<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sjögren syndrome and can you explain it in depth? [/INST] Sjögren syndrome or Sjögrens syndrome (SjS, SS) is a long-term autoimmune disease that affects the bodys moisture-producing (lacrimal and salivary) glands, and often seriously affects other organ systems, such as the lungs, kidneys, and nervous system. Primary symptoms are dryness (dry mouth and dry eyes), pain and fatigue. Other symptoms can include dry skin, vaginal dryness, a chronic cough, numbness in the arms and legs, feeling tired, muscle and joint pains, and thyroid problems. Those affected are also at an increased risk (15%) of lymphoma.While the exact cause is unclear, it is believed to involve a combination of genetics and an environmental trigger such as exposure to a virus or bacterium. It can occur independently of other health problems (primary Sjögrens syndrome) or as a result of another connective tissue disorder (secondary Sjögrens syndrome). Sjögrens syndrome may be associated with other autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis. The inflammation that results progressively damages the glands. Diagnosis is by biopsy of moisture-producing glands and blood tests for specific antibodies. On biopsy there are typically lymphocytes within the glands.While Sjögrens syndrome is one of the most common auto-immune diseases, it has no specific and non-invasive diagnostic tests and treatment is directed at managing the persons symptoms. For dry eyes, artificial tears, medications to reduce inflammation, punctal plugs, or surgery to shut the tear ducts may be tried. For a dry mouth, chewing gum (preferably sugar-free), sipping water, or a saliva substitute may be used. In those with joint or muscle pain, ibuprofen may be used. Medications that can cause dryness, such as antihistamines, may also be stopped. The most specific extant diagnostic test requires lip biopsy.
The disease was described in 1933 by Henrik Sjögren, after whom it is named; however, a number of earlier descriptions of people with the symptoms exist. Between 0.2 and 1.2% of the population is affected, with half having the primary form and half the secondary form. Females are affected about 10 times as often as are males. Though the disease commonly begins in middle age, anyone can be affected. Among those without other autoimmune disorders, life expectancy is unchanged.

Signs and symptoms
The hallmark symptom of Sjögren syndrome is dry mouth and keratoconjunctivitis sicca (dry eyes). Vaginal dryness, dry skin, and dry nose may also occur. Other organs of the body may also be affected, including the kidneys, blood vessels, lungs, liver, pancreas, and brain.Skin dryness in some people with SS may be the result of lymphocytic infiltration into skin glands. The symptoms may develop insidiously, with the diagnosis often not considered for several years because sicca may be attributed to medications, a dry environment, or aging, or may be regarded as not of a severity warranting the level of investigation necessary to establish the presence of the underlying autoimmune disorder.Sjögrens syndrome can damage vital organs, with symptoms that may plateau or worsen, or go into remission, as with other autoimmune diseases. Some people may experience only the mild symptoms of dry eyes and mouth, while others have symptoms of severe disease. Many patients can treat problems symptomatically. Others experience blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, dysphonia (vocal disorders including hoarseness), and difficulty in swallowing and eating. Debilitating fatigue and joint pain can seriously impair quality of life. Some patients can develop kidney involvement (autoimmune tubulointerstitial nephritis) leading to proteinuria (excess protein in urine), urinary concentrating defect, and distal renal tubular acidosis.Hypokalemic paralysis due to primary Sjögren syndrome was rarely reported in the literature.

Complications
Among the complications discussed above, women with anti-Ro/SS-A and anti-La/SS-B antibodies who become pregnant have an increased rate of neonatal lupus erythematosus with congenital heart block requiring a pacemaker. Type I cryoglobulinemia is a known complication of Sjögrens syndrome.Sjögrens syndrome can affect such organs as the liver, pancreas, kidneys, lungs, and central nervous system.

Associated conditions
Sjögrens syndrome is associated with a number of other medical conditions, many of which are autoimmune or rheumatic disorders, such as celiac disease, fibromyalgia, SLE (lupus), autoimmune thyroiditis, multiple sclerosis and spondyloarthropathy, and several malignancies, principally non-Hodgkin lymphoma.

Causes
The cause of Sjögrens syndrome is unknown, but it may be the influence of a combination of genetic, environmental, and other factors, as is the case with many other autoimmune disorders. Around 20 autoantibodies could be involved.

Genetics
The observation of high rates of autoimmune disorders in families with a history of Sjögrens syndrome is linked with a genetic predisposition to the syndrome. Studies on the polymorphisms of human leukocyte antigen (HLA)-DR and HLA-DQ gene regions in Sjögrens patients show differential susceptibility to the syndrome as the result of different types of the resulting autoantibody production.

Hormones
Since Sjögrens syndrome is associated with a high prevalence in women, sex hormones, especially estrogen, are believed to affect humoral and cell-mediated immune responses affecting susceptibility to the syndrome. Androgens are generally considered to prevent autoimmunity. Studies on mice models suggest estrogen deficiency stimulates presentation of autoantigens, inducing Sjögrens-like symptoms.

Microchimerism
Microchimerism of fetal cells (offspring lymphoid cells in maternal circulation) may generate autoimmunity in women who have previously been pregnant. Generation of an autoimmune potential via microchimerism may lead to a switch from a silent form of autoimmunity with age-dependent decrease in self-tolerance.

Environment
Viral proteins, engulfed molecules, or degraded self-structures may initiate autoimmunity by molecular mimicry and increase the chances of Sjögrens syndrome development. Epstein–Barr virus, hepatitis C, and human T-cell leukemia virus-1 are among the most studied infectious agents in Sjögrens syndrome. To date, no direct causes and effect relationship has been identified between these pathogens and the development of Sjögrens syndrome.  Damaged self-structures targeted for apoptosis may be mistakenly exposed to the immune system, triggering autoimmunity in exocrine glands, which are often prone to autoimmune responses.

Pathogenesis
The pathogenetic mechanisms of Sjögrens syndrome have not been fully elucidated, resulting in the lack of pathophysiology knowledge of the management of this autoimmune exocrinopathy. Although the numerous factors contributing to the progression of this disease have made  discovering the exact origin and cause difficult, major advances over the past decade have contributed to a proposed set of pathogenic events that occur prior to the diagnosis of Sjögrens syndrome.Sjögrens syndrome was originally proposed as a specific, self-perpetuating, immune system-mediated loss of exocrine glands, specifically acinar and ductal cells. Although this explains the more obvious symptoms (such as the lack of saliva and lacrimal fluid), it does not explain the more widespread systemic effects seen in the progression of the disease.In the presence of a susceptible genetic background, both environmental and hormonal factors are thought capable of triggering the infiltration of lymphocytes, specifically CD4+ T cells, B cells, and plasma cells, causing glandular dysfunction in the salivary and lacrimal glands.Sjögrens syndrome is associated with increased levels in cerebrospinal fluid (CSF) of IL-1RA, an interleukin 1 antagonist. This suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatory upregulation of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. Interleukin 1 likely is the marker for fatigue, but increased IL-1RA is observed in the CSF and is associated with increased fatigue through cytokine-induced sickness behavior. However, Sjögrens syndrome is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness. Patients with secondary Sjögrens syndrome also often exhibit signs and symptoms of their primary rheumatic disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis.

Genetic predisposition
The genetic locus most significantly associated with primary SS is the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region, as demonstrated by the preliminary results of the first genome-wide association study. This study included data from a discovery cohort of 395 patients of European ancestry with primary Sjögrens syndrome, and 1,975 healthy control individuals, and from a replication study that comprised 1,234 cases and 4,779 healthy controls. Associations with polymorphisms located at six independent loci were also detected; IRF5, STAT4, BLK, IL12A, TNIP1, and CXCR5. This also suggested the activation of the innate immune system, notably through the IFN system, B-cell activation through CXCR5-directed recruitment to lymphoid follicles and B-cell receptor (BCR) activation involving BLK, and T-cell activation owing to HLA susceptibility and the IL-12-IFN-γ-axis.Patients of different ethnic origin carry different HLA-susceptibility alleles, of which HLA-DR and HLA-DQ are involved in the pathogenesis of Sjögrens syndrome. For example, patients from Northern and Western Europe and from North America show a high prevalence of B8, DRw52, and DR3 genes. HLA class II alleles are associated with the presence of specific subsets of autoantibodies, rather than with the disease itself. Autoantibodies refer to the loss of B-cell tolerance leading to production of antibodies directed against diverse organ-specific and organ nonspecific antigens. Association between HLA and SS is restricted to patients with anti-SSA/Ro or anti-SSB/La antibodies. Seropositivity for anti-Ro and anti-La is associated with greater severity and longer duration of disease, and findings of their high abundance from the salivary glands of Sjögrens patients suggests their imperative role in the pathogenesis of SS.Beyond genetics, epigenetic abnormality related to DNA methylation, histone acetylation, or microRNA expression probably has a key role in the pathogenesis of autoimmune diseases, including Sjögrens syndrome, though research in this area is very limited.

Environmental triggers
Environmental factors, such as glandular viral infection, could prompt epithelial cells to activate the HLA-independent innate immune system through toll-like receptors. Although a number of infectious, exogenous agents have been implicated in the pathogenesis of Sjögrens syndrome, such as Epstein-Barr virus (EBV), human T-lymphotropic virus 1, and hepatitis C virus, their association with Sjögrens syndrome appears weak. While EBV is present in the salivary glands of normal individuals, a high incidence of EBV reactivation in Sjögrens patients has been reported with increased levels of EBV DNA. This indicates viral reactivation and inability of lymphoid infiltrates to control EBV replication in Sjögrens syndrome, leading to the initiation or perpetuation of an immune response in target organs. Nonetheless,  exactly how reactivation of EBV is induced in lesions of patients with Sjögrens syndrome, and which specific molecular mechanisms are involved in the process of viral reactivation,  remain to be clarified.

Inflammation
Epithelial cells in Sjögrens syndrome lesions are active participants in the induction and perpetuation of the inflammatory process. Environmental and hormonal factors, in concert with an appropriate genetic background, are believed to trigger Sjögrens syndrome, which dysregulates epithelial cells and allows aberrant homing and activation of dendritic cells (DCs), T cells, and B cells. Dendritic cells are antigen-presenting cells  that process antigen material and present it to other T cells. Following the migration of lymphocytes into the glands in response to chemokines and specific adhesion molecules, T cells interact with epithelial cells. Epithelial cells are further activated by proinflammatory cytokines (IL-1β, IFN-γ, and TNF), which are produced by adjacent T cells. The early accumulation of plasmacytoid dendritic cells in the target tissues, which produce high levels of type 1 IFNs, seems important, as these cells can further dysregulate the immune response through abnormal retention of lymphocytes in the tissues and their subsequent activation. IFN-α stimulates the production of B-cell activating factor (BAFF) by epithelial cells, DCs, and T cells. BAFF stimulates aberrant B-cell maturation, leading to the emergence of self-reactive B cells, which locally produce autoantibodies, in a germinal centre-like structure (GC-like), which is also the location of lymphomagenesis (origin of lymphoma).

Programmed cell death
Dysregulation of apoptosis (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases, though its role in Sjögrens syndrome is controversial. Both the Fas and Fas ligand proteins are overexpressed in primary Sjögrens patients, while expression of BCL-1, which is known to downregulate apoptosis, was found significantly reduced in acinar and ductal epithelial cells of Sjögrens patients compared to healthy people. In situ studies did not show increased apoptosis among glandular epithelial cells, but did show reduced apoptosis among infiltrating mononuclear cells. Reduced apoptosis was also implicated in the accumulation of autoreactive B-cells found in the glands. The relationship of autoantibodies expressed in Sjögrens syndrome with apoptosis is still being researched.

Hormonal factors
Sex hormones seem to influence humoral and cell-mediated immune response, with estrogen being considered one of the biggest factors responsible for sex-immunologic dimorphism. Estrogen deficiency appears to play a role in development of Sjögrens syndrome. It has been hypothesized that androgen administration to the ocular surface may serve as an effective therapy for dry eyes.

Diagnosis
Diagnosing Sjögrens syndrome (SS) is complicated by the range of symptoms that a patient may manifest, and the similarity between symptoms of Sjögrens syndrome and those of other conditions. Also, patients with SS symptoms approach different specialities for treatment, which can make diagnosis difficult. Since dry eyes and dry mouth are very common symptoms, and frequently occur in people over 40, affected people may believe that the symptoms are age-related, so ignore them. Some medications can cause symptoms similar to those of Sjögrens syndrome. The combination of several tests, which can be done in a series, can eventually diagnose Sjögrens syndrome.Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such as antinuclear antibody (ANA) and rheumatoid factor (because Sjögrens syndrome frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns are SSA/Ro and SSB/La, of which anti-SSB/La is far more specific; anti-SSA/Ro is associated with numerous other autoimmune conditions, but is often present in SS, but aAnti-SSA and anti-SSB tests are frequently not positive in SS.The rose bengal test uses a stain that measures state and function of the lacrimal glands. This test involves placing the nontoxic dye rose bengal on the eyes. The dyes distinctive colour helps in determining the state and functioning of tear film and the rate of tear evaporation. Any distinctive colour change can indicate SS, but confirming the condition requires many related diagnostic tools.Schirmers test measures the production of tears: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. Producing less than 5 mm (0.20 in) of liquid is usually indicative of SS. This measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken. A slit-lamp examination can reveal dryness on the surface of the eye.Symptoms of dry mouth and dryness in the oral cavity are caused by the reduced production of saliva from the salivary glands (parotid gland, submandibular gland, and sublingual gland). To check the status of salivary glands and the production of saliva, a salivary flow-rate test is performed, in which the person is asked to spit as much as they can into a cup, and the resulting saliva sample is collected and weighed. This tests results can determine whether the salivary glands are functioning adequately. Not enough saliva produced could mean the person has SS. An alternative test is nonstimulated whole saliva flow collection, in which the person spits into a test tube every minute for 15 minutes. A resultant collection of less than 1.5 ml (0.053 imp fl oz; 0.051 US fl oz) is considered a positive result.
A lip/salivary gland biopsy takes a tissue sample that can reveal lymphocytes clustered around salivary glands, and damage to these glands from inflammation. This test involves removing a sample of tissue from a persons inner lip/salivary gland and examining it under a microscope. On such biopsies, the single most important test result in the diagnosis of the oral component of Sjögren syndrome is likely the focus score, which is the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section. The Chisholm-Mason grades are also widely used for salivary gland biopsies (see table).A radiological procedure is available as a reliable and accurate test for Sjögrens syndrome, in the form of a sialogram. A contrast agent is injected into the parotid duct, which opens from the cheek into the vestibule of the mouth opposite the neck of the upper second molar tooth. The test is intended to detect any blockage in the salivary gland ducts (i.e. parotid duct) and the amount of saliva that flows into the mouth.For Sjögrens syndrome, sudomotor function through electrochemical skin conductance may help in the diagnosis process.Sjögrens syndrome can be excluded from people with past head and neck radiation therapy, acquired immunodeficiency syndrome, pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs.

Prevention
No prevention mechanism exists for Sjögrens syndrome (SS) because of its complexity as an autoimmune disorder, but lifestyle changes can reduce the risk factors related to developing SS or reduce the severity of the condition for patients who have already been diagnosed. Diet is strongly associated with the inflammation seen in many autoimmune related diseases, including SS. An experimental study concluded that SS patients often show high sensitivity to gluten that directly relates to inflammation. Moderate exercise is also helpful in SS patients, mainly reducing the effect of lung inflammation.

Treatment
Neither a cure nor a specific treatment for Sjögrens syndrome is known to permanently restore gland secretion. Instead, treatment is generally symptomatic and supportive.

Eye care
Moisture replacement therapies such as artificial tears may ease the symptoms of dry eyes. Some patients with more severe problems use goggles to increase local humidity or have punctal plugs inserted to help retain tears on the ocular surface for a longer time.Additionally, cyclosporine (Restasis) is available by prescription to treat chronic dry eye by suppressing the inflammation that disrupts tear secretion. Prescription drugs are also available that help to stimulate salivary flow, such as cevimeline (Evoxac) and pilocarpine. Salagen, a manufactured form of pilocarpine, can be used to help produce tears, as well as saliva in the mouth and intestines. It is derived from the jaborandi plant.

Vaginal dryness
In women with Sjögrens syndrome, vaginal dryness, vulvodynia and dyspareunia (painful sexual intercourse) are often reported; personal lubricants are recommended to help lessen irritation or pain that may result from dryness in the vaginal and vulval areas.

Musculoskeletal
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to treat musculoskeletal symptoms. For individuals with severe complications, corticosteroids or immunosuppressive drugs may be prescribed, and sometimes intravenous immunoglobulins. Also, disease-modifying antirheumatic drugs  such as methotrexate may be helpful. Hydroxychloroquine (Plaquenil) is another option and is generally considered safer than methotrexate. However, these prescribed drugs have a range of side effects such as nausea, loss of appetite, dizziness, hair loss, stomach aches/cramps, headache, liver toxicity and increased risk of infections. Also, those who take drugs to suppress the immune system are more likely to develop cancer later.

Systemic
For systemic symptoms, including fatigue, joint pain, myositis and neuropathy, biologic immunosuppressant drugs such as rituximab and belimumab that work via B-cell pathology are often used and have less toxic profiles than traditional immunosuppressive regimens.

Dental care
Preventive dental treatment is also necessary (and often overlooked by the patient), as the lack of saliva associated with xerostomia creates an ideal environment for the proliferation of bacteria that cause cavities. Treatments include at-home topical fluoride application to strengthen tooth enamel and frequent teeth cleanings by a dental hygienist. Existing cavities must also be treated, as cavities that extend into the tooth cannot be effectively treated by teeth cleaning alone, and are at a high risk of spreading into the pulp of the tooth, leading to the loss of vitality and need for extraction or root canal therapy. This treatment regimen is the same as for all xerostomia patients, such as for those undergoing head and neck radiation therapy, which often damages the salivary glands; these glands are more susceptible to radiation than are other body tissues.

Prognosis
Published studies on the survival of Sjögrens syndrome patients are limited in varied respects, perhaps owing to the relatively small sample sizes, and the fact that secondary Sjögrens syndrome is associated with other autoimmune diseases. Results from a number of studies indicate that, compared to other autoimmune diseases, Sjögrens syndrome is associated with a notably high incidence of malignant non-Hodgkin lymphoma, a cancer of white blood cells. About 5% of patients with SS develop some form of lymphoid malignancy. Patients with severe cases are much more likely to develop lymphomas than patients with mild or moderate cases. The most common lymphomas are salivary extranodal marginal zone B cell lymphomas (MALT lymphomas in the salivary glands) and diffuse large B-cell lymphoma.Lymphomagenesis in primary Sjögrens syndrome patients is considered as a multistep process, with the first step being chronic stimulation of autoimmune B cells, especially B cells that produce rheumatoid factor  at sites targeted by the disease. This increases the frequency of oncogenic mutation, leading to any dysfunction at checkpoints of autoimmune B-cell activation to transform into malignancy. A studys finding has concluded the continuous stimulation of autoimmune B cells, leading to subtle germinal abnormalities in genes having specific consequences in B cells, which underlies the susceptibility to lymphoma.Apart from this notably higher incidence of malignant NHL, Sjögrens patients show only modest or clinically insignificant deterioration in specific organ-related function, which explains the only slight increases in mortality rates of Sjögrens patients in comparison with the remainder of the population.Sjögrens syndrome is associated with a high burden of illness, and has been shown to markedly reduce quality of life (QoL), with a significant impact on ability to work resulting from increased rates of disability. The reduction in QoL is similar to that seen in other chronic conditions such as rheumatoid arthritis, lupus and fibromyalgia.

Epidemiology
Sjögrens syndrome (SS) is the second-most common rheumatic autoimmune disorder, behind rheumatoid arthritis and systemic lupus erythematosus. There are no geographical differences in the rates of SS. Sjögrens syndrome has been reported in all areas of the world, although regional rates have not been well studied. Depending on the criteria for determining prevalence, studies estimate the prevalence of SS at between 500,000 and two million people in the United States. Broader studies of SS prevalence range widely, with some reports of up to a prevalence of 3% of the population. A few studies have reported that the incidence of the syndrome varies between three and six per 100,000 per year.Nine out of 10 SS patients are women. In addition to prevalence in women, having a first-degree relative with an autoimmune disease and previous pregnancies have been identified as epidemiological risk factors. Despite the lower risk for men, primary SS in men tends to represent a more severe form of the disease. The role of race and ethnicity in the prevalence of the disease is unknown.Although Sjögrens syndrome occurs in all age groups, the average age of onset is between ages 40 and 60, although as many as half of all cases may be left undiagnosed or unreported. The prevalence of SS generally increases with age.Sjögrens syndrome is reported in 30-50% of people with rheumatoid arthritis and in 10-25% with systemic lupus erythematosus.

History
Jan Mikulicz-Radecki (1850–1905) is generally credited with the first description of SS. In 1892, he described a 42-year-old man with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. However, the criteria that Mikulicz established for diagnosis often led to misdiagnosis of Mikuliczs syndrome. Many conditions, such as tuberculosis, infections, sarcoidosis and lymphoma present with similar conditions to those ascribed to Mikuliczs syndrome. Nevertheless, the term "Mikulicz’s syndrome" is still used occasionally to describe the appearance of lymphocytic infiltrates on salivary-gland biopsies.In 1930, Henrik Sjögren (1899–1986), an ophthalmologist in Jönköping, Sweden, observed a patient with low secretions from the lacrimal and salivary glands. Sjögren introduced the term keratoconjunctivitis sicca for the symptom of dry eyes (keratoconjunctivitis). In 1933, he published his doctoral thesis describing 19 females, most of whom were postmenopausal and had arthritis, showing clinical and pathological manifestations of the syndrome. Sjögren clarified that keratoconjunctivitis sicca, resulting from water deficiency, had no relation to xerophthalmia, resulting from vitamin A deficiency. Sjögrens thesis was not well received as the Board of Examiners criticized some clinical aspects.After extensive research and data collection, Sjögren published an essential paper in 1951, describing 80 patients with keratoconjunctivitis sicca, 50 of whom also had arthritis. His subsequent follow-up conference trips pertaining to his paper led to an international interest in Sjögrens syndrome. The term "keratoconjunctivitis sicca" was coined by Sjögren himself and began to be identified as Sjögrens syndrome in literature, although it can now have more general usage.

Research
Research into multifactorial autoimmune diseases such as SS focuses on expanding the knowledge surrounding the disorder, improving diagnostic tools and finding ways to prevent, manage and cure the disorder. The United Kingdom Primary Sjögrens Syndrome Registry, a tissue biobank of samples taken for research, supported by the Medical Research Council, UK, was established in 2010. It supports clinical trials and genetic studies of Sjögrens syndrome and is open to those wishing to participate in research studies and to researchers studying the disease.As with other autoimmune diseases, susceptibility to Sjögrens syndrome is greatly influenced by the human leukocyte antigen. DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were identified as risk factors, while DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were found to be protective factors for the disease. The relationship between alleles and specific race was also established. HLA-DQ2 and HLA-B8 are generally found in Caucasian patients, while HLA-DR5 is related to Greek and Israeli patients. Multiple genome-wide association scans may be conducted in the future to identify key risk variants.Viruses that have been associated with Sjögrens syndrome include human T-lymphotropic virus type 1 (HTLV-1), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), hepatitis delta virus (HDV) and hepatitis C virus (HCV).Some research has showed that the lack of vitamin A and vitamin D are associated with the disease </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Inflammatory myopathy and can you explain it in depth? [/INST] Inflammatory myopathy  is disease featuring weakness and inflammation of muscles and (in some types) muscle pain. The cause of much inflammatory myopathy is unknown (idiopathic), and such cases are classified according to their symptoms and signs and electromyography, MRI and laboratory findings. It can also be associated with underlying cancer. The main classes of idiopathic inflammatory myopathy are polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM).

Diagnosis
There are a number of known causes of myopathy, and it is only once these have been ruled out that a clinician will assign an idiopathic inflammatory myopathy (IIM) syndrome to a case. The usual criteria for a diagnosis of PM are weakness in muscles of the head, neck, trunk, upper arms or upper legs; raised blood serum concentrations of some muscle enzymes such as creatine kinase; unhealthy muscle changes on electromyography; and biopsy findings of (i) muscle cell degeneration and regeneration and (ii) chronic inflammatory infiltrates in muscle cells. If heliotrope (purple) rash or Gottrons papules are also present, then the diagnosis is DM. In DM, myositis may not be clinically apparent but detectable via biopsy or MRI. If the criteria for PM are met but muscle weakness also affects the hands and feet or is not accompanied by pain IBM should be suspected, and confirmed when muscle cell biopsy reveals (i) cytoplasmic vacuoles fringed by basophilic granules and (ii) inflammatory infiltrate comprising mostly CD8 T lymphocytes and macrophages; and electron microscopy reveals filamentous inclusions in both cytoplasm and nucleus.

Treatment
There have been few randomized treatment trials, due to the relative rarity of inflammatory myopathies. The goal of treatment is improvement in activities of daily living and muscle strength. Suppression of immune system activity (immunosuppression) is the treatment strategy. Patients with PM or DM almost always improve to some degree in response to treatment, at least initially, and many recover fully with maintenance therapy. (If there is no initial improvement from treatment of PM or DM, the diagnosis should be carefully re-examined.) There is no proven effective therapy for IBM, and most IBM patients will need assistive devices such as a cane, a walking frame or a wheelchair. The later in life IBM arises, the more aggressive it appears to be.

Polymyositis and dermatomyositis
In severe cases of PM and DM with systemic signs, an initial three to five days on intravenous corticosteroid (methylprednisolone) may be used; but normally treatment begins with a single daily (after breakfast) high dose of oral corticosteroid (prednisone). After a month or so the strength of every second days dose is very gradually reduced over three to four months, to minimize the negative effects of the prednisone. When a high dose of prednisone cannot be reduced without losing muscle strength, or when prednisone is effective but it is producing significant complications, "steroid sparing" oral immunosuppressants such as azathioprine, mycophenolate mofetil, methotrexate and cyclosporine, may be used in combination with reduced prednisone. Some of these steroid sparing drugs can take several months to demonstrate an effect.To minimize side effects, patients on corticosteroids should follow a strict high-protein, low-carbohydrate, low-salt diet; and with long-term corticosteroid use a daily calcium supplement and weekly vitamin D supplement (and a weekly dose of Fosamax for postmenopausal women) should be considered.For patients not responding to this approach there is weak evidence supporting the use of intravenous immunoglobulin, ciclosporin, tacrolimus, mycophenolate mofetil and other agents; and trials of rituximab have indicated a potential therapeutic effect.

Inclusion-body myositis
Despite its very similar clinical presentation to PM, IBM does not respond to the drugs that effectively treat PM, and there is no proven effective therapy for IBM </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hemolytic disease of the newborn and can you explain it in depth? [/INST] Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts (immature red blood cells) are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis (British English: erythroblastosis foetalis).
HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance in pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. The types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell. Although global prevalence studies of the differential contribution of those types are lacking, regional population studies have shown the anti-RhD type to be the most common cause of HDFN, followed by anti-RhE, anti-RhC, and anti-Rhc.

Signs and symptoms
Signs of hemolytic disease of the newborn include a positive direct Coombs test (also called direct agglutination test), elevated cord bilirubin levels, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well. Hemolysis leads to elevated bilirubin levels. After delivery, bilirubin is no longer cleared (via the placenta) from the neonates blood and the symptoms of jaundice (yellowish skin and yellow discoloration of the whites of the eyes, or icterus) increase within 24 hours after birth. Like other forms of severe neonatal jaundice, there is the possibility of the neonate developing acute or chronic kernicterus, however the risk of kernicterus in HDN is higher because of the rapid and massive destruction of blood cells. It is important to note that isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.

Complications
Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Conditions that may cause similar symptoms in the newborn period include: acquired hemolytic anemia, congenital toxoplasma, congenital syphilis infection, congenital obstruction of the bile duct, and cytomegalovirus (CMV) infection.
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin Induced Neurological Dysfunction
Cerebral Palsy
Kernicterus
Neutropenia
Thrombocytopenia
Hemolytic anemia – must not be treated with iron
Late onset anemia – must not be treated with iron. Can persist up to 12 weeks after birth.

Pathophysiology
Antibodies are produced when the body is exposed to an antigen foreign to the make-up of the body. If a mother is exposed to a foreign antigen and produces IgG (as opposed to IgM which does not cross the placenta), the IgG will target the antigen, if present in the fetus, and may affect it in utero and persist after delivery. The three most common models in which a woman becomes sensitized toward (i.e., produces IgG antibodies against) a particular antigen are hemorrhage, blood transfusion, and ABO incompatibility.Fetal-maternal hemorrhage, which is the movement of fetal blood cells across the placenta, can occur during abortion, ectopic pregnancy, childbirth, ruptures in the placenta during pregnancy (often caused by trauma), or medical procedures carried out during pregnancy that breach the uterine wall. In subsequent pregnancies, if there is a similar incompatibility in the fetus, these antibodies are then able to cross the placenta into the fetal bloodstream to attach to the red blood cells and cause their destruction (hemolysis). This is a major cause of HDN, because 75% of pregnancies result in some contact between fetal and maternal blood, and 15–50% of pregnancies have hemorrhages with the potential for immune sensitization. The amount of fetal blood needed to cause maternal sensitization depends on the individuals immune system and ranges from 0.1 mL to 30 mL.The woman may have received a therapeutic blood transfusion. ABO blood group system and the D antigen of the Rhesus (Rh) blood group system typing are routine prior to transfusion. Suggestions have been made that women of child-bearing age or young girls should not be given a transfusion with Rhc-positive blood or Kell1-positive blood to avoid possible sensitization, but this would strain the resources of blood transfusion services, and it is currently considered uneconomical to screen for these blood groups. HDFN can also be caused by antibodies to a variety of other blood group system antigens, but Kell and Rh are the most frequently encountered.The third sensitization model can occur in women of blood type O. The immune response to A and B antigens, which are widespread in the environment, usually leads to the production of IgM or IgG anti-A and anti-B antibodies early in life. Women of blood type O are more prone than women of types A and B to making IgG anti-A and anti-B antibodies, and these IgG antibodies are able to cross the placenta. For unknown reasons, the incidence of maternal antibodies against type A and B antigens of the IgG type that could potentially cause hemolytic disease of the newborn is greater than the observed incidence of "ABO disease." About 15% of pregnancies involve a type O mother and a type A or type B child; only 3% of these pregnancies result in hemolytic disease due to A/B/O incompatibility. In contrast to antibodies to A and B antigens, production of Rhesus antibodies upon exposure to environmental antigens seems to vary significantly across individuals. In cases where there is ABO incompatibility and Rh incompatibility, the risk of alloimmunization is decreased because fetal red blood cells are removed from maternal circulation due to anti-ABO antibodies before they can trigger an anti-Rh response.

Serological types
HDN is classified by the type of antigens involved. The main types are ABO HDN, Rhesus HDN, Kell HDN, and other antibodies. Combinations of antibodies (for example, anti-Rhc and anti-RhE occurring together) can be especially severe.ABO hemolytic disease of the newborn can range from mild to severe, but generally, it is a mild disease. It can be caused by anti-A and anti-B antibodies.Rhesus D hemolytic disease of the newborn (often called Rh disease) is the most common and only preventable form of severe HDN. Since the introduction of Rho-D immunoglobulin, (Rhogam, at 1968, which prevents the production of maternal Rho-D antibodies, the incidence of anti-D HDN has decreased dramatically.Rhesus c HDFN can range from a mild to severe disease and is the third most common form of severe HDN. Rhesus e and rhesus C hemolytic disease of the newborn are rare. Anti-C and anti-c can both show a negative DAT but still have a severely affected infant. An indirect Coombs must also be run.
Anti-Kell hemolytic disease of the newborn is most commonly caused by anti-K1 antibodies, the second most common form of severe HDN. Over half of the cases of anti-K1 related HDN are caused by multiple blood transfusions. Antibodies to the other Kell antigens are rare. Anti-Kell can cause severe anemia regardless of titer. It suppresses the bone marrow by inhibiting the erythroid progenitor cells.Anti-M also recommends antigen testing to rule out the presence of HDN as the direct coombs can come back negative in a severely affected infant.Kidd antigens are also present on the endothelial cells of the kidneys.One study states that it would be unwise to routinely dismiss anti-E as being of little clinical consequence. It also found that the most severe case of anti-E HDFN occurred with titers 1:2, concluding that titers are not reliable for the diagnosis of the anti-E type.

Diagnosis
The diagnosis of HDN is based on history and laboratory findings:Blood tests done on the newborn baby

Biochemistry tests for jaundice including total and direct bilirubin levels.
Complete blood count (CBC) which may show a decreased hemoglobin and hematocrit due to red blood cell destruction
Reticulocyte count which will usually be increased as the bone marrow makes new red blood cells to replace the ones that are being destroyed, and a peripheral blood smear to look at cell morphology. In the presence of significant hemolysis the smear will show schistocytes (fragmented red blood cells), reticulocytosis, and in severe cases Erythroblasts (also known as nucleated red blood cells).
Positive direct Coombs test (might be negative after fetal interuterine blood transfusion)Blood tests done on the mother

Positive indirect Coombs testBlood tests done on the father (rarely needed)

Erythrocyte antigen status

Prevention
In cases of Rho(D) incompatibility, Rho(D) immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.Early pregnancy

IVIG – IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. IVIG can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
Plasmapheresis – Plasmapheresis aims to decrease the maternal titer by direct plasma replacement and physical removal of antibody. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and fetal losses.Mid- to late- pregnancy

IUT – Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
Steroids – Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
Phenobarbital – Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
Early Delivery – Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.Rhesus-negative mothers who are pregnant with a rhesus-positive infant are offered Rho(D) immune globulin (RhIG, or RhoGam) at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production. Without Rho(D) immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration, the risk is reduced to less than 0.1–0.2%.

After birth testing
Coombs – in certain instances (when there is concern for blood group incompatibility between mother and baby for example), after birth a baby will have a direct Coombs test run to confirm the antibodies attached to the infants red blood cells. This test is run on the infants cord blood.In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur. An indirect Coombs needs to be run in cases of anti-C, anti-c, and anti-M. Infants with Anti-M are also recommended to receive antigen testing to rule out the presence of HDN. The below tests are often useful in cases of hemolytic disease of the newborn but are not required for treatment of all newborns.

Hgb – the infants hemoglobin should be tested from cord blood.
Reticulocyte count – Reticulocytes are elevated when the infant is producing more red blood cells in response to anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell.
Neutrophils – as neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin – because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.
Newborn Screening Tests – Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.

Treatment
After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
Phototherapy – Exposure to ultraviolet light (phototherapy) is recommended when the cord bilirubin is 3 or higher. Some doctors use it at lower levels while awaiting lab results. This converts unconjugated bilirubin to an conjugated form that is easier for the infant to clear.
IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hand, foot, and mouth disease and can you explain it in depth? [/INST] Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of enteroviruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blister, on the hands, feet and mouth and occasionally buttocks and groin. Signs and symptoms normally appear 3–6 days after exposure to the virus. The rash generally resolves on its own in about a week. Fingernail and toenail loss may occur a few weeks later, but they will regrow with time.The viruses that cause HFMD are spread through close personal contact, through the air from coughing and the feces of an infected person. Contaminated objects can also spread the disease. Coxsackievirus A16 is the most common cause, and enterovirus 71 is the second-most common cause. Other strains of coxsackievirus and enterovirus can also be responsible. Some people may carry and pass on the virus despite having no symptoms of disease. Other animals are not involved. Diagnosis can often be made based on symptoms. Occasionally, a throat or stool sample may be tested for the virus.Handwashing may prevent spread, and those infected should not go to work, daycare or school. No antiviral medication or vaccine is available, but development efforts are underway. Most cases require no specific treatment. Simple pain medication such as ibuprofen or numbing mouth gel may be used. Occasionally, intravenous fluids are given to children who are unable to drink enough. Rarely, viral meningitis or encephalitis may complicate the disease.HFMD occurs in all areas of the world. It often occurs in small outbreaks in nursery schools or kindergartens. Large outbreaks have been occurring in Asia since 1997. It usually occurs during the spring, summer and fall months. Typically it occurs in children less than five years old but can occasionally occur in adults. HFMD should not be confused with foot-and-mouth disease (also known as hoof-and-mouth disease), which mostly affects livestock.

Signs and symptoms
Common constitutional signs and symptoms of the HFMD include fever, nausea, vomiting, feeling tired, generalized discomfort, loss of appetite, and irritability in infants and toddlers. Skin lesions frequently develop in the form of a rash of flat discolored spots and bumps which may be followed by vesicular sores with blisters on palms of the hands, soles of the feet, buttocks, and sometimes on the lips. The rash is rarely itchy for children, but can be extremely itchy for adults. Painful facial ulcers, blisters, or lesions may also develop in or around the nose or mouth. HFMD usually resolves on its own after 7–10 days. Most cases of the disease are relatively harmless, but complications including encephalitis, meningitis, and paralysis that mimics the neurological symptoms of polio can occur.

Cause
The viruses that cause the disease are of the Picornaviridae family. Coxsackievirus A16 is the most common cause of HFMD. Enterovirus 71 (EV-71) is the second-most common cause. Many other strains of coxsackievirus and enterovirus can also be responsible.

Transmission
HFMD is highly contagious and is transmitted by nasopharyngeal secretions such as saliva or nasal mucus, by direct contact, or by fecal-oral transmission. It is possible to be infectious for days to weeks after the symptoms have resolved.Child care settings are the most common places for HFMD to be contracted because of toilet training, diaper changes, and the fact that children often put their hands into their mouths. HFMD is contracted through nose and throat secretions such as saliva, sputum, nasal mucus and as well as fluid in blisters, and stool.

Diagnosis
A diagnosis usually can be made by the presenting signs and symptoms alone. If the diagnosis is unclear, a throat swab or stool specimen may be taken to identify the virus by culture. The common incubation period (the time between infection and onset of symptoms) ranges from three to six days. Early detection of HFMD is important in preventing an outbreak in the pediatric population.

Prevention
Preventive measures include avoiding direct contact with infected individuals (including keeping infected children home from school), proper cleaning of shared utensils, disinfecting contaminated surfaces, and proper hand hygiene. These measures have been shown to be effective in decreasing the transmission of the viruses responsible for HFMD.Protective habits include hand washing and disinfecting surfaces in play areas. Breast-feeding has also shown to decrease rates of severe HFMD, though does not reduce the risk for the infection of the disease.

Vaccine
A vaccine known as the EV71 vaccine is available to prevent HFMD in China as of December 2015.  No vaccine is currently available in the United States.

Treatment
Medications are usually not needed as hand, foot, and mouth disease is a viral disease that typically resolves on its own. Currently, there is no specific curative treatment for hand, foot and mouth disease. Disease management typically focuses on achieving symptomatic relief. Pain from the sores may be eased with the use of analgesic medications. Infection in older children, adolescents, and adults is typically mild and lasts approximately 1 week, but may occasionally run a longer course. Fever reducers can help decrease body temperature.In 2018, National Health Commission of China assembled a panel of experts to revise their guidelines for the diagnosis and treatment of hand, foot and mouth disease. Consumption of Traditional Chinese medicine, prescribed by certified physicians, are recommended to clear the symptoms.A minority of individuals with hand, foot and mouth disease may require hospital admission due to complications such as inflammation of the brain, inflammation of the meninges, or acute flaccid paralysis. Non-neurologic complications such as inflammation of the heart, fluid in the lungs, or bleeding into the lungs may also occur.

Complications
Complications from the viral infections that cause HFMD are rare, but require immediate medical treatment if present. HFMD infections caused by Enterovirus 71 tend to be more severe and are more likely to have neurologic or cardiac complications including death than infections caused by Coxsackievirus A16. Viral or aseptic meningitis can occur with HFMD in rare cases and is characterized by fever, headache, stiff neck, or back pain.  The condition is usually mild and clears without treatment; however, hospitalization for a short time may be needed. Other serious complications of HFMD include encephalitis (inflammation of the brain), or flaccid paralysis in rare circumstances.Fingernail and toenail loss have been reported in children 4–8 weeks after having HFMD. The relationship between HFMD and the reported nail loss is unclear; however, it is temporary and nail growth resumes without treatment.Minor complications due to symptoms can occur such as dehydration, due to mouth sores causing discomfort with intake of foods and fluid.

Epidemiology
Hand, foot and mouth disease most commonly occurs in children under the age of 10 and more often under the age of 5, but it can also affect adults with varying symptoms. It tends to occur in outbreaks during the spring, summer, and autumn seasons. This is believed to be due to heat and humidity improving spread. HFMD is more common in rural areas than urban areas; however, socioeconomic status and hygiene levels need to be considered. Poor hygiene is a risk factor for HFMD.

Outbreaks
In 1997, an outbreak occurred in Sarawak of Malaysia with 600 cases and over 30 children died.
In 1998, there was an outbreak in Taiwan, affecting mainly children. There were 405 severe complications, and 78 children died. The total number of cases in that epidemic is estimated to have been 1.5 million.
In 2008 an outbreak in China, beginning in March in Fuyang, Anhui, led to 25,000 infections, and 42 deaths, by May 13. Similar outbreaks were reported in Singapore (more than 2,600 cases as of April 20, 2008), Vietnam (2,300 cases, 11 deaths), Mongolia (1,600 cases), and Brunei (1053 cases from June–August 2008)
In 2009 17 children died in an outbreak during March and April 2009 in Chinas eastern Shandong Province, and 18 children died in the neighboring Henan Province. Out of 115,000 reported cases in China from January to April, 773 were severe and 50 were fatal.
In 2010 in China, an outbreak occurred in southern Chinas Guangxi Autonomous Region as well as Guangdong, Henan, Hebei and Shandong provinces. Until March, 70,756 children were infected and 40 died from the disease. By June, the peak season for the disease, 537 had died.
The World Health Organization reporting between January to October 2011 (1,340,259) states the number of cases in China had dropped by approx 300,000 from 2010 (1,654,866) cases, with new cases peaking in June. There were 437 deaths, down from 2010 (537 deaths).
In December 2011, the California Department of Public Health identified a strong form of the virus, coxsackievirus A6 (CVA6), where nail loss in children is common.
In 2012 in Alabama, United States there was an outbreak of an unusual type of the disease. It occurred in a season when it is not usually seen and affected teenagers and older adults </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sialadenitis and can you explain it in depth? [/INST] Sialadenitis (sialoadenitis) is inflammation of salivary glands, usually the major ones, the most common being the parotid gland, followed by submandibular and sublingual glands. It should not be confused with sialadenosis (sialosis) which is a non-inflammatory enlargement of the major salivary glands.Sialadenitis can be further classed as acute or chronic. Acute sialadenitis is an acute inflammation of a salivary gland which may present itself as a red, painful swelling that is tender to touch. Chronic sialadenitis is typically less painful but presents as recurrent swellings, usually after meals, without redness.Causes of sialadenitis are varied, including bacterial (most commonly Staphylococcus aureus), viral and autoimmune conditions.

Types
Acute
Predisposing factorssialolithiasis
decreased flow (dehydration, post-operative, drugs)
poor oral hygiene
exacerbation of low grade chronic sialoadenitisClinical featurespainful swelling
reddened skin
edema of the cheek, periorbital region and neck
low grade fever
malaise
raised ESR, CRP, leucocytosis
purulent exudate from duct punctum

Chronic
Clinical featuresunilateral
mild pain / swelling
common after meals
duct orifice is reddened and flow decreases
may or may not have visible/palpable stone.
Parotid gland
recurrent painful swellings
Submandibular gland
usually secondary to sialolithiasis or stricture

Signs and Symptoms
Sialadenitis is swelling and inflammation of the parotid, submandibular, or sublingual major salivary glands. It may be acute or chronic, infective or autoimmune.

Acute
Acute sialadenitis secondary to obstruction (sialolithiasis) is characterised by increasingly, painful swelling of 24–72 hours, purulent discharge and systemic manifestations.

Chronic
Chronic sialadenitis causes intermittent, recurrent periods of tender swellings.  Chronic sclerosing sialadenitis is commonly unilateral and can mimic a tumour.

Autoimmune
Autoimmune sialadenitis (i.e Sjogren’s syndrome) causes unilateral or bilateral painless swellings unless there is a secondary infection.

Infection
The most common salivary gland infection is mumps. It is characterised by bilateral swelling of the parotid glands, however other major salivary glands may also be affected in around 10% of cases. The swelling persists for about a week, along with low grade fever and general malaise.
Recurrent parotitis of childhood is characterised by periods of pain and swelling in the parotid gland accompanied by a fever

Complications
Causes
Sialadenitis can be caused by cancer, autoimmune conditions, viral and bacterial infections, idiopathic causes or stones formed mainly from calculus. It was thought that morphological characteristics of the salivary ducts could also be a contributing factor, as stagnation of saliva due to these could perhaps cause an increased incidence of sialadenitis. However, one study found no statistically significant difference between the length of ducts or the angles they incorporate within them and the likelihood of developing sialadenitis, although this study only had a small sample size of 106. The study also confirmed that age, gender, side of face and degree of sialadenitis had no impact on the length of the ducts or the angles formed within the ducts.Viral pathogens more commonly cause sialadenitis in comparison to bacterial pathogens. Mumps is the most common virus that affects the parotid and submandibular glands, with the parotid gland affected most often out of these two. Other viruses that have been shown to cause sialadenitis in both these glands include HIV, coxsackie, and parainfluenza. Classically, HIV parotitis is either asymptomatic or a non-painful swelling, which is not characteristic of sialadenitis. Some common bacterial causes are S. aureus, S. pyogenes, viridans streptococci and H. influenzae.Autoimmune conditions that can cause sialadenitis include Sjögren’s syndrome, sarcoidosis, and granulomatosis with polyangiitis. Sjögren’s syndrome and Sarcoidosis are the most common causes of chronic sialadenitis and are often closely associated with it, and in many cases are believed to be the primary cause, although often with other contributing factors present also. One well known form of sarcoidosis is known as Heerfordt’s syndrome which is characterized by facial nerve palsy, enlargement of the parotid and anterior uveitis. One study came to the conclusion that the presence of salivary calculi is the main indicator for the removal of the submandibular gland, in patients where neoplasia is absent. This was because 82% of glands removed in an ENT department in Stockholm were found to have salivary calculi within them and all of these cases but one had chronic sialadenitis. A mucous retention cyst was found in one patient, but this was not considered to have contributed to the sialadenitis in this case.The duration of the sialadenitis was found to be closely linked to atrophy, fibrosis and the degree of the inflammation in another study, which looked primarily at microliths found in the ducts and glands. Liths were also found to be related to the duration that the individual had symptoms of sialadenitis, whereas microliths were found in normal glands and varied with age. Microliths could possibly form reservoirs, thus allowing infection to ascend further towards the glands but this could not be confirmed due to the liths and microliths being distinct in this study. However, many glands did show only very minimal variations, which could allow the opportunity for more conservative treatment instead of the surgical removal of the affected gland in the future.

Histopathology
Initial stage of acute bacterial sialadenitis involves the accumulation of bacteria, neutrophils and inspissated fluid in lumen of ductal structures. Damage to ductal epithelium results in sialodochitis (periductal inflammation), accumulation of neutrophils in glandular stroma, followed by acini necrosis with microabscesses formation. Recurrent episodes results in chronic stage, which involves the establishment of periductal lymph follicles and further destruction of salivary acini.

Infective sialadenitis
Generally, in acute bacterial and viral sialadenitis cases, the lobular architecture of the gland is maintained or may be slightly expanded. Areas of liquefaction, indicating presence of abscess, may also be seen microscopically.
In Acute bacterial sialadenitis, acinar destruction with interstitial neutrophil infiltrates is observed. Small abscesses with necrosis are common.
In Viral sialadenitis, vacuolar changes are seen in the acini with lymphocytic and monocytic infiltrate found in the interstitium
Cytomegalovirus (CMV) sialadenitis may show no gross symptoms
Chronic sialadenitis (also known as lymphoepithelial sialadenitis (LESA)) presents with 50% of which are monoclonal by PCR while mucosa-associated lymphoid tissue (MALT) lymphoma has ducts surrounded by broad coronas of monocytoid cells, infiltration of interfollicular region by monocytoid cells or atypical plasma cells containing Dutcher bodies, monoclonality by immunohistochemistry or flow cytometry, and monocytoid infiltrates in regional lymph nodes.Histologically, chronic sialadenitis can appear from unremarkable to a firm tan with expansion or atrophy of the lobular structure depending on the degree of inflammation and chronicity. Salivary stones (Sialolith) may be evident with cystic dilation of the salivary ducts and periductal fibrosis. Mucus extravasation may also be observed.
Common observations of chronic sialadenitis include chronic inflammatory infiltrate (lymphocytes, plasma cells and macrophages), fibrosis, acinar atrophy, mucous cell metaplasia of the ductal system is observed.
In Sialoithiasis, concomitant squamous metaplasia may be observed in the salivary ducts with dark calcific stone fragments.

Chronic sialadenitis
Chronic sclerosing sialadenitis has various degrees of inflammation which can include focal lymphocytic sialadenitis to widespread salivary gland cirrhosis with obliteration of acini. This can be a result of obstruction of salivary ducts by microliths (due to associated intercurrent infections), or a result of immune reaction with the formation of secondary lymph follicles. Chronic sclerosing sialadenitis is characterised by presence of three major criteria of dense lymphoplasmacytic infiltrate, storiform pattern of fibrosis and obliterative phlebitis. Minor criteria include phlebitis without obliteration of the lumen and increased numbers of eosinophils. There are two features relatively inconsistent with diagnosis of IgG4-related disease which are the presence of epithelioid cell granulomas and a prominent neutrophilic infiltrate.Sclerosing polycystic sialadenitis histologically resembles sclerosing adenosis/fibrocystic change of breast tissue. It composes of acini and ductal elements embedded in dense sclerotic stroma, and has a characteristic finding of large acinar cells present with abundant eosinophilic cytoplasmic granules. In addition, it may also present ductal epithelial proliferation which could range from hyperplasia, atypia to DCIS-like. Its stroma may show focal adipose tissue with myxoid change and variable radial scar. At present, there are immunohistochemical studies of limited value only. It is cytologically difficult to diagnose this type of sialadenitis due to the rarity of this condition and the presence of variable cell types in a cystic background.In autoimmune sialadenitis, activation of T and B cells that infiltrate the interstitium occurs due to a response to an unidentified antigen present in the salivary gland parenchyma. This response then results in acini destruction and the formation of epimyoepithelial islands.

Autoimmune sialadenitis
Most histological appearance of autoimmune sialadenitis are similar to that of Myoepithelial sialadenitis. In general, a diffuse to multinodular expansion is observed in myoepithelial sialadenitis. A distinguishing feature is the presence of epithelial-myoepithelial islands infiltrated by lymphocytes. Germinal centers may form with the progression of lymphoid infiltrate resulting in acinar atrophy. Proliferation of ductal epithelium-myoepithelium arises causing the obliteration of ductal lumina causing the formation of the epithelial-myoepithelial islands.
Granulomatosis with polyangiitis may have areas of liquefaction necrosis caused by vasculitis. A triad of vasculitis, necrosis and granulomatous inflammation may be observed.
In secondary Sjogren’s syndrome, periglandular fibrosis with the absence of inflammation may also be observed in addition to that of Myoepithelial sialadenitis from the progressive systemic sclerosis.
Sarcoid has tight epithelioid granulomas and lymphoid infiltrate.
Chronic Sclerosing Sialadenitis has peridutcal fibrosis with a dense lymphoplasmacytic infiltrate with lymphoid follicles. Eosinophils may be seen.

Diagnosis
According to the British Medical Journal (The BMJ) Best Practice on Sialadenitis, there are multiple factors to consider during the diagnosis of sialadenitis, including history, presenting signs and symptoms, followed by appropriate investigations in relation to the presenting case. Other factors to also consider include the type of gland affected as well as underlying conditions such as an autoimmune disease or ductal stones.

Acute bacterial sialadenitis
May present with a history of recent surgical intervention or use of medications such as antihistamines, antidepressants, or anticholinergic agents. These medications may lead to objective hypofunction or subjective feeling of a dry mouth without hypofunction. There may also be a history of decrease in salivary volume secondary to a systemic disease.
A unilateral or bilateral painful swelling of the parotid or submandibular regions may be present upon a physical examination. This could be accompanied by an external displacement of the earlobe usually adjacent to an inflamed parotid gland. Pus suppuration from major salivary gland duct openings may occur spontaneously or after manipulation of the affected gland. Mandibular trismus is a rare finding but may be present with larger swellings. Dysphagia may also be present in some cases. Fever may also be noted, whilst spiking temperatures may be suggestive of an abscess formation.

Chronic recurrent sialadenitis
The occurrence of chronic recurrent episodes may be due to underlying Sjogrens syndrome or ductal abnormalities. Prodrome of tingling in the gland preceding pain and swelling may be reported in such cases.

Chronic sclerosing sialadenitis
Typically presents unilaterally in submandibular gland that cannot be differentiated clinically from a neoplasm, with pain an inconsistent finding.

Obstructive sialadenitis
Formation of stones in glandular ducts (sialoliths) can result in the development of obstructive sialadenitis. There may be a history of abrupt episodic swelling of the parotid or submandibular gland which is usually painful. These episodes typically occur around meal times, lasting 2 – 3 hours and gradually subsides.

Autoimmune sialadenitis
Characterised by persistent, asymptomatic bilateral swelling of parotid glands, and may represent as a manifestation of more widespread systemic disease. Dry eyes and dry mouth are commonly present and may be indicative of concomitant connective tissue disease (e.g. SLE, RA, or scleroderma). Oral candidiasis may also be present.
Common key diagnostic factors
1. Fever – may present with an acute infective sialadenitis or autoimmune aetiology suggestive of an infection or inflammation.
2. Pain and dysphagia (ie. difficulty swallowing) – usually unilateral affecting the parotid or submandibular regions, with worse pain during eating and swallowing.
3. Facial swelling – usually unilaterally and affecting parotid region, under the tongue, or below the jaw. May have acute onset and may have a history of repeated episodes.
4. Recurrent painful swellings – indicative of chronic recurrent sialadenitis, may have similar signs and symptoms to an acute episode.
5. Pus exudation from salivary gland openings – indicative of bacterial infection, may occur on manipulation of the affected gland or spontaneously.
Other common diagnostic factors to consider
1. Episodic swelling during meal times – may present as an acute salivary gland swelling without visible salivary flow from ductal openings. While palpation of affected glad may reveal an indurated salivary gland and presence of a sialolith.
2. Use of xerostomic medications – these medications will result in a decreased salivary flow rate which can predispose to infections of glands. Examples of medications that may contribute to this include antihistamines, antidepressant, and anticholinergic agents.
3. Recent surgical intervention under general anaesthetic – this could predispose to sialadenitis due to direct effects of anaesthetic agents used and volume depletion from surgery.
4. Dry eyes and mouth – dryness affecting the eyes and oral cavity are key symptoms of Sjogren’s syndrome and may be seen in combination with a connective tissue disease such as rheumatoid arthritis, scleroderma, or dermatomyositis.
5. Oral candidiasis – may be present in cases of Sjogren’s syndrome or in associate with a connective tissue disorder.
Key factors to also consider which are less common
1. Mandibular trismus – restricted mouth opening to its full extent (of approximately 40mm) may be present with large swellings typically due to acute bacterial infection of affected gland.
2. Respiratory distress – this could present in the form of stridor, use or reliance on accessory muscles of respiratory, nasal flaring, or wheeze. These signs may develop if glandular swelling is significant enough, resulting in airway obstruction.
3. Cranial nerve palsy – swelling increases the risk of compression of cranial nerves VII, IX and XII.
Other diagnostic factors which are less common
1. Connective tissue disorder or Sjogren’s syndrome – history of Sjogren’s syndrome, or a concomitant connect tissue disorder such as systemic lupus erythematosus, rheumatoid arthritis, or scleroderma.
2. Recurrent painless swellings – indicative of underlying autoimmune aetiology.
3. Displacement of earlobe – may be present when swelling of the parotid gland is present.
4. Prodrome of tingling in the affected gland
5. Swelling on hard palate

Diagnostic tests
Tests available as part of diagnosing sialadenitis include:

Culture and sensitivity testing of exudate from salivary duct. Culturing of purulent discharge is advisable in acute presentations of sialadenitis to allow targeted antibiotic therapy.
Full blood count if infection is suspected.
Facial radiographs such as dental radiographic views should be taken to exclude an obstructive element due to presence of sialolith or evolving abscess. However, sialoliths with low calcium phosphate content may not be visible.

Treatment
In chronic recurrent sialadenitis or chronic sclerosing sialadenitis, acute attacks are managed with conservative therapies such as hydration, analgesics (mainly NSAIDs), sialogogues to stimulate salivary secretion, and regular, gentle gland massage </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Molluscum contagiosum and can you explain it in depth? [/INST] Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the skin may be affected, with abdomen, legs, arms, neck, genital area, and face being the most common. Onset of the lesions is around seven weeks after infection. They usually go away within a year without scarring.The infection is caused by a poxvirus called the molluscum contagiosum virus (MCV). The virus is spread either by direct contact, including sexual activity, or via contaminated objects such as towels. The condition can also be spread to other areas of the body by the person themselves. Risk factors include a weak immune system, atopic dermatitis, and crowded living conditions. Following one infection, it is possible to get re-infected. Diagnosis is typically based on the appearance of the lesions.Prevention includes hand washing and not sharing personal items. While treatment is not necessary, some may wish to have the lesions removed for cosmetic reasons or to prevent spread. Removal may occur with freezing, laser therapy, or opening up the lesion and scraping the inside. Scraping the lesion can, however, result in scarring. The oral medication cimetidine, or podophyllotoxin cream applied to the skin, may also be used for treatment.Approximately 122 million people globally were affected by molluscum contagiosum as of 2010 (1.8% of the population). It is more common in children between the ages of one and ten years old. The condition has become more common in the United States since 1966. But having an infection is not a reason to keep a child out of school or daycare.

Signs and symptoms
Molluscum contagiosum lesions are flesh-colored, dome-shaped, and pearly in appearance. They are often 1–5 mm in diameter, with a dimpled center. Molluscum lesions are most commonly found on the face, arms, legs, torso, and armpits in children. Adults typically have molluscum lesions in the genital region and this is considered to be a sexually transmitted infection; because of this, if genital lesions are found on a child, sexual abuse should be suspected.  These lesions are generally not painful, but they may itch or become irritated.  Picking or scratching the bumps may lead to a spread of the viral infection responsible for molluscum contagiosum, an additional bacterial infection, and scarring. In some cases, eczema develops around the lesions.Individual molluscum lesions may go away on their own within two months and generally clear completely without treatment or scarring in six to twelve months. Mean durations for an outbreak are variously reported from eight to about 18 months, but durations are reported as widely as six months to five years, lasting longer in immunosuppressed individuals.

Transmission
As the name implies, molluscum contagiosum is extremely contagious. Transmission of the molluscum contagiosum virus can occur many different ways including direct skin contact (e.g., contact sports or sexual activity), contact with an infected surface (fomite), or autoinoculation (self-infection) by scratching or picking molluscum lesions and then touching other parts of the skin not previously affected by the virus. Children are particularly susceptible to autoinoculation and may have widespread clusters of lesions.The viral infection is limited to a localized area on the topmost layer of the superficial layer of the skin.  Once the virus-containing head of the lesion has been destroyed, the infection is gone. The central waxy core contains the virus.

Diagnosis
Diagnosis is made on the appearance; the virus cannot routinely be cultured. The diagnosis can be confirmed by excisional biopsy.Histologically, molluscum contagiosum is characterized by molluscum bodies (also known as Henderson-Patersen bodies) in the epidermis, above the stratum basale, which consist of cells with abundant large granular eosinophilic cytoplasmic inclusion bodies (accumulated virions) and a small nucleus that has been pushed to the periphery.

Management
Because molluscum contagiosum usually resolves without treatment and treatment options can cause discomfort to children, initial recommendations are often to simply wait for the lesions to resolve on their own. Of the treatments available, a meta-analysis of randomized controlled trials suggested that there is no difference between treatments in short term improvement, and no single treatment is significantly better than natural resolution of the condition.Bumps located in the genital area may be treated in an effort to prevent them from spreading. When treatment has resulted in the elimination of all bumps, the infection has been effectively cured and will not reappear unless the person is reinfected.

Medications
For mild cases, over-the-counter wart medicines, such as salicylic acid may shorten infection duration. Daily topical application of tretinoin cream may also trigger resolution.Studies have found cantharidin to be an effective and safe treatment for removing molluscum contagiosum. This medication is usually well tolerated though mild side effects such as pain or blistering are common.
There is no high-quality evidence for cimetidine. However, oral cimetidine has been used as an alternative treatment for the pediatric population as it is generally well tolerated and less invasive.

Imiquimod
Imiquimod is a form of immunotherapy initially proposed as a treatment for molluscum based on promising results in small case series and clinical trials. However, two large randomized controlled trials, specifically requested by the U.S. Food and Drug Administration under the Best Pharmaceuticals for Children Act both demonstrated that imiquimod cream applied three times per week was no more effective than placebo cream for treating molluscum after 18 weeks of treatment in a total of 702 children aged 2–12 years. In 2007, results from those trials—which remain unpublished—were incorporated into FDA-approved prescribing information for imiquimod, which states: "Limitations of Use: Efficacy was not demonstrated for molluscum contagiosum in children aged 2–12." In 2007, the FDA also updated imiquimods label concerning safety issues raised in the two large trials and an FDA-requested pharmacokinetic study (the latter of which was published). The updated safety label reads as follows:

Potential adverse effects of imiquimod use: "Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in Aldara-treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% Aldara vs. 3% vehicle) and conjunctivitis (3% Aldara vs. 2% vehicle) </s>