC function and survival [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. Indeed, RBC deformability can be a diagnostic indicator of RBC abnormalities and the quality of stored RBC prior to transfusion [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28].
\nIntracellular viscosity and membrane structure are similarly key to the rheological deformability of WBC. However, in contrast to RBC, WBC intracellular viscosity is more complex and affected by multiple components including the: nuclear to cytoplasm (N:C) ratio; intracellular granule composition; presence of cytoplasmic vacuoles; as well as the activation state of the immune cell (Figure 1B) [28, 29, 30]. Similarly, membrane rigidity is also more complex due to: abundance of membrane proteins and protein rafts; changes in protein structure and polymerization consequent to immune activation; and the variability of the membrane and cytoskeletal protein composition of immune cell populations (e.g., monocytes, lymphocytes, granulocytes) and subsets (e.g., T cells versus B cells; CD4+ versus CD8+ T cells; NK cells) [30, 31, 32, 33, 34, 35]. Perhaps surprisingly, despite the biologic importance of its rheological deformability within the vasculature, WBC deformability is both poorly defined and much less understood. Indeed, previous studies on WBC have most commonly defined “deformability” as cellular shape change or spreading under extrinsic suction (e.g., micropipette aspiration), compression pressure (e.g., centrifugation and cell poker/probe), or upon activation induced motility [30, 31, 32, 34, 35, 36]. However, vascular deformability is vastly different from cellular shape change or spreading which are most commonly induced by immune cell activation and, importantly, the actual loss of vascular rheologically-mediated (i.e., fluid motion and spatial confinement) deformability. The paucity of data relating to vascular deformability of WBC has, in large part, been due to the absence of suitable tools for measuring deformability across the broad range of cell types encompassed within leukocyte population. However, the complexity of the leukocyte population and resultant changes in rheological deformability upon activation (e.g., granule release) potentially arising in peripheral blood WBC may be of clinical importance as a biomarker of acute or chronic immune activation.
\nBecause of the crucial role that cellular deformability plays in vascular circulation of RBC, methods to quantitate this biomechanical-aspect of normal and abnormal RBC has been of interest to hematologists since the 1960s [3, 5, 6, 7, 9, 10, 37, 38, 39, 40]. Historically, multiple technological tools have been employed to study RBC (but rarely WBC) deformability including: micropipette aspiration; ektacytometry; cell transit times; and, most recently, microfluidic analysis.
\nPerhaps the earliest experimental approach to measure RBC deformability was the micropipette aspiration (Figure 2). Initial studies examined the ability of normal and stored RBC to traverse the length of a micropipette of known diameter [38]. This early “microfluidic” single cell analytical approach, while very low throughput and time consuming, did demonstrate that damaged or stored RBC were less deformable than fresh normal RBC. Subsequent variations of these micropipette studies further examined the localized elasticity of the membrane in both intact cells and RBC ghosts using ever smaller micropipettes to deform a small segment of the membrane to characterize static deformability via membrane extensional rigidity and bending rigidity. To further characterize dynamic deformability of the cells, the time constants for rapid elastic recovery from extensional and bending deformations were also quantitated [41, 42, 43, 44, 45, 46, 47]. However, micropipette, single-cell aspiration, measurements did not adequately reflect the biomechanical heterogeneity of even a relatively homogenous cell population (e.g., normal RBC), much less, the highly divergent population of cells encompassed within the WBC population. Hence newer methods were devised in an attempt to study large number of RBC under flow-like conditions. In contrast to RBC, micropipette studies are still commonly used to examine leukocytes; though these approaches tend not to be focused on rheological deformability [22, 35, 48, 49, 50, 51, 52, 53].
\nOverview of micropipette aspiration analysis of blood cells. Micropipette-based analyses were first used to explore the crucial role of cellular deformability in the circulation of red blood cells. As noted, these single cell analyses were low throughput and time consuming. Multiple variation of this technique have been developed ranging from whole cell aspiration to localized membrane deformation. Studies could be done on intact cells or membrane ghosts.
Perhaps the most glaring flaw of the various micropipette aspiration approaches were their limitation to single cell analyses. To overcome this limitation, ektacytometry was developed. Ektacytometry measures deformability by suspending RBC in a viscous solution and applying rotational shear stress such that the normal discoid cells form ellipsoids which is measured by laser diffraction (Figure 3) [13, 14, 54, 55, 56, 57]. The extent of ellipsoid formation is dependent on the deformability of the sample population. Abnormal RBC can be detected by shifts relative to the scatter intensity pattern of normal cells. Abnormal (i.e., non-deformable) cells can result in any combinations of left or right shifts in response to hypo- or hypertonicity, and/or a decrease in the maximum deformation observed under isotonic conditions. Relative to micropipette studies, ektacytometry provided a relative rapid assay to examine RBC. Numerous ektacytometry studies have elucidated the profound influence that mean corpuscular hemoglobin concentration (hence intracellular viscosity), abnormal hemoglobins, cytoskeletal aberrations, drugs and oxidant challenge exert on the cellular deformability [13, 14, 18, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64]. Importantly, ektacytometry only measures the “average deformability” of a cell population and cannot accurately and efficiently quantify the abundance of rigid cells in a bimodal population where both normal and abnormal cells are present [57, 65]. In the context of blood banking, ektacytometry has been used for assessing RBC following blood bank storage [66, 67, 68]. Of note, ektacytometry has been used exclusively in the context of erythrocytes; with no known studies examining the shear-induced deformability of lymphocytes, neutrophils, monocytes or other leukocytes. Thus, despite some promising data regarding its clinical use in transfusion medicine, ektacytometry has not become commonly used in transfusion medicine due to both the cost of instrumentation and the relatively low throughput of the existing testing protocols. Moreover, ektacytometry does have some significant drawbacks as it cannot, without experimental manipulations (e.g., density separation), provide any information on subsets of cells within the larger population—the results obtained are simply the “average” of the population. This limitation is, perhaps, the critical failure of ektacytometry because, in many pathologic states, abnormal RBC represent a minor (<10%) fraction of the overall RBC mass hence subtle changes will not be clearly obvious. Moreover, it is difficult to recover RBC subsequent to ektacytometric analysis for further biologic testing due to the viscous media utilized and, using traditional ektacytometry, the fact that the RBC are irreversibly (in most cases) altered by the osmotic gradient employed during the assay.
\nOverview of ektacytometric analysis of blood cells. To overcome the single cell limitations inherent to micropipette aspiration, the ektacytometer can analyze the shear-induced deformability of a much larger population of RBC; though at the expense of information of single cell data acquisition. Ektacytometry measures deformability by subjecting RBC suspended in a viscous solution to rotational shear stress such that the normal cells form ellipsoids. The scatter intensity pattern from laser diffraction produces isointensity curves and deformability indices. Additionally, the most common approach of ektacytometry examines RBC deformability over a broad osmotic gradient (hypotonic → isotonic → hypertonic). Deformability is measured via laser diffraction as the shear stress forces the RBC to assume an elongated shape.
In contrast to micropipette analysis and ektacytometry, cell transit analysis provides information at both the single cell and populational level (Figure 4). To accomplish this, cell transit analysis combines features of both the traditional micropore filtration assay and the micropipette aspiration methodology, in that deformability of each RBC constitutes a single data point and can be used to then generate a populational distribution curve. In a cell transit analyzer, a single RBC passes through a micropore of fixed diameter and length with the transit time (in milliseconds; ms) of the cell calculated using the electrical resistance generated by the RBC within the channel as detected via a conductometer. However, the sensitivity of this method varies with cell size. Smaller cells, even if less deformable, pass through the pores with less resistance. In contrast, abnormally large or rigid cells, which are clinically important, are also be problematic as they block the micropore and are excluded from analysis [17, 69, 70]. Despite these limitations, cell transit analysis is very useful in that it provides subset/heterogeneity analysis via binning of the cells based on the transit time thus providing a continuous measure of the deformability profile of a sample and/or the severity of the deformability defect. The comparative utility of ektacytometry and cell transit analysis of RBC can be seen in normal and model ß thalassemic RBC in which purified alpha-hemoglobin chains are entrapped within normal RBC (Figure 5) [17, 19, 61, 62, 63]. While the ektacytometry and cell transit analysis have proven very useful as research tools, they have not been used to any great extent clinically. This is in large part due to the expense and complexity of the devices as well as their slow throughput making them impractical for clinical laboratories. Moreover, these in vitro studies often lack biological validation to the very low throughput of the assay (e.g., micropipette aspiration studies), overly small cell numbers, difficulty/impossibility of cell recovery post assessment, or more importantly, an inability to either identify or collect specific sample subsets (e.g., low versus high deformability) following analysis (e.g., Ektacytometry and Cell Transit Analysis studies).
\nOverview of cell transit analysis of blood cells. In contrast to micropipette analysis and ektacytometry, cell transit analysis provides information at both the single cell and populational level. Cellular deformability is indirectly measured via transit time (ms) of RBC through pores of defined diameter and length. Transit time is measured by the change in electrical resistance as an RBC passes through a micropore. Cell transit analysis is, in essence, an early micro (macro) fluidics approach.
Comparative data of normal versus model ß thalassemic RBC as assessed by ektacytometry and cell transit analysis. Panel A: as shown, ektacytometry provides the mean diffraction profile of a population of cells over a broad osmotic gradient; however, it does not provide any information as to the deformability distribution of the cells within the total population. Panel B: cell transit analysis gives information regarding both the deformability profile of the entire population and the individual cells within the tested population. Data derived from Refs. [17, 63].
As noted in the preceding discussion, multiple micro/macro fluidic approaches have been used to model hemorheology of circulating blood cells; albeit almost exclusively RBC. Despite their valuable contributions to our understanding of blood cell deformability, these methods are inherently low throughput and dependent on relatively expensive instrumentation. But perhaps one of the biggest issues challenging these previous methodologies is the inability to recover substantial, or any, subpopulations (e.g., highly versus poorly deformable cells) from the analyzed sample. This weakness precludes additional in vitro or in vivo studies to tease out biological variations leading to the differential deformability profiles. Microfluidics approaches (Figure 6) potentially offers a cost-effective, high throughput, alternative to assessing blood cell deformability relative to these previous, and now rather ancient (as reflected by the key research papers relating to these approaches) technologies [22, 23, 24, 25, 27, 28, 71, 72, 73, 74, 75, 76, 77, 78]. Deformability measurement using microfluidics uses minute amounts of a whole blood or purified RBC/WBC in suspension flowing through a funnel-shaped micro-constriction(s) in a disposable plate. As demonstrated in our previous publications, and discussed in the following section, microfluidics devices are capable of providing reproducible intra- and inter-individual data, detecting oxidatively damaged RBC, identifying changes in RBC deformability consequent to storage, and identifying leukocytes [20, 21, 22, 23, 24, 25, 26, 27, 28].
\nOverview of microfluidic analysis of blood cells. Recent advances in microscale fabrication technologies have allowed for the development of an exceedingly broad array of microfluidic devices that may have utility in assessing the deformability of blood cells. These approaches range from single to multi-channel devices with channels of single or variable lengths and diameters. In addition, some designs incorporate collection ports so that cell exhibiting differential deformability profiles can be collected for further in vitro or in vivo study. Device shown is adapted from Guo et al. and Kang et al. [26, 28].
As evidenced by the number of publications and patents being generated annually, the promise of microfluidic devices in medicine is seemingly unbounded. One area of particular interest to our laboratories has been in the field of transfusion medicine [20, 21, 22, 23, 24, 25, 26, 27, 28]. Annually over 100,000,000 units of blood are collected worldwide for transfusion purposes. Despite the volume collected, our tools for assessing the quality of the stored blood products remains primarily centered on 1950–80s technology. Upon collection of whole blood in Canada the blood is processed to produce 3 major components: RBC, platelets and plasma. The RBC component for use in blood transfusion therapy are stored at 4°C for up to 42 days. The maximum storage window for RBC is based on studies dating from the 1950s on that defined a ≥ 75% recovery rate at 24 hours post-transfusion as the clinical “quality control” standard for stored donor RBC [79, 80]. Despite decades of research into RBC biology and advances in other aspects of transfusion medicine, the 24 hour survival rule remains the current gold standard for determining acceptable donor RBC quality in transfusion medicine. Currently there are no other established biomarkers by which blood services can discriminate “good” versus “bad” units. Note however, that ultimately the survival of the donor RBC is consequent to their vascular deformability (which is in turn governed by a multitude of biologic/metabolic factors). Hence, cost effectively assessing the deformability of stored RBC could serve as an excellent biomarker for the quality of stored donor RBC. Intriguingly, RBC deformability may also be a potent pre-screening tool that could be used to exclude potential donors from RBC donations. RBC which demonstrate poor initial deformability upon collection do not store well and may lead to adverse events in patients who receive these units. Poor deformability of potential donor RBC may arise from a broad range of issues including: undiagnosed RBC abnormalities (e.g., cytoskeletal, hemoglobin or metabolic aberrations); vascular inflammation; or dietary or drug-mediated alterations of the RBC.
\nTo assess the deformability of blood cells, our laboratories have utilized a variety of microfluidic devices ranging from a simple, low throughput, funnel chain (prone to clogging) to a much more advanced and robust high throughput ratchet device. The ratchet microfluidic approach has proved better at assessing vascular deformability as blood cells are pushed laterally and vertically through tapered microchannels of decreasing size thus modeling the process of cellular deformation in microvasculature (Figure 7). Vertical movement is done via an oscillatory vertical pressure deferential that allows both a net vertical filtration flow and a downward declogging flow to minimize microchannel obstruction by blood cells as they reach their deformability limit. Importantly, this design also incorporates collection outlets allowing for recovery, and further testing, of cell populations with differential deformability profiles. Our research to date has demonstrated that this microfluidic microfiltration device is capable of isolating circulating tumor cells from leukocytes, malaria-infected and oxidized RBC from normal cells, granulocytes and lymphocytes from whole blood, and detecting early immune cell activation consequent to degranulation [26, 27, 28, 81].
\nGeneral schematic of a ratchet microfluidic device. Panel A: shown is a photograph of the ratchet microfluidic device infused with different color dyes to highlight the design features: cross flow inlet (a), sample inlet (b), upward (c) and downward (d) oscillatory flow inlets, sorting region (dashed blue box) and outlets 1–8. In this design, outlets 8–1 corresponds to blocking pore sizes of ≥6.5, 5.5, 4.5, 4.0, 3.5, 3.0, 2.5 and 2.0 μm, respectively. Panel B: schematic of the sorting region showing the decreasing size of the tapered microchannels as well as the deformability of normal and oxidized RBC through these microchannels. Poorly deformable cells (e.g., oxidized RBC) are collected in outlets 8 and 7 while highly deformable cells are collected in outlets 3 thru 1. The downward oscillatory pressure minimizes channel obstruction by poorly deformable cells which are pushed horizontally into the collection outlets by the cross flow pressure. This device is suitable for use for both human RBC and WBC.
Key to the use of microfluidic devices in RBC blood banking is documenting the ability of the device(s) to discriminate between “normal” and abnormal cellular deformability and document that the loss of deformability is associated with diminished in vivo circulation. Loss of cellular deformability can arise from a host of causes, most of which, due to the iron and oxygen rich environment of the RBC, leads to cellular oxidation [17, 18, 19, 23, 57, 61, 63, 82]. As shown in Figure 8, human or murine RBC oxidized by exposure to 50 μM phenazine methosulfate (PMS) were readily discriminated from normal RBC as measured by the cortical tension required to push the RBC through a funnel shaped micropore However, as noted by the differences between the human and murine RBC, the microchannel size (2–2.5 μm in this experiment) relative to the mean diameter of the RBC itself (~8 versus 6.7 μm for human and mouse RBC, respectively) will also play a role. Most importantly however, the loss of murine deformability in the oxidized RBC sample, as noted in the microfluidic device, correlated closely with the loss of in vivo survival. These findings suggest that microfluidic devices could prove useful for both diagnostic purposes (e.g., hemoglobinopathies such as sickle cell disease and thalassemia) as well as in evaluating the quality of stored human RBC prior to transfusion into a patient.
\nAnalysis of human and murine RBC deformability using a conical microfluidic array. The width of the funnel shaped micropore constriction used to measure RBC deformability was approximately 2–2.5 μm in size at its minimum. (a) and (b) equals peak count for oxidized and normal RBC respectively. Human blood was obtained via a finger prick while mouse blood was obtained by saphenous bleed. Also noted is the 50% in vivo survival point for oxidized (~5 days) and normal (~26 days) murine RBC. Data derived from Kwan et al. [23].
Indeed, microfluidics analysis of stored human RBC suggests that deformability is affected by storage time. As demonstrated by Matthews et al., using a microfluidic device, there is a significant loss of RBC deformability as early as 2 weeks into storage [25]. This finding confirms single-cell deformability studies that similarly indicated that RBC deformability remained fairly constant in the first 2–3 weeks of storage and then rapidly decreased [83, 84]. However, in contrast to these single cell studies, our high throughput device can rapidly assess the proportion of individual RBCs that are too rigid to transit the microconstrictions and may, upon transfusion into an individual, be cleared by the spleen. Indeed, by day 42 of storage, 30% of all donor RBCs were too rigid to transit the device. Interestingly, a small subset of donors had RBC that demonstrated poor storage in that >50% of their RBC were too rigid to passage the microconstriction. These research findings suggest that the RBC quality of individual donors are, not unexpectedly, variable. The source of inter-individual variability causing the poor storage could be either inherent to the donor RBC itself (e.g., metabolic, structural or hemoglobin abnormalities) or transient (e.g., inflammation, food or drug induced).
\nThe prescreening questionnaire completed by both new and repeat blood donors is focused, in part, on identifying factors that could adversely affect the quality of the blood product(s) produced from a donation. While most biologically-mediated RBC defects are likely to have been previously detected during normal medical surveillance of the prospective donor, transient inflammatory-mediated effects, such as those arising from viral, bacterial, drug or autoimmune events, are most likely to impact blood component quality. To address these potential risks, at the time of blood donation, all donors are asked if they feel ill or have had a recent fever. While the primary purpose of these self-reporting questions is to avoid transfusion of blood-borne infective agents or plasma that may contain potent immunomodulatory chemokines and cytokines, systemic inflammatory events may also result in bystander injury to the RBC that may compromise RBC storage and safety. The described microfluidics ratchet device may also provide a means of assessing both the WBC population and activation state of an individual [26, 28]. As shown in Figure 9, the ratchet microfluidic device described in Figure 7, is capable of differentially sorting monocytes from lymphocytes. The same device can also differentiate between resting (granule containing) from activated (degranulated) CD8+ T lymphocytes. Further refinement of the microchannel geometry will be capable of improving cell separation making it possible to readily prescreen individuals for evidence of immune activation thus improving blood component safety consequent to empirical donor evaluation versus self-reporting. Finally, microfluidic devices could also be used during the blood collection process, as well as in the field, to screen individuals who have reported recent travel to malarial endemic areas, for actual malaria infection [27, 85, 86, 87, 88]. Currently, individuals traveling to malarial endemic regions are deferred from blood donation; an action that often results in their permanent loss from the blood donor pool.
\nAnalysis of human monocyte and lymphocyte populations showing differential sorting on the ratchet microfluidic device. Note that the prototype device can also detect degranulation of lymphocytes (shown are CD8+ T cells) which occurs upon inflammatory activation. The vertical dashed line separates cells based on less deformable (collection outlets 8–6) and more deformable (collection outlets 5–3). Data derived from Kang et al. [28].
Microfluidics devices have the potential to dramatically, and cost-effectively, change the practice of transfusion medicine. As illustrated, purpose-specific development of ratchet microfluidics devices will make it possible, via a finger prick (e.g., as shown in Figure 8), to prescreen donors at the time of pre-donation testing (i.e., simultaneously with determining the donor’s hematocrit prior to unit donation) to select donors whose RBC show normal deformability profiles prior to storage. Donors with RBC deformability profiles outside of the normal range would be deferred from RBC donation, though potentially, still donating plasma for fractionation into plasma protein components. Moreover, the same microfluidic approach could improve the detection of patients with recent/current systemic immune activation that could result in the presence of undesirable cytokines/chemokines within the donated blood or that might have adversely affected normal RBC deformability. Hence, the cost-effective microfluidic-based prescreening process would potentially diminish the risk to patient safety that accompanies ineffectual RBC transfusion and/or the presence of inflammatory mediators in blood products. Not inconsequentially, prescreening for good donors would reduce the expense to the blood operator associated with the production and distribution of a potentially ineffectual, or unsafe, blood unit. Beyond prescreening donors, patient safety would also be enhanced by doing point-of-care deformability analysis of stored RBC prior to transfusion. Such analysis would enhance patient safety by reducing the aggregate transfusion needs of a patient by preventing the transfusion of RBC which would have poor in vivo survivability. Such an approach would be of particular value in the chronically transfused patient (e.g., sickle cell, thalassemic and myelodysplastic) populations.
\nThis work was supported by grants from the Canadian Institutes of Health Research (325,373, HM and MDS, 322375, HM; and 362,500, HM), Canadian Blood Services-CIHR Partnership program (BUC21403-HM; HM and MDS), Canadian Blood Services (MDS) and Health Canada (MDS). The views expressed herein do not necessarily represent the view of the federal government of Canada. We thank the Canada Foundation for Innovation and the Michael Smith Foundation for Health Research for infrastructure funding at the University of British Columbia Centre for Blood Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
\nThe University of British Columbia and HM have pending patent applications relating to the described microfluidic devices.
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\\n\\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
\n\nWhich scientific publication to choose?
\n\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\n\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\n\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
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