<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 Epithelioid hemangioendothelioma and can you explain it in depth? [/INST] Epithelioid hemangioendothelioma (eHAE) is a rare tumor, first characterized by Sharon Weiss and Franz Enzinger in 1982 that both clinically and histologically is intermediate between angiosarcoma and hemangioma. However, a distinct, disease-defining genetic alteration recently described for EHE indicates that it is an entirely separate entity from both angiosarcoma and hemangioma.
EHE is a soft tissue sarcoma and is generally considered a vascular cancer insofar as the ‘lesional’ cells have surface markers typical of endothelial cells (cells lining the interior of blood vessels). EHE was originally described as occurring most commonly in the veins of the extremities (arms and legs) and two organs, the liver and lungs. It has since been described in organs throughout the body. In addition to liver and lungs, bones and skin have been the most frequent organs.
Before the initial description of Weiss, the tumor had been reported under a variety of other names, including histiocytoid hemangioendothelioma, intravascular bronchoalveolar tumor (in the lung), and sclerosing cholangiocarcinoma. In the lung and liver, common sites of metastatic tumor, it was most likely to be confused with carcinoma a far more common type of tumor.
EHE typically occurs in the 20 – 40 age range although the overall age range involved is much broader and a modest predilection for females over males. It often has an indolent course, and many affected people have survived for decades with multi-organ disease.[1]:601 The extent and number of organs involved apparently has little effect on longevity.

Genetics
The cytogenetics of EHE gave some of the first clues of an underlying genetic alteration. A balanced, reciprocal translocation t(1;3)(p36.3;q25) in EHE tumor cells was first described by Mendlick et al. in 2001 (Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara G, Rosenthal H, Bridge JA (2001). "Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma". Am. J. Surg. Pathol. 25 (5): 684–7. doi:10.1097/00000478-200105000-00019. PMID 11342784.{{cite journal}}:  CS1 maint: multiple names: authors list (link)). This led to the landmark paper by Tanas et al. in 2011(Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP (2011). "Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma". Sci Transl Med. 3 (98): 98ra82. doi:10.1126/scitranslmed.3002409. PMID 21885404.{{cite journal}}:  CS1 maint: multiple names: authors list (link)) describing the specific genes involved in the translocation associated with the most common forms of EHE. This alteration results in the fusion of genes coding for two transcription co-activators (transcriptional regulators): TAZ (transcriptional co-activator with PDZ-binding motif) also known as WWTR1 (WW domain-containing transcription regulator protein 1) and CAMTA1 (calmodulin-binding transcription activator 1). The names in parenthesis are not relevant to casual (or even science) readers but are included to help distinguish them from other genes. For instance, another gene with an entirely different function, Tafazzin, is unrelated to EHE but confusingly, also referred to as TAZ. In any case, the EHE translocation results in an abnormal ‘fusion gene’ that expresses an abnormal mRNA resulting in synthesis of a fusion protein variant of TAZ that is always turned on. This form of TAZ always resides in the nucleus and therefore is constitutively active. It binds and turns on a very important member of the TEAD family of transcription factors and this causes cells to proliferate. It is this production of the TAZ-TEAD transcriptome that causes the affected endothelial cells to grow into tumors. In normal cells, TAZ is considered a major negative transducer of the Hippo pathway, a signaling system that regulates organ size by causing cells to stop growing when they touch each other (contact inhibition). Many upstream inputs regulate the Hippo signal which normally functions to turn off or de-activate TAZ by keeping it in the cytoplasm and out of the nucleus. In EHE cells, the abnormal fusion TAZ is ‘immune’ to this input and just stays in the nucleus, and continuing to stimulate cell growth.
Note that about 10% of EHE patients harbor a different translocation. This one similarly results in the constitutive activation of YAP, an orthologue of TAZ (i.e., a gene that has sequence and function that are very similar to TAZ). This also results in persistent, unregulated growth of the affected cells and therefore causes EHE-type tumors.

Treatment
•Sirolimus: Also known as rapamycin, this oral medication suppresses the immune system and slows the growth of abnormal lymphatic vessels that form the tumor. This can help shrink EHE tumors and improve symptoms, including pain
•Tyrosine kinase inhibitors: These drugs, designed as targeted therapies for cancers, have shown short-term success with EHE. Examples include sorafenib, sunitinib and pazopanib.
•Vincristine: This chemotherapy drug targets all dividing cells within the body and is therefore used to treat many cancers. It is also used for aggressive benign vascular tumors.
•Interferon: The body produces interferon to combat infections or control inflammation. It has been formulated into a medication that targets blood vessel growth.
•Multi-agent chemotherapy: EHE tumors that grow rapidly, spread to other tissues or do not respond to other medications may require more aggressive drug therapy </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 Acute proliferative glomerulonephritis and can you explain it in depth? [/INST] Acute proliferative glomerulonephritis is a disorder of the small blood vessels of the kidney. It is a common complication of bacterial infections, typically skin infection by Streptococcus bacteria types 12, 4 and 1 (impetigo) but also after streptococcal pharyngitis, for which it is also known as postinfectious glomerulonephritis (PIGN) or poststreptococcal glomerulonephritis (PSGN). It can be a risk factor for future albuminuria. In adults, the signs and symptoms of infection may still be present at the time when the kidney problems develop, and the terms infection-related glomerulonephritis or bacterial infection-related glomerulonephritis are also used. Acute glomerulonephritis resulted in 19,000 deaths in 2013, down from 24,000 deaths in 1990 worldwide.

Signs and symptoms
Among the signs and symptoms of acute proliferative glomerulonephritis are the following:

Hematuria
Oliguria
Edema
Hypertension
Fever (headache, malaise, anorexia, nausea.)

Causes
Acute proliferative glomerulonephritis (post-streptococcal glomerulonephritis) is caused by an infection with streptococcus bacteria, usually three weeks after infection, usually of the pharynx or the skin, given the time required to raise antibodies and complement proteins. The infection causes blood vessels in the kidneys to develop inflammation, this hampers the renal organs ability to filter urine. Acute proliferative glomerulonephritis most commonly occurs in children.

Pathophysiology
The pathophysiology of this disorder is consistent with an immune-complex-mediated mechanism, a type III hypersensitivity reaction. This disorder produces proteins that have different antigenic determinants, which in turn have an affinity for sites in the glomerulus. As soon as binding occurs to the glomerulus, via interaction with properdin, the complement is activated. Complement fixation causes the generation of additional inflammatory mediators.Complement activation is very important in acute proliferative glomerulonephritis </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 Focal dermal hypoplasia and can you explain it in depth? [/INST]  </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 Rubeosis iridis and can you explain it in depth? [/INST] Rubeosis iridis is a medical condition of the iris of the eye in which new abnormal blood vessels (formed by neovascularization) are found on the surface of the iris.

Causes
This condition is often associated with diabetes in advanced proliferative diabetic retinopathy. Other conditions causing rubeosis iridis include central retinal vein occlusion, ocular ischemic syndrome, and chronic retinal detachment.

Pathophysiology
It is usually associated with disease processes in the retina, which involve the retina becoming starved of oxygen (ischaemic).   The ischemic retina releases a variety of factors, the most important of which is vascular endothelial growth factor (VEGF).  These factors stimulate the formation of new blood vessels (angiogenesis).  These new vessels do not have the same characteristics as the blood vessels originally formed in the eye </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 Wernicke–Korsakoff syndrome and can you explain it in depth? [/INST] Wernicke–Korsakoff syndrome (WKS) is the combined presence of Wernicke encephalopathy (WE) and Korsakoff syndrome. Due to the close relationship between these two disorders, people with either are usually diagnosed with WKS as a single syndrome. It mainly causes vision changes, ataxia and impaired memory.The cause of the disorder is thiamine (vitamin B1) deficiency. This can occur due to Wernicke encephalopathy, eating disorders, malnutrition, and alcohol abuse. These disorders may manifest together or separately. WKS is usually secondary to prolonged alcohol abuse.
Wernicke encephalopathy and WKS are most commonly seen in people with an alcohol use disorder. Failure in diagnosis of WE and thus treatment of the disease leads to death in approximately 20% of cases, while 75% are left with permanent brain damage associated with WKS.  Of those affected, 25% require long-term institutionalization in order to receive effective care.

Signs and symptoms
The syndrome is a combined manifestation of two namesake disorders, Wernicke encephalopathy and alcoholic Korsakoff syndrome. It involves an acute Wernicke-encephalopathy phase, followed by the development of a Korsakoff syndrome phase.

Wernicke encephalopathy
WE is characterized by the presence of a triad of symptoms:
Ocular disturbances (ophthalmoplegia)
Changes in mental state (confusion)
Unsteady stance and gait (ataxia)This triad of symptoms results from a deficiency in vitamin B1 which is an essential coenzyme. The aforementioned changes in mental state occur in approximately 82% of patients symptoms of which range from confusion, apathy, inability to concentrate, and a decrease in awareness of the immediate situation they are in. If left untreated, WE can lead to coma or death. In about 29% of patients, ocular disturbances consist of nystagmus and paralysis of the lateral rectus muscles or other muscles in the eye. A smaller percentage of patients experience a decrease in reaction time of the pupils to light stimuli and swelling of the optic disc which may be accompanied by retinal hemorrhage. Finally, the symptoms involving stance and gait occur in about 23% of patients and result from dysfunction in the cerebellum and vestibular system. Other symptoms that have been present in cases of WE are stupor, low blood pressure (hypotension), elevated heart rate (tachycardia), as well as hypothermia, epileptic seizures and a progressive loss of hearing.About 19% of patients have none of the symptoms in the classic triad at first diagnosis of WE; however, usually one or more of the symptoms develops later as the disease progresses.

Korsakoff syndrome
The DSM-V classifies Korsakoff syndrome under Substance/Medication-Induced Major or Mild Neurocognitive Disorders, specifically alcohol-induced amnestic confabulatory. The diagnostic criteria defined as necessary for diagnosis includes prominent amnesia, forgetting quickly, and difficulty learning. Presence of thiamine deficient encephalopathy can occur in conjunction with these symptoms.Despite the assertion that alcoholic Korsakoff syndrome must be caused by the use of alcohol, there have been several cases where it has developed from other instances of thiamine deficiency resulting from gross malnutrition due to conditions such as stomach cancer, anorexia nervosa, and gastrectomy.

Cognitive effects
Several cases have been documented where Wernicke–Korsakoff syndrome has been seen on a large scale. In 1947, 52 cases of WKS were documented in a prisoner of war hospital in Singapore where the prisoners diets included less than 1 mg of thiamine per day. Such cases provide an opportunity to gain an understanding of what effects this syndrome has on cognition. In this particular case, cognitive symptoms included insomnia, anxiety, difficulties in concentration, loss of memory for the immediate past, and gradual degeneration of mental state; consisting of confusion, confabulation, and hallucinations. In other cases of WKS, cognitive effects such as severely disrupted speech, giddiness, and heavy-headedness have been documented. In addition to this, it has been noted that some patients displayed an inability to focus, and the inability of others to catch patients attention.In a study conducted in 2003 by Brand et al. on the cognitive effects of WKS, the researchers used a neuropsychological test battery which included tests of intelligence, speed of information processing, memory, executive function and cognitive estimation. They found that subjects with WKS showed impairments in all aspects of this test battery but most noticeably, on the cognitive estimation tasks. This task required subjects to estimate a physical quality such as size, weight, quantity or time (e.g. What is the average length of a shower?), of a particular item. Patients with WKS performed worse than normal control participants on all of the tasks in this category. The patients found estimations involving time to be the most difficult, whereas quantity was the easiest estimation to make. Additionally, the study included a category for classifying "bizarre" answers, which included any answer that was far outside of the normal range of expected responses. WKS patients did give answers that could fall into such a category and these included answers such as 15s or 1 hour for the estimated length of a shower, or 4 kg or 15 tonnes as the weight of a car.

Memory deficits
As mentioned previously, the amnesic symptoms of WKS include both retrograde and anterograde amnesia. The retrograde deficit has been demonstrated through an inability of WKS patients to recall or recognize information for recent public events. The anterograde memory loss is demonstrated through deficits in tasks that involve encoding and then recalling lists of words and faces, as well as semantic learning tasks. WKS patients have also demonstrated difficulties in perseveration as evidenced by a deficit in performance on the Wisconsin Card Sorting Test. The retrograde amnesia that accompanies WKS can extend as far back as twenty to thirty years, and there is generally a temporal gradient seen, where earlier memories are recalled better than more recent memories. It has been widely accepted that the critical structures that lead to the memory impairment in WKS are the mammillary bodies, and the thalamic regions. Despite the aforementioned memory deficits, non-declarative memory functions appear to be intact in WKS patients. This has been demonstrated through measures that assess perceptual priming.Other studies have shown deficits in recognition memory and stimulus-reward associative functions in patients with WKS. The deficit in stimulus-reward functions was demonstrated by Oscar-Berman and Pulaski who presented patients with reinforcements for certain stimuli but not others, and then required the patients to distinguish the rewarded stimuli from the non-rewarded stimuli. WKS patients displayed significant deficits in this task. The researchers were also successful in displaying a deficit in recognition memory by having patients make a yes/no decision as to whether a stimulus was familiar (previously seen) or novel (not previously seen). The patients in this study also showed a significant deficit in their ability to perform this task.

Confabulation
People with WKS often show confabulation, spontaneous confabulation being seen more frequently than provoked confabulation. Spontaneous confabulations refer to incorrect memories that the patient holds to be true, and may act on, arising spontaneously without any provocation. Provoked confabulations can occur when a patient is cued to give a response, this may occur in test settings. The spontaneous confabulations viewed in WKS are thought to be produced by an impairment in source memory, where they are unable to remember the spatial and contextual information for an event, and thus may use irrelevant or old memory traces to fill in for the information that they cannot access. It has also been suggested that this behaviour may be due to executive dysfunction where they are unable to inhibit incorrect memories or because they are unable to shift their attention away from an incorrect response.

Causes
WKS is usually found in people who have used alcohol chronically. Wernicke–Korsakoff syndrome results from thiamine deficiency. It is generally agreed that Wernicke encephalopathy results from severe acute deficiency of thiamine (vitamin B1), whilst Korsakoffs psychosis is a chronic neurologic sequela of Wernicke encephalopathy. The metabolically active form of thiamine is thiamine pyrophosphate, which plays a major role as a cofactor or coenzyme in glucose metabolism. The enzymes that are dependent on thiamine pyrophosphate are associated with the citric acid cycle (also known as the Krebs cycle), and catalyze the oxidation of pyruvate, α-ketoglutarate and branched chain amino acids. Thus, anything that encourages glucose metabolism will exacerbate an existing clinical or sub-clinical thiamine deficiency.As stated above, Wernicke–Korsakoff syndrome in the United States is usually found in malnourished chronic alcoholics, though it is also found in patients who undergo prolonged intravenous (IV) therapy without vitamin B1 supplementation, gastric stapling, intensive care unit (ICU) stays, hunger strikes, or people with eating disorders. In some regions, physicians have observed thiamine deficiency brought about by severe malnutrition, particularly in diets consisting mainly of polished rice, which is thiamine-deficient. The resulting nervous system ailment is called beriberi. In individuals with sub-clinical thiamine deficiency, a large dose of glucose (either as sweet food, etc. or glucose infusion) can precipitate the onset of overt encephalopathy.Wernicke–Korsakoff syndrome in people with chronic alcohol use particularly is associated with atrophy/infarction of specific regions of the brain, especially the mammillary bodies. Other regions include the anterior region of the thalamus (accounting for amnesic symptoms), the medial dorsal thalamus, the basal forebrain, the median and dorsal raphe nuclei, and the cerebellum.One as-yet-unreplicated study has associated susceptibility to this syndrome with a hereditary deficiency of transketolase, an enzyme that requires thiamine as a coenzyme.

Post-gastrectomy
The fact that gastrointestinal surgery can lead to the development of WKS was demonstrated in a study that was completed on three patients who recently undergone a gastrectomy. These patients had developed WKS but were not alcoholics and had never suffered from dietary deprivation. WKS developed between 2 and 20 years after the surgery. There were small dietary changes that contributed to the development of WKS but overall the lack of absorption of thiamine from the gastrointestinal tract was the cause. Therefore, it must be ensured that patients who have undergone gastrectomy have a proper education on dietary habits, and carefully monitor their thiamine intake. Additionally, an early diagnosis of WKS, should it develop, is very important.

Alcohol–thiamine interactions
Strong evidence suggests that ethanol interferes directly with thiamine uptake in the gastrointestinal tract. Ethanol also disrupts thiamine storage in the liver and the transformation of thiamine into its active form. The role of alcohol consumption in the development of WKS has been experimentally confirmed through studies in which rats were subjected to alcohol exposure and lower levels of thiamine through a low-thiamine diet. In particular, studies have demonstrated that clinical signs of the neurological problems that result from thiamine deficiency develop faster in rats that have received alcohol and were also deficient in thiamine than rats who did not receive alcohol. In another study, it was found that rats that were chronically fed alcohol had significantly lower liver thiamine stores than control rats. This provides an explanation for why alcoholics with liver cirrhosis have a higher incidence of both thiamine deficiency and WKS.

Pathophysiology
The vitamin thiamine also referred to as Vitamin B1, is required by three different enzymes to allow for conversion of ingested nutrients into energy. Thiamine can not be produced in the body and must be obtained through diet and supplementation. The duodenum is responsible for absorbing thiamine.  The liver can store thiamine for 18 days. Prolonged and frequent consumption of alcohol causes a decreased ability to absorb thiamine in the duodenum. Thiamine deficiency is also related to malnutrition from poor diet, impaired use of thiamine by the cells and impaired storage in the liver. Without thiamine the Krebs Cycle enzymes pyruvate dehydrogenase complex (PDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) are impaired. The impaired functioning of the Krebs Cycle results in inadequate production of adenosine triphosphate (ATP) or energy for the cells functioning. Energy is required by the brain for proper functioning and use of its neurotransmitters. Injury to the brain occurs when neurons that require high amounts of energy from thiamine dependent enzymes are not supplied with enough energy and die.Brain atrophy associated with WKS occurs in the following regions of the brain:

the mammillary bodies,
the thalamus,
the periaqueductal grey,
the walls of the 3rd ventricle,
the floor of the 4th ventricle,
the cerebellum, and
the frontal lobe.In addition to the damage seen in these areas there have been reports of damage to cortex, although it was noted that this may be due to the direct toxic effects of alcohol as opposed to thiamine deficiency that has been attributed as the underlying cause of Wernicke-Korsakoff Syndrome.The amnesia that is associated with this syndrome is a result of the atrophy in the structures of the diencephalon (the thalamus, hypothalamus and mammillary bodies), and is similar to amnesia that is presented as a result of other cases of damage to the medial temporal lobe. It has been argued that the memory impairments can occur as a result of damage along any part of the mammillo-thalamic tract, which explains how WKS can develop in patients with damage exclusively to either the thalamus or the mammillary bodies.

Diagnosis
Diagnosis of Wernicke–Korsakoff syndrome is by clinical impression and can sometimes be confirmed by a formal neuropsychological assessment. Wernicke encephalopathy typically presents with ataxia and nystagmus, and Korsakoffs psychosis with anterograde and retrograde amnesia and confabulation upon relevant lines of questioning.Frequently, secondary to thiamine deficiency and subsequent cytotoxic edema in Wernicke encephalopathy, patients will have marked degeneration of the mammillary bodies. Thiamine (vitamin B1) is an essential coenzyme in carbohydrate metabolism and is also a regulator of osmotic gradient.  Its deficiency may cause swelling of the intracellular space and local disruption of the blood-brain barrier.  Brain tissue is very sensitive to changes in electrolytes and pressure and edema can be cytotoxic.  In Wernicke this occurs specifically in the mammillary bodies, medial thalami, tectal plate, and periaqueductal areas.  People with the condition may also exhibit a dislike for sunlight and so may wish to stay indoors with the lights off. The mechanism of this degeneration is unknown, but it supports the current neurological theory that the mammillary bodies play a role in various "memory circuits" within the brain. An example of a memory circuit is the Papez circuit.

Prevention
As described, Korsakoff syndrome usually follows or accompanies Wernicke encephalopathy. If treated quickly, it may be possible to prevent the development of WKS with thiamine treatments. This treatment is not guaranteed to be effective and the thiamine needs to be administered adequately in both dose and duration. A study on Wernicke–Korsakoff syndrome showed that with consistent thiamine treatment there were noticeable improvements in mental status after only 2–3 weeks of therapy. Thus, there is hope that with treatment Wernicke encephalopathy will not necessarily progress to WKS.In order to reduce the risk of developing WKS it is important to limit the intake of alcohol in order to ensure that proper nutrition needs are met. A healthy diet is imperative for proper nutrition which, in combination with thiamine supplements, may reduce the chance of developing WKS. This prevention method may specifically help heavy drinkers who refuse to or are unable to quit.A number of proposals have been put forth to fortify alcoholic beverages with thiamine to reduce the incidence of WKS among those heavily abusing alcohol. To date, no such proposals have been enacted.Daily recommendations of thiamine requirements are 0.66 mg per 8,400 kilojoules (2,000 kilocalories) of food energy intake – approximately equivalent to 1.2 mg for men and 1.1 mg for women.

Treatment
The onset of Wernicke encephalopathy is considered a medical emergency, and thus thiamine administration should be initiated immediately when the disease is suspected. Prompt administration of thiamine to patients with Wernicke encephalopathy can prevent the disorder from developing into Wernicke–Korsakoff syndrome, or reduce its severity. Treatment can also reduce the progression of the deficits caused by WKS, but will not completely reverse existing deficits. WKS will continue to be present, at least partially, in 80% of patients. Patients with WE should be given a minimum dose of 500 mg of thiamine hydrochloride, delivered by infusion over a 30-minute period for two to three days. If no response is seen then treatment should be discontinued but for those patients that do respond, treatment should be continued with a 250 mg dose delivered intravenously or intramuscularly for three to five days unless the patient stops improving. Such prompt administration of thiamine may be a life-saving measure. Banana bags, a bag of intravenous fluids containing vitamins and minerals, is one means of treatment.

Epidemiology
WKS occurs more frequently in men than women and has the highest prevalence in the ages 55–65.  Approximately 71% are unmarried.Internationally, the prevalence rates of WKS are relatively standard, being anywhere between zero and two percent. Despite this, specific sub-populations seem to have higher prevalence rates including people who are homeless, older individuals (especially those living alone or in isolation), and psychiatric inpatients. Additionally, studies show that prevalence is not connected to alcohol consumption per capita </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 Pneumothorax and can you explain it in depth? [/INST] A pneumothorax is an abnormal collection of air in the pleural space between the lung and the chest wall. Symptoms typically include sudden onset of sharp, one-sided chest pain and shortness of breath. In a minority of cases, a one-way valve is formed by an area of damaged tissue, and the amount of air in the space between chest wall and lungs increases; this is called a tension pneumothorax. This can cause a steadily worsening oxygen shortage and low blood pressure. This leads to a type of shock called obstructive shock, which can be fatal unless reversed. Very rarely, both lungs may be affected by a pneumothorax. It is often called a "collapsed lung", although that term may also refer to atelectasis.A primary spontaneous pneumothorax is one that occurs without an apparent cause and in the absence of significant lung disease. A secondary spontaneous pneumothorax occurs in the presence of existing lung disease. Smoking increases the risk of primary spontaneous pneumothorax, while the main underlying causes for secondary pneumothorax are COPD, asthma, and tuberculosis. A traumatic pneumothorax can develop from physical trauma to the chest (including a blast injury) or from a complication of a healthcare intervention.Diagnosis of a pneumothorax by physical examination alone can be difficult (particularly in smaller pneumothoraces). A chest X-ray, computed tomography (CT) scan, or ultrasound is usually used to confirm its presence. Other conditions that can result in similar symptoms include a hemothorax (buildup of blood in the pleural space), pulmonary embolism, and heart attack. A large bulla may look similar on a chest X-ray.A small spontaneous pneumothorax will typically resolve without treatment and requires only monitoring. This approach may be most appropriate in people who have no underlying lung disease. In a larger pneumothorax, or if there is shortness of breath, the air may be removed with a syringe or a chest tube connected to a one-way valve system. Occasionally, surgery may be required if tube drainage is unsuccessful, or as a preventive measure, if there have been repeated episodes. The surgical treatments usually involve pleurodesis (in which the layers of pleura are induced to stick together) or pleurectomy (the surgical removal of pleural membranes). About 17–23 cases of pneumothorax occur per 100,000 people per year. They are more common in men than women.

Signs and symptoms
A primary spontaneous pneumothorax (PSP) tends to occur in a young adult without underlying lung problems, and usually causes limited symptoms. Chest pain and sometimes mild breathlessness are the usual predominant presenting features. People who are affected by a PSP are often unaware of the potential danger and may wait several days before seeking medical attention. PSPs more commonly occur during changes in atmospheric pressure, explaining to some extent why episodes of pneumothorax may happen in clusters. It is rare for a PSP to cause a tension pneumothorax.Secondary spontaneous pneumothoraces (SSPs), by definition, occur in individuals with significant underlying lung disease. Symptoms in SSPs tend to be more severe than in PSPs, as the unaffected lungs are generally unable to replace the loss of function in the affected lungs. Hypoxemia (decreased blood-oxygen levels) is usually present and may be observed as cyanosis (blue discoloration of the lips and skin). Hypercapnia (accumulation of carbon dioxide in the blood) is sometimes encountered; this may cause confusion and – if very severe – may result in comas. The sudden onset of breathlessness in someone with chronic obstructive pulmonary disease (COPD), cystic fibrosis, or other serious lung diseases should therefore prompt investigations to identify the possibility of a pneumothorax.Traumatic pneumothorax most commonly occurs when the chest wall is pierced, such as when a stab wound or gunshot wound allows air to enter the pleural space, or because some other mechanical injury to the lung compromises the integrity of the involved structures. Traumatic pneumothoraces have been found to occur in up to half of all cases of chest trauma, with only rib fractures being more common in this group. The pneumothorax can be occult (not readily apparent) in half of these cases, but may enlarge – particularly if mechanical ventilation is required. They are also encountered in people already receiving mechanical ventilation for some other reason.Upon physical examination, breath sounds (heard with a stethoscope) may be diminished on the affected side, partly because air in the pleural space dampens the transmission of sound. Measures of the conduction of vocal vibrations to the surface of the chest may be altered. Percussion of the chest may be perceived as hyperresonant (like a booming drum), and vocal resonance and tactile fremitus can both be noticeably decreased. Importantly, the volume of the pneumothorax may not be well correlated with the intensity of the symptoms experienced by the victim, and physical signs may not be apparent if the pneumothorax is relatively small.

Tension pneumothorax
Tension pneumothorax is generally considered to be present when a pneumothorax (primary spontaneous, secondary spontaneous, or traumatic) leads to significant impairment of respiration and/or blood circulation. This causes a type of circulatory shock, called obstructive shock. Tension pneumothorax tends to occur in clinical situations such as ventilation, resuscitation, trauma, or in people with lung disease. It is a medical emergency and may require immediate treatment without further investigations (see Treatment section).The most common findings in people with tension pneumothorax are chest pain and respiratory distress, often with an increased heart rate (tachycardia) and rapid breathing (tachypnea) in the initial stages. Other findings may include quieter breath sounds on one side of the chest, low oxygen levels and blood pressure, and displacement of the trachea away from the affected side. Rarely, there may be cyanosis (bluish discoloration of the skin due to low oxygen levels), altered level of consciousness, a hyperresonant percussion note on examination of the affected side with reduced expansion and decreased movement, pain in the epigastrium (upper abdomen), displacement of the apex beat (heart impulse), and resonant sound when tapping the sternum.Tension pneumothorax may also occur in someone who is receiving mechanical ventilation, in which case it may be difficult to spot as the person is typically receiving sedation; it is often noted because of a sudden deterioration in condition. Recent studies have shown that the development of tension features may not always be as rapid as previously thought. Deviation of the trachea to one side and the presence of raised jugular venous pressure (distended neck veins) are not reliable as clinical signs.

Cause
Primary spontaneous
Spontaneous pneumothoraces are divided into two types: primary, which occurs in the absence of known lung disease, and secondary, which occurs in someone with underlying lung disease. The cause of primary spontaneous pneumothorax is unknown, but established risk factors include being of the male sex, smoking, and a family history of pneumothorax. Smoking either cannabis or tobacco increases the risk. The various suspected underlying mechanisms are discussed below.

Secondary spontaneous
Secondary spontaneous pneumothorax occurs in the setting of a variety of lung diseases. The most common is chronic obstructive pulmonary disease (COPD), which accounts for approximately 70% of cases. Known lung diseases that may significantly increase the risk for pneumothorax are

In children, additional causes include measles, echinococcosis, inhalation of a foreign body, and certain congenital malformations (congenital pulmonary airway malformation and congenital lobar emphysema).11.5% of people with a spontaneous pneumothorax have a family member who has previously experienced a pneumothorax. The hereditary conditions – Marfan syndrome, homocystinuria, Ehlers–Danlos syndromes, alpha 1-antitrypsin deficiency (which leads to emphysema), and Birt–Hogg–Dubé syndrome – have all been linked to familial pneumothorax. Generally, these conditions cause other signs and symptoms as well, and pneumothorax is not usually the primary finding. Birt–Hogg–Dubé syndrome is caused by mutations in the FLCN gene (located at chromosome 17p11.2), which encodes a protein named folliculin. FLCN mutations and lung lesions have also been identified in familial cases of pneumothorax where other features of Birt–Hogg–Dubé syndrome are absent. In addition to the genetic associations, the HLA haplotype A2B40 is also a genetic predisposition to PSP.

Traumatic
A traumatic pneumothorax may result from either blunt trauma or penetrating injury to the chest wall. The most common mechanism is due to the penetration of sharp bony points at a new rib fracture, which damages lung tissue. Traumatic pneumothorax may also be observed in those exposed to blasts, even though there is no apparent injury to the chest.They may be classified as "open" or "closed". In an open pneumothorax, there is a passage from the external environment into the pleural space through the chest wall. When air is drawn into the pleural space through this passageway, it is known as a "sucking chest wound". A closed pneumothorax is when the chest wall remains intact.Medical procedures, such as the insertion of a central venous catheter into one of the chest veins or the taking of biopsy samples from lung tissue, may lead to pneumothorax. The administration of positive pressure ventilation, either mechanical ventilation or non-invasive ventilation, can result in barotrauma (pressure-related injury) leading to a pneumothorax.Divers who breathe from an underwater apparatus are supplied with breathing gas at ambient pressure, which results in their lungs containing gas at higher than atmospheric pressure. Divers breathing compressed air (such as when scuba diving) may develop a pneumothorax as a result of barotrauma from ascending just 1 metre (3 ft) while breath-holding with their lungs fully inflated. An additional problem in these cases is that those with other features of decompression sickness are typically treated in a diving chamber with hyperbaric therapy; this can lead to a small pneumothorax rapidly enlarging and causing features of tension.

Newborn infants
Newborn babies between 3–9 days of birth with low birth weight have a higher risk of pneumothorax.

Mechanism
The thoracic cavity is the space inside the chest that contains the lungs, heart, and numerous major blood vessels. On each side of the cavity, a pleural membrane covers the surface of lung (visceral pleura) and also lines the inside of the chest wall (parietal pleura). Normally, the two layers are separated by a small amount of lubricating serous fluid. The lungs are fully inflated within the cavity because the pressure inside the airways (intrapulmonary pressure) is higher than the pressure inside the pleural space (intrapleural pressure). Despite the low pressure in the pleural space, air does not enter it because there are no natural connections to an air-containing passage, and the pressure of gases in the bloodstream is too low for them to be forced into the pleural space. Therefore, a pneumothorax can only develop if air is allowed to enter, through damage to the chest wall or damage to the lung itself, or occasionally because microorganisms in the pleural space produce gas. Once air enters the pleural cavity, the intrapleural pressure increases resulting in the difference between the intrapulmonary pressure and the intrapleural pressure (defined as the transpulmonary pressure) to equal zero which cause the lungs to deflate in contrast to a normal transpulmonary pressure of ~4 mm Hg.Chest-wall defects are usually evident in cases of injury to the chest wall, such as stab or bullet wounds ("open pneumothorax"). In secondary spontaneous pneumothoraces, vulnerabilities in the lung tissue are caused by a variety of disease processes, particularly by rupturing of bullae (large air-containing lesions) in cases of severe emphysema. Areas of necrosis (tissue death) may precipitate episodes of pneumothorax, although the exact mechanism is unclear. Primary spontaneous pneumothorax (PSP) has for many years been thought to be caused by "blebs" (small air-filled lesions just under the pleural surface), which were presumed to be more common in those classically at risk of pneumothorax (tall males) due to mechanical factors. In PSP, blebs can be found in 77% of cases, compared to 6% in the general population without a history of PSP. As these healthy subjects do not all develop a pneumothorax later, the hypothesis may not be sufficient to explain all episodes; furthermore, pneumothorax may recur even after surgical treatment of blebs. It has therefore been suggested that PSP may also be caused by areas of disruption (porosity) in the pleural layer, which are prone to rupture. Smoking may additionally lead to inflammation and obstruction of small airways, which account for the markedly increased risk of PSPs in smokers. Once air has stopped entering the pleural cavity, it is gradually reabsorbed.Tension pneumothorax occurs when the opening that allows air to enter the pleural space functions as a one-way valve, allowing more air to enter with every breath but none to escape. The body compensates by increasing the respiratory rate and tidal volume (size of each breath), worsening the problem. Unless corrected, hypoxia (decreased oxygen levels) and respiratory arrest eventually follow.

Diagnosis
The symptoms of pneumothorax can be vague and inconclusive, especially in those with a small PSP; confirmation with medical imaging is usually required. In contrast, tension pneumothorax is a medical emergency and may be treated before imaging – especially if there is severe hypoxia, very low blood pressure, or an impaired level of consciousness. In tension pneumothorax, X-rays are sometimes required if there is doubt about the anatomical location of the pneumothorax.

Chest X-ray
A plain chest radiograph, ideally with the X-ray beams being projected from the back (posteroanterior, or "PA"), and during maximal inspiration (holding ones breath), is the most appropriate first investigation. It is not believed that routinely taking images during expiration would confer any benefit. Still, they may be useful in the detection of a pneumothorax when clinical suspicion is high but yet an inspiratory radiograph appears normal. Also, if the PA X-ray does not show a pneumothorax but there is a strong suspicion of one, lateral X-rays (with beams projecting from the side) may be performed, but this is not routine practice.

It is not unusual for the mediastinum (the structure between the lungs that contains the heart, great blood vessels, and large airways) to be shifted away from the affected lung due to the pressure differences. This is not equivalent to a tension pneumothorax, which is determined mainly by the constellation of symptoms, hypoxia, and shock.The size of the pneumothorax (i.e. the volume of air in the pleural space) can be determined with a reasonable degree of accuracy by measuring the distance between the chest wall and the lung. This is relevant to treatment, as smaller pneumothoraces may be managed differently. An air rim of 2 cm means that the pneumothorax occupies about 50% of the hemithorax. British professional guidelines have traditionally stated that the measurement should be performed at the level of the hilum (where blood vessels and airways enter the lung) with 2 cm as the cutoff, while American guidelines state that the measurement should be done at the apex (top) of the lung with 3 cm differentiating between a "small" and a "large" pneumothorax. The latter method may overestimate the size of a pneumothorax if it is located mainly at the apex, which is a common occurrence. The various methods correlate poorly but are the best easily available ways of estimating pneumothorax size. CT scanning (see below) can provide a more accurate determination of the size of the pneumothorax, but its routine use in this setting is not recommended.Not all pneumothoraces are uniform; some only form a pocket of air in a particular place in the chest. Small amounts of fluid may be noted on the chest X-ray (hydropneumothorax); this may be blood (hemopneumothorax). In some cases, the only significant abnormality may be the "deep sulcus sign", in which the normally small space between the chest wall and the diaphragm appears enlarged due to the abnormal presence of fluid.

Computed tomography
A CT scan is not necessary for the diagnosis of pneumothorax, but it can be useful in particular situations. In some lung diseases, especially emphysema, it is possible for abnormal lung areas such as bullae (large air-filled sacs) to have the same appearance as a pneumothorax on chest X-ray, and it may not be safe to apply any treatment before the distinction is made and before the exact location and size of the pneumothorax is determined. In trauma, where it may not be possible to perform an upright film, chest radiography may miss up to a third of pneumothoraces, while CT remains very sensitive.A further use of CT is in the identification of underlying lung lesions. In presumed primary pneumothorax, it may help to identify blebs or cystic lesions (in anticipation of treatment, see below), and in secondary pneumothorax, it can help to identify most of the causes listed above.

Ultrasound
Ultrasound is commonly used in the evaluation of people who have sustained physical trauma, for example with the FAST protocol. Ultrasound may be more sensitive than chest X-rays in the identification of pneumothorax after blunt trauma to the chest. Ultrasound may also provide a rapid diagnosis in other emergency situations, and allow the quantification of the size of the pneumothorax. Several particular features on ultrasonography of the chest can be used to confirm or exclude the diagnosis.

Treatment
The treatment of pneumothorax depends on a number of factors and may vary from discharge with early follow-up to immediate needle decompression or insertion of a chest tube. Treatment is determined by the severity of symptoms and indicators of acute illness, the presence of underlying lung disease, the estimated size of the pneumothorax on X-ray, and – in some instances – on the personal preference of the person involved.In traumatic pneumothorax, chest tubes are usually inserted. If mechanical ventilation is required, the risk of tension pneumothorax is greatly increased and the insertion of a chest tube is mandatory. Any open chest wound should be covered with an airtight seal, as it carries a high risk of leading to tension pneumothorax. Ideally, a dressing called the "Asherman seal" should be utilized, as it appears to be more effective than a standard "three-sided" dressing. The Asherman seal is a specially designed device that adheres to the chest wall and, through a valve-like mechanism, allows air to escape but not to enter the chest.Tension pneumothorax is usually treated with urgent needle decompression. This may be required before transport to the hospital, and can be performed by an emergency medical technician or other trained professional. The needle or cannula is left in place until a chest tube can be inserted. Critical care teams are able to incise the chest to create a larger conduit as performed when placing a chest drain, but without inserting the chest tube. This is called a simple thoracostomy. If tension pneumothorax leads to cardiac arrest, needle decompression or simple thoracostomy is performed as part of resuscitation as it may restore cardiac output.

Conservative
Small spontaneous pneumothoraces do not always require treatment, as they are unlikely to proceed to respiratory failure or tension pneumothorax, and generally resolve spontaneously. This approach is most appropriate if the estimated size of the pneumothorax is small (defined as <50% of the volume of the hemithorax), there is no breathlessness, and there is no underlying lung disease. It may be appropriate to treat a larger PSP conservatively if the symptoms are limited. Admission to hospital is often not required, as long as clear instructions are given to return to hospital if there are worsening symptoms. Further investigations may be performed as an outpatient, at which time X-rays are repeated to confirm improvement, and advice given with regard to preventing recurrence (see below). Estimated rates of resorption are between 1.25% and 2.2% the volume of the cavity per day. This would mean that even a complete pneumothorax would spontaneously resolve over a period of about 6 weeks. There is, however, no high quality evidence comparing conservative to non conservative management.Secondary pneumothoraces are only treated conservatively if the size is very small (1 cm or less air rim) and there are limited symptoms. Admission to the hospital is usually recommended. Oxygen given at a high flow rate may accelerate resorption as much as fourfold.

Aspiration
In a large PSP (>50%), or in a PSP associated with breathlessness, some guidelines recommend that reducing the size by aspiration is equally effective as the insertion of a chest tube. This involves the administration of local anesthetic and inserting a needle connected to a three-way tap; up to 2.5 liters of air (in adults) are removed. If there has been significant reduction in the size of the pneumothorax on subsequent X-ray, the remainder of the treatment can be conservative. This approach has been shown to be effective in over 50% of cases. Compared to tube drainage, first-line aspiration in PSP reduces the number of people requiring hospital admission, without increasing the risk of complications.Aspiration may also be considered in secondary pneumothorax of moderate size (air rim 1–2 cm) without breathlessness, with the difference that ongoing observation in hospital is required even after a successful procedure. American professional guidelines state that all large pneumothoraces – even those due to PSP – should be treated with a chest tube. Moderately sized iatrogenic traumatic pneumothoraces (due to medical procedures) may initially be treated with aspiration.

Chest tube
A chest tube (or intercostal drain) is the most definitive initial treatment of a pneumothorax. These are typically inserted in an area under the axilla (armpit) called the "safe triangle", where damage to internal organs can be avoided; this is delineated by a horizontal line at the level of the nipple and two muscles of the chest wall (latissimus dorsi and pectoralis major). Local anesthetic is applied. Two types of tubes may be used. In spontaneous pneumothorax, small-bore (smaller than 14 F, 4.7 mm diameter) tubes may be inserted by the Seldinger technique, and larger tubes do not have an advantage. In traumatic pneumothorax, larger tubes (28 F, 9.3 mm) are used. When chest tubes are placed due to either blunt or penetrating trauma, antibiotics decrease the risks of infectious complications.Chest tubes are required in PSPs that have not responded to needle aspiration, in large SSPs (>50%), and in cases of tension pneumothorax. They are connected to a one-way valve system that allows air to escape, but not to re-enter, the chest. This may include a bottle with water that functions like a water seal, or a Heimlich valve. They are not normally connected to a negative pressure circuit, as this would result in rapid re-expansion of the lung and a risk of pulmonary edema ("re-expansion pulmonary edema"). The tube is left in place until no air is seen to escape from it for a period of time, and X-rays confirm re-expansion of the lung.If after 2–4 days there is still evidence of an air leak, various options are available. Negative pressure suction (at low pressures of –10 to –20 cmH2O) at a high flow rate may be attempted, particularly in PSP; it is thought that this may accelerate the healing of the leak. Failing this, surgery may be required, especially in SSP.Chest tubes are used first-line when pneumothorax occurs in people with AIDS, usually due to underlying pneumocystis pneumonia (PCP), as this condition is associated with prolonged air leakage. Bilateral pneumothorax (pneumothorax on both sides) is relatively common in people with pneumocystis pneumonia, and surgery is often required.It is possible for a person with a chest tube to be managed in an ambulatory care setting by using a Heimlich valve, although research to demonstrate the equivalence to hospitalization has been of limited quality.

Pleurodesis and surgery
Pleurodesis is a procedure that permanently eliminates the pleural space and attaches the lung to the chest wall. No long-term study (20 years or more) has been performed on its consequences. Good results in the short term are achieved with a thoracotomy (surgical opening of the chest) with identification of any source of air leakage and stapling of blebs followed by pleurectomy (stripping of the pleural lining) of the outer pleural layer and pleural abrasion (scraping of the pleura) of the inner layer. During the healing process, the lung adheres to the chest wall, effectively obliterating the pleural space. Recurrence rates are approximately 1%. Post-thoracotomy pain is relatively common.

A less invasive approach is thoracoscopy, usually in the form of a procedure called video-assisted thoracoscopic surgery (VATS). The results from VATS-based pleural abrasion are slightly worse than those achieved using thoracotomy in the short term, but produce smaller scars in the skin. Compared to open thoracotomy, VATS offers a shorter in-hospital stays, less need for postoperative pain control, and a reduced risk of lung problems after surgery. VATS may also be used to achieve chemical pleurodesis; this involves insufflation of talc, which activates an inflammatory reaction that causes the lung to adhere to the chest wall.If a chest tube is already in place, various agents may be instilled through the tube to achieve chemical pleurodesis, such as talc, tetracycline, minocycline or doxycycline. Results of chemical pleurodesis tend to be worse than when using surgical approaches, but talc pleurodesis has been found to have few negative long-term consequences in younger people.

Aftercare
If pneumothorax occurs in a smoker, this is considered an opportunity to emphasize the markedly increased risk of recurrence in those who continue to smoke, and the many benefits of smoking cessation. It may be advisable for someone to remain off work for up to a week after a spontaneous pneumothorax. If the person normally performs heavy manual labor, several weeks may be required. Those who have undergone pleurodesis may need two to three weeks off work to recover.Air travel is discouraged for up to seven days after complete resolution of a pneumothorax if recurrence does not occur. Underwater diving is considered unsafe after an episode of pneumothorax unless a preventive procedure has been performed. Professional guidelines suggest that pleurectomy be performed on both lungs and that lung function tests and CT scan normalize before diving is resumed. Aircraft pilots may also require assessment for surgery.

Neonatal period
For newborn infants with pneumothorax, different management strategies have been suggested including careful observation, thoracentesis (needle aspiration), or insertion of a chest tube. Needle aspiration may reduce the need for a chest tube, however, the effectiveness and safety of both invasive procedures have not been fully studied.

Prevention
A preventative procedure (thoracotomy or thoracoscopy with pleurodesis) may be recommended after an episode of pneumothorax, with the intention to prevent recurrence. Evidence on the most effective treatment is still conflicting in some areas, and there is variation between treatments available in Europe and the US. Not all episodes of pneumothorax require such interventions; the decision depends largely on estimation of the risk of recurrence. These procedures are often recommended after the occurrence of a second pneumothorax. Surgery may need to be considered if someone has experienced pneumothorax on both sides ("bilateral"), sequential episodes that involve both sides, or if an episode was associated with pregnancy.

Epidemiology
The annual age-adjusted incidence rate (AAIR) of PSP is thought to be three to six times as high in males as in females. Fishman cites AAIRs of 7.4 and 1.2 cases per 100,000 person-years in males and females, respectively. Significantly above-average height is also associated with increased risk of PSP – in people who are at least 76 inches (1.93 meters) tall, the AAIR is about 200 cases per 100,000 person-years. Slim build also seems to increase the risk of PSP.The risk of contracting a first spontaneous pneumothorax is elevated among male and female smokers by factors of approximately 22 and 9, respectively, compared to matched non-smokers of the same sex. Individuals who smoke at higher intensity are at higher risk, with a "greater-than-linear" effect; men who smoke 10 cigarettes per day have an approximate 20-fold increased risk over comparable non-smokers, while smokers consuming 20 cigarettes per day show an estimated 100-fold increase in risk.In secondary spontaneous pneumothorax, the estimated annual AAIR is 6.3 and 2.0 cases per 100,000 person-years for males and females, respectively, with the risk of recurrence depending on the presence and severity of any underlying lung disease. Once a second episode has occurred, there is a high likelihood of subsequent further episodes. The incidence in children has not been well studied, but is estimated to be between 5 and 10 cases per 100,000 person-years.Death from pneumothorax is very uncommon (except in tension pneumothoraces). British statistics show an annual mortality rate of 1.26 and 0.62 deaths per million person-years in men and women, respectively. A significantly increased risk of death is seen in older patients and in those with secondary pneumothoraces.

History
An early description of traumatic pneumothorax secondary to rib fractures appears in Imperial Surgery by Turkish surgeon Şerafeddin Sabuncuoğlu (1385–1468), which also recommends a method of simple aspiration.Pneumothorax was described in 1803 by Jean Marc Gaspard Itard, a student of René Laennec, who provided an extensive description of the clinical picture in 1819. While Itard and Laennec recognized that some cases were not due to tuberculosis (then the most common cause), the concept of spontaneous pneumothorax in the absence of tuberculosis (primary pneumothorax) was reintroduced by the Danish physician Hans Kjærgaard in 1932. In 1941, the surgeons Tyson and Crandall introduced pleural abrasion for the treatment of pneumothorax.Prior to the advent of anti-tuberculous medications, pneumothoraces were intentionally caused by healthcare providers in people with tuberculosis in an effort to collapse a lobe, or entire lung, around a cavitating lesion </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 Subglottic stenosis and can you explain it in depth? [/INST] Subglottic stenosis is a congenital or acquired narrowing of the subglottic airway. It can be congenital, acquired, iatrogenic, or very rarely, idiopathic. It is defined as the narrowing of the portion of the airway that lies between the vocal cords and the lower part of the cricoid cartilage. In a normal infant, the subglottic airway is 4.5-5.5 millimeters wide, while in a premature infant, the normal width is 3.5 millimeters. Subglottic stenosis is defined as a diameter of under 4 millimeters in an infant. Acquired cases are more common than congenital cases due to prolonged intubation being introduced in the 1960s. It is most frequently caused by certain medical procedures or external trauma, although infections and systemic diseases can also cause it.

Signs and symptoms
Symptoms may range from stridor during exercise to complete obstruction of the airway. In idiopathic cases, symptoms may be mistaken for asthma. In congenital cases, symptoms occur soon after birth, and include difficulty breathing, stridor, and air hunger. If the vocal cords are affected, symptoms may include inability to make sound, and an unusual cry.

Causes
Most commonly, acquired cases are caused by trauma or certain medical procedures. The condition is more often caused by external trauma in adults. External injuries occur from vehicular accidents or clothesline injuries. Iatrogenic cases can occur from intubation, tracheostomy, and an endotracheal tube cuff pressure that is too high. 17 hours of intubation in adults and 1 week of intubation in neonates can cause the injury. Infants born prematurely can be intubated for a longer amount of time due to the fact that they have more flexible cartilage and a larynx located high in the airway. 90% of acquired cases in children are due to intubation, due to the ring of cartilage in the upper airway. Less commonly, infections, such as bacterial tracheitis, tuberculosis, histoplasmosis, diphtheria, and laryngeal papillomatosis can cause it. Systemic diseases, such as amyloidosis, granulomatosis with polyangiitis, sarcoidosis, inflammatory bowel disease, scleroderma, relapsing polychondritis, and polyarthritis, can also cause it. Other causes may include aspiration of foreign bodies, burns, and exposure to occupational hazards. Very rarely, the condition may also have no known cause, in which case it is known as idiopathic subglottic stenosis.

Mechanism
High cuff pressure or long-term intubation can cause damage to the tracheal mucosa, causing inflammation, ulceration, and breakdown of cartilage. When the injury heals, scarring occurs, narrowing the airway. Treatment-related risk factors include repeated intubation, the presence of a nasogastric tube, and size of an endotracheal tube. Person-related risk factors include systemic diseases, the likelihood of infection, and inadequate perfusion. Acid reflux may cause narrowing due to scarring resulting from stomach acid damaging the tracheal mucosa. 10-23% of causes result due to narrowing arising from granulomatosis with polyangiitis. In these cases, it is believed that this is more common in people under the age of 20. Around 66% of sarcoidosis cases involve the airway.

Diagnosis
CT scans and MRI (magnetic resonance imaging) can help in diagnosis. X-rays can determine the location and size of the narrowed airway portion. Optical coherence tomography (OCT) can help observe the progression of the injury. Esophageal pH monitoring can help detect any acid reflux, which can worsen the condition. An endoscope can be inserted and used to see the vocal cords, airway, and esophagus. Spirometry is a useful way to measure respiratory function. People affected by subglottic stenosis have a FEV1 of over 10.
Subglottic stenosis is graded according to the Cotton-Myer classification system from one to four based on the severity of the blockage. Grade 1  is up to 50% obstruction, Grade 2 is 50-70% obstruction, Grade 3 is 70-99% obstruction, and Grade 4 is with no visible lumen.

Treatment
The goal of treatment is to relieve any breathing difficulty and to ensure that the airway remains open in the long term. In mild cases, the disease can be treated with endoscopic balloon dilation. In severe cases, open surgery is done. Owing to the risk of complications, tracheostomy is avoided if possible.

Surgery
In severe cases, the condition frequently recurs after dilation, and the main treatment is open surgery. There are three main surgical procedures that are used when treating subglottic stenosis. These include endoscopy, open neck surgery, and tracheotomy </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 Arrhythmogenic cardiomyopathy and can you explain it in depth? [/INST] Arrhythmogenic cardiomyopathy (ACM), arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC), most commonly is an inherited heart disease.ACM is caused by genetic defects of the parts of heart muscle (also called myocardium or cardiac muscle) known as desmosomes, areas on the surface of heart muscle cells which link the cells together. The desmosomes are composed of several proteins, and many of those proteins can have harmful mutations.
ARVC can also develop in intense endurance athletes in the absence of desmosomal abnormalities. Exercise-induced ARVC cause possibly is a result of excessive right ventricular wall stress during high intensity exercise.The disease is a type of non-ischemic cardiomyopathy that primarily involves the right ventricle, though cases of exclusive left ventricular disease have been reported. It is characterized by hypokinetic areas involving the free wall of the ventricle, with fibrofatty replacement of the myocardium, with associated arrhythmias often originating in the right ventricle. The nomenclature ARVD is currently thought to be inappropriate and misleading as ACM does not involve dysplasia of the ventricular wall. Cases of ACM originating from the left ventricle led to the abandonment of the name ARVC.
ACM can be found in association with diffuse palmoplantar keratoderma, and woolly hair, in an autosomal recessive condition called Naxos disease, because this genetic abnormality can also affect the integrity of the superficial layers of the skin most exposed to pressure stress.: 513 ACM is an important cause of ventricular arrhythmias in children and young adults. It is seen predominantly in males, and 30–50% of cases have a familial distribution.

Signs and symptoms
Those affected by arrhythmogenic cardiomyopathy may not have any symptoms at all despite having significant abnormalities in the structure of their hearts. If symptoms do occur, the initial presentation is often due to abnormal heart rhythms (arrhythmias) which in arrhythmogenic cardiomyopathy may take the form of palpitations, or blackouts. Sudden death may be the first presentation of ACM without any preceding symptoms. These symptoms often occur during adolescence and early adulthood, but signs of ACM may rarely be seen in infants.
As ACM progresses, the muscle tissue within the ventricles may dilate and weaken. The right ventricle typically weakens first, leading to fatigue and ankle swelling. In the later stages of the disease in which both ventricles are involved shortness of breath may develop, especially when lying flat.The first clinical signs of ACM are usually during adolescence and early adulthood. However, rarely, signs of ACM have been demonstrated in infants.

Causes
Genetics
ACM is usually inherited in an autosomal dominant pattern, with variable expression. Only 30% to 50% of individuals affected by ACM will test positive to one of the known genetic mutations in chromosomal loci associated with the disease. Novel studies showed that mutations (point mutations) in genes encoding for desmosomal proteins (see intercalated disc) are the main causatives for the development of this disease. Recently it has been shown, that mutations in the desmin DES gene could cause ACM. Desmin is an intermediate filament protein, which is linked to the desmosomes. Different DES mutations cause an abnormal aggregation of desmin and associated proteins. The penetrance is 20–35% in general, but significantly higher in Italy. Seven gene loci have been implicated in ACM. It is unclear whether the pathogenesis varies with the different loci involved. Standard genetic screening test are currently tested and evaluated in different state of the art cardiovascular research centres and hospitals. Types include:

Exercise-induced ARVC
In recent years, several studies have found excessive long-term sports activity to be a cause of exercise-induced arrhythmogenic right ventricular cardiomyopathy (EIARVC). For some athletes ARVC might develop due to high-endurance exercise and it most often develops without an underlying desmosomal abnormalities, possibly only as a result of excessive right ventricular (RV) wall stress during very high volumes of training, which is known to be causing a disproportionate remodeling of RV.In a 2003 study, 46 endurance athletes (mostly cyclists) presented with various symptoms suggestive of arrhythmia of RV origin. 59% of participants testing met criteria for ARVC and another 30% for possible ARVC. And only 1 athlete of the group had a family history of hereditable ARVC.Exercise-induced ARVC and athletes heart has an overlapping features.

Pathogenesis
The pathogenesis of ACM is largely unknown. Apoptosis (programmed cell death) appears to play a large role. It was previously thought that only the right ventricle is involved, but recent cohorts have shown many cases of left ventricular disease and biventricular disease. The disease process starts in the subepicardial region and works its way towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the ventricles). Residual myocardium is confined to the subendocardial region and the trabeculae of the ventricles. These trabeculae may become hypertrophied.
Aneurysmal dilatation is seen in 50% of cases at autopsy. It usually occurs in the diaphragmatic, apical, and infundibular regions (known as the triangle of dysplasia). The left ventricle is involved in 50–67% of individuals. If the left ventricle is involved, it is usually late in the course of disease, and confers a poor prognosis.
There are two pathological patterns seen in ACM, Fatty infiltration and fibro-fatty infiltration.

Fatty infiltration
The first, fatty infiltration, is confined to the right ventricle. This involves a partial or near-complete substitution of myocardium with fatty tissue without wall thinning. It involves predominantly the apical and infundibular regions of the RV. The left ventricle and ventricular septum are usually spared. No inflammatory infiltrates are seen in fatty infiltration. There is evidence of myocyte (myocardial cell) degeneration and death seen in 50% of cases of fatty infiltration.

Fibro-fatty infiltration
The second, fibro-fatty infiltration, involves replacement of myocytes with fibrofatty tissue. A patchy myocarditis is involved in up to 2/3 of cases, with inflammatory infiltrates (mostly T cells) seen on microscopy. Myocardial atrophy is due to injury and apoptosis. This leads to thinning of the RV free wall (to < 3 mm thickness) Myocytes are replaced with fibrofatty tissue. The regions preferentially involved include the RV inflow tract, the RV outflow tract, and the RV apex. However, the LV free wall may be involved in some cases. Involvement of the ventricular septum is rare. The areas involved are prone to aneurysm formation.

The Role of Exercise
Recently, some studies have identified strenuous exercise as a novel risk for accelerated progression of the disease. One retrospective study on 301 patients conclusively demonstrated that the subpopulations participating in strenuous physical activity (professional athletes for example) had an earlier onset of symptoms and earlier mortality compared to other populations.

Ventricular arrhythmias
Ventricular arrhythmias due to ACM typically arise from the diseased right ventricle. The type of arrhythmia ranges from frequent premature ventricular complexes (PVCs) to ventricular tachycardia (VT) to ventricular fibrillation (VF).
While the initiating factor of the ventricular arrhythmias is unclear, it may be due to triggered activity or reentry.
Ventricular arrhythmias are usually exercise-related, suggesting that they are sensitive to catecholamines. The ventricular beats typically have a right axis deviation. Multiple morphologies of ventricular tachycardia may be present in the same individual, suggesting multiple arrhythmogenic foci or pathways.
Right ventricular outflow tract (RVOT) tachycardia is the most common VT seen in individuals with ACM. In this case, the EKG shows a left bundle branch block (LBBB) morphology with an inferior axis.

Diagnosis
The differential diagnosis for the ventricular tachycardia due to ACM include:

Congenital heart disease
Repaired tetralogy of Fallot
Ebsteins anomaly
Uhls anomaly
Atrial septal defect
Partial anomalous venous return
Acquired heart disease
Tricuspid valve disease
Pulmonary hypertension
Right ventricular infarction
Bundle-branch re-entrant tachycardia
Miscellaneous
Pre-excited AV re-entry tachycardia
Idiopathic RVOT tachycardia
SarcoidosisIn order to make the diagnosis of ACM, a number of clinical tests are employed, including the electrocardiogram (EKG), echocardiography, right ventricular angiography, cardiac MRI, and genetic testing.

Electrocardiogram
90% of individuals with ARVD have some EKG abnormality. The most common EKG abnormality seen in ACM is T wave inversion in leads V1 to V3. However, this is a non-specific finding, and may be considered a normal variant in right bundle branch block (RBBB), women, and children under 12 years old.
RBBB itself is seen frequently in individuals with ACM. This may be due to delayed activation of the right ventricle, rather than any intrinsic abnormality in the right bundle branch.

The epsilon wave is found in about 50% of those with ACM. This is described as a terminal notch in the QRS complex. It is due to slowed intraventricular conduction. The epsilon wave may be seen on a surface EKG; however, it is more commonly seen on signal averaged EKGs.
Ventricular ectopy seen on a surface EKG in the setting of ACM is typically of left bundle branch block (LBBB) morphology, with a QRS axis of −90 to +110 degrees. The origin of the ectopic beats is usually from one of the three regions of fatty degeneration (the "triangle of dysplasia"): the RV outflow tract, the RV inflow tract, and the RV apex.
Signal averaged ECG (SAECG) is used to detect late potentials and epsilon waves in individuals with ACM.

Echocardiography
Echocardiography may reveal an enlarged, hypokinetic right ventricle with a paper-thin RV free wall. The dilatation of the RV will cause dilatation of the tricuspid valve annulus, with subsequent tricuspid regurgitation. Paradoxical septal motion may also be present.

MRI
Fatty infiltration of the RV free wall can be visible on cardiac MRI. Fat has increased intensity in T1-weighted images. However, it may be difficult to differentiate intramyocardial fat and the epicardial fat that is commonly seen adjacent to the normal heart. Also, the sub-tricuspid region may be difficult to distinguish from the atrioventricular sulcus, which is rich in fat.
Cardiac MRI can visualize the extreme thinning and akinesis of the RV free wall. However, the normal RV free wall may be about 3 mm thick, making the test less sensitive.

Angiography
Right ventricular angiography is considered the gold standard for the diagnosis of ACM. Findings consistent with ACM are an akinetic or dyskinetic bulging localized to the infundibular, apical, and subtricuspid regions of the RV. The specificity is 90%; however, the test is observer dependent.

Biopsy
Transvenous biopsy of the right ventricle can be highly specific for ACM, but it has low sensitivity. False positives include other conditions with fatty infiltration of the ventricle, such as long-term excessive alcohol use and Duchenne or Becker muscular dystrophy.
False negatives are common, however, because the disease progresses typically from the epicardium to the endocardium (with the biopsy sample coming from the endocardium), and the segmental nature of the disease. Also, due to the paper-thin right ventricular free wall that is common in this disease process, most biopsy samples are taken from the ventricular septum, which is commonly not involved in the disease process.
A biopsy sample that is consistent with ACM would have > 3% fat, >40% fibrous tissue, and <45% myocytes.
A post mortem histological demonstration of full thickness substitution of the RV myocardium by fatty or fibro-fatty tissue is consistent with ACM.

Genetic testing
ACM is an autosomal dominant trait with reduced penetrance. Approximately 40–50% of ACM patients have a mutation identified in one of several genes encoding components of the desmosome, which can help confirm a diagnosis of ACM. Since ACM is an autosomal dominant trait, children of an ACM patient have a 50% chance of inheriting the disease-causing mutation. Whenever a mutation is identified by genetic testing, family-specific genetic testing can be used to differentiate between relatives who are at-risk for the disease and those who are not. ACM genetic testing is clinically available.

Diagnostic criteria
There is no pathognomonic feature of ACM. The diagnosis of ACM is based on a combination of major and minor criteria. To make a diagnosis of ACM requires either 2 major criteria or 1 major and 2 minor criteria or 4 minor criteria.Major criteria

Right ventricular dysfunction
Severe dilatation and reduction of RV ejection fraction with little or no LV impairment
Localized RV aneurysms
Severe segmental dilatation of the RV
Tissue characterization
Fibrofatty replacement of myocardium on endomyocardial biopsy
Electrocardiographical abnormalities
Epsilon waves in V1 – V3
Localized prolongation (>110 ms) of QRS in V1 – V3
Inverted T waves in V1 -V3 in an individual over 12 years old, in the absence of a right bundle branch block (RBBB)
Ventricular tachycardia with a left bundle branch block (LBBB) morphology, with superior axis
Family history
Familial disease confirmed either clinically or on autopsy or surgeryMinor criteria

Right ventricular dysfunction
Mild global RV dilatation and/or reduced ejection fraction with normal LV.
Mild segmental dilatation of the RV
Regional RV hypokinesis
Tissue characterization
Electrocardiographical abnormalities
Late potentials on signal averaged EKG.
Ventricular tachycardia with a left bundle branch block (LBBB) morphology, with inferior or unknown axis
Frequent PVCs (> 500 PVCs / 24 hours)

Management
The goal of management of ACM is to decrease the incidence of sudden cardiac death. This raises a clinical dilemma: How to prophylactically treat the asymptomatic patient who was diagnosed during family screening.
A certain subgroup of individuals with ACM are considered at high risk for sudden cardiac death. Associated characteristics include:

Young age
Competitive sports activity
Malignant familial history
Extensive RV disease with decreased right ventricular ejection fraction.
Left ventricular involvement
Syncope
Episode of ventricular arrhythmiaManagement options include pharmacological, surgical, catheter ablation, and placement of an implantable cardioverter-defibrillator.
Prior to the decision of the treatment option, programmed electrical stimulation in the electrophysiology laboratory may be performed for additional prognostic information. Goals of programmed stimulation include:

Assessment of the diseases arrhythmogenic potential
Evaluate the hemodynamic consequences of sustained VT
Determine whether the VT can be interrupted via antitachycardia pacing (ATP).Regardless of the management option chosen, the individual is typically advised to undergo lifestyle modification, including avoidance of strenuous exercise, cardiac stimulants (i.e.: caffeine, nicotine, pseudoephedrine) and alcohol.
Regarding physical activity and exercise, ARVC patients, as well as gene carriers of pathogenic ARVC-associated desmosomal mutations, should not participate in competitive sports. These patients should be advised to limit their exercise programmes to leisure-time activities and remain under clinical surveillance.

Medications
Pharmacologic management of ACM involves arrhythmia suppression and prevention of thrombus formation.
Sotalol, a beta blocker and a class III antiarrhythmic agent, is the most effective antiarrhythmic agent in ACM. Other antiarrhythmic agents used include amiodarone and conventional beta blockers (i.e.: metoprolol). If antiarrhythmic agents are used, their efficacy should be guided by series ambulatory Holter monitoring, to show a reduction in arrhythmic events.
While angiotensin converting enzyme inhibitors (ACE Inhibitors) are well known for slowing progression in other cardiomyopathies, they have not been proven to be helpful in ACM.
Individuals with decreased RV ejection fraction with dyskinetic portions of the right ventricle may benefit from long term anticoagulation with warfarin to prevent thrombus formation and subsequent pulmonary embolism.

Catheter ablation
Catheter ablation may be used to treat intractable ventricular tachycardia.
It has a 60–90% success rate. Unfortunately, due to the progressive nature of the disease, recurrence is common (60% recurrence rate), with the creation of new arrhythmogenic foci. Indications for catheter ablation include drug-refractory VT and frequent recurrence of VT after ICD placement, causing frequent discharges of the ICD.

Implantable cardioverter-defibrillator
An ICD is the most effective prevention against sudden cardiac death. Due to the prohibitive cost of ICDs, they are not routinely placed in all individuals with ACM.
Indications for ICD placement in the setting of ACM include:

Cardiac arrest due to VT or VF
Symptomatic VT that is not inducible during programmed stimulation
Failed programmed stimulation-guided drug therapy
Severe RV involvement with poor tolerance of VT
Sudden death of immediate family memberSince ICDs are typically placed via a transvenous approach into the right ventricle, there are complications associated with ICD placement and follow-up.
Due to the extreme thinning of the RV free wall, it is possible to perforate the RV during implantation, potentially causing pericardial tamponade. Because of this, every attempt is made at placing the defibrillator lead on the ventricular septum.
After a successful implantation, the progressive nature of the disease may lead to fibro-fatty replacement of the myocardium at the site of lead placement. This may lead to undersensing of the individuals electrical activity (potentially causing inability to sense VT or VF), and inability to pace the ventricle.

Heart transplant
Heart transplant may be performed in ACM. It may be indicated if the arrhythmias associated with the disease are uncontrollable or if there is severe bi-ventricular heart failure that is not manageable with pharmacological therapy.

Family screening
All first degree family members of the affected individual should be screened for ACM. This is used to establish the pattern of inheritance. Screening should begin during the teenage years unless otherwise indicated. Screening tests include:

Echocardiogram
EKG
Signal averaged EKG
Holter monitoring
Cardiac MRI
Exercise stress test

Prognosis
There is a long asymptomatic lead-time in individuals with ACM. While this is a genetically transmitted disease, individuals in their teens may not have any characteristics of ACM on screening tests.
Many individuals have symptoms associated with ventricular tachycardia, such as palpitations, light-headedness, or syncope. Others may have symptoms and signs related to right ventricular failure, such as lower extremity edema, or liver congestion with elevated hepatic enzymes.
ACM is a progressive disease. Over time, the right ventricle becomes more involved, leading to right ventricular failure. The right ventricle will fail before there is left ventricular dysfunction. However, by the time the individual has signs of overt right ventricular failure, there will be histological involvement of the left ventricle. Eventually, the left ventricle will also become involved, leading to bi-ventricular failure </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 Mastocytosis and can you explain it in depth? [/INST] Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called mastocytes) and CD34+ mast cell precursors.People affected by mastocytosis are susceptible to a variety of symptoms, including itching, hives, and anaphylactic shock, caused by the release of histamine and other pro-inflammatory substances from mast cells.

Signs and symptoms
When mast cells undergo degranulation, the substances that are released can cause a number of symptoms that can vary over time and can range in intensity from mild to severe. Because mast cells play a role in allergic reactions, the symptoms of mastocytosis often are similar to the symptoms of an allergic reaction. They may include, but are not limited to
Fatigue
Skin lesions (urticaria pigmentosa), itching, and dermatographic urticaria (skin writing)
"Dariers Sign", a reaction to stroking or scratching of urticaria lesions.
Abdominal discomfort
Nausea and vomiting
Diarrhea
Olfactive intolerance
Ear/nose/throat inflammation
Anaphylaxis (shock from allergic or immune causes)
Episodes of very low blood pressure (including shock) and faintness
Bone or muscle pain
Decreased bone density or increased bone density (osteoporosis or osteosclerosis)
Headache
Depression
Ocular discomfort
Increased stomach acid production causing peptic ulcers (increased stimulation of enterochromaffin cell and direct histamine stimulation on parietal cell)
Malabsorption (due to inactivation of pancreatic enzymes by increased acid)
HepatosplenomegalyThere are few qualitative studies about the effects of mastocytosis on daily life. However, a Danish study from 2018 describes the multidimensional impact of the disease on everyday life.

Pathophysiology
Mast cells are located in connective tissue, including the skin, the linings of the stomach and intestine, and other sites. They play an important role in the immune defence against bacteria and parasites. By releasing chemical "alarms" such as histamine, mast cells attract other key players of the immune defense system to areas of the body where they are needed.Mast cells seem to have other roles as well. Because they gather together around wounds, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by histamine released by mast cells. Researchers also think mast cells may have a role in the growth of blood vessels (angiogenesis). No one with too few or no mast cells has been found, which indicates to some scientists we may not be able to survive with too few mast cells.Mast cells express a cell surface receptor, c-kit (CD117), which is the receptor for stem cell factor (scf). In laboratory studies, scf appears to be important for the proliferation of mast cells. Mutations of the gene coding for the c-kit receptor (mutation KIT(D816V)), leading to constitutive signalling through the receptor is found in >90% of patients with systemic mastocytosis.

Diagnosis
Diagnosis of urticaria pigmentosa (cutaneous mastocytosis, see above) can often be done by seeing the characteristic lesions that are dark brown and fixed. A small skin sample (biopsy) may help confirm the diagnosis.In case of suspicion of systemic disease the level of serum tryptase in the blood can be of help. If the base level of s-tryptase is elevated, this implies that the mastocytosis can be systemic. In cases of suspicion of SM help can also be drawn from analysis of mutation in KIT(D816V) in peripheral blood using sensitive PCR-technologyTo set the diagnosis of systemic mastocytosis, certain criteria must be met. Either one major + one minor criterium or 3 minor criteria has to be fulfilled:

Major criterion
Dense infiltrates of >15 mast cells in the bone marrow or an extracutaneous organ

Minor criteria
Aberrant phenotype on the mast cells (pos. for CD2 and/or CD25)
Aberrant mast cell morphology (spindle-shaped)
Finding of mutation in KIT(D816V)
S-tryptase >20 ng/ml

Other mast cell diseases
Other types of mast cell disease include:

Monoclonal mast cell activation, defined by the World Health Organization definitions 2010, also has increased mast cells but insufficient to be systemic mastocytosis (in World Health Organization Definitions)
Mast cell activation syndrome – has normal number of mast cells, but all the symptoms and in some cases the genetic markers of systemic mastocytosis
Another known but rare mast cell proliferation disease is mast cell sarcoma.

Classification
Mastocytosis can occur in a variety of forms:

Cutaneous mastocytosis (CM)
The most common cutaneous mastocytosis is maculopapular cutaneous mastocytosis, previously named papular urticaria pigmentosa (UP), more common in children, although also seen in adults. Telangiectasia macularis eruptiva perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.[2] MPCM and TMEP can be a part of indolent systemic mastocytosis. This should be considered if patients develop any systemic symptoms
Generalized eruption of cutaneous mastocytosis (adult type) is the most common pattern of mastocytosis presenting to the dermatologist, with the most common lesions being macules, papules, or nodules that are disseminated over most of the body but especially on the upper arms, legs, and trunk
Diffuse cutaneous mastocytosis has diffuse involvement in which the entire integument may be thickened and infiltrated with mast cells to produce a peculiar orange color, giving rise to the term "homme orange."Cutaneous mastocytosis in children usually presents in the first year after birth and in most cases vanishes during adolescence.

Systemic mastocytosis (SM)
Systemic mastocytosis involves the bone marrow in the majority of cases and in some cases other internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs where mast cells do not normally inhabit such as the liver, spleen and lymph nodes, and organs which have normal populations but where numbers are increased. In the bowel, it may manifest as mastocytic enterocolitis. However, normal ranges for mast cell counts in the gastrointestinal tract mucosa are not well established in the literature, and depend upon the exact location (e.g. right versus left colon), gender, and patient populations (such as asymptomatic patients versus patients with chronic diarrhea of unknown etiology).  Quantitative mast cell stains may yield little diagnostic information, and further research studies are warranted to determine whether "mastocytic enterocolitis" truly represents a distinct entity.There are five types of systemic mastocytosis:
Indolent systemic mastocytosis (ISM). The most common SM (>90%)
Smouldering systemic mastocytosis (SSM)
Systemic mastocytosis with associated hematological neoplasm (SM-AHN)
Aggressive systemic mastocytosis (ASM)
Mast cell leukemia (MCL)

Treatment
There is no cure for mastocytosis, but there are a number of medicines to help treat the symptoms:

Anti-mediator therapy
Antihistamines block receptors targeted by histamine released from mast cells. Both H1 and H2 blockers may be helpful, often in combination.
Leukotriene antagonists block receptors targeted by leukotrienes released from mast cells.
Mast cell stabilizers help prevent mast cells from releasing their chemical contents. Cromoglicic acid is the only medicine specifically approved by the FDA for the treatment of mastocytosis. Ketotifen is available in Canada and Europe and more recently in the U.S. It is also available as eyedrops (Zaditor).
Proton-pump inhibitors help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
Epinephrine constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused anaphylaxis.
Salbutamol and other beta-2 agonists open airways that can constrict in the presence of histamine.
Corticosteroids can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.
Drugs to prevent/treat osteoporosis include Calcium-Vitamine D, bisphosphonates and in rare cases inhibitors of RANK-LAntidepressants are an important and often overlooked tool in the treatment of mastocytosis. Depression and other neurological symptoms have been noted in mastocytosis. Some antidepressants, such as doxepin and mirtazapine, are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

Cytoreductive therapy
In cases of advanced systemic mastocytosis or rare cases with indolent systemic mastocytosis with very troublesome symptoms, cytoreductive therapy can be indicated.
ɑ-interferon. Given as subcutaneous injections. Side effects include fatigue and influenza-like symptoms
Cladribine (CdA). Chemotherapy which is given as subcutaneous injections. Side effects include immunodeficiency and infections.
Tyrosine kinase inhibitors (TKI)
Midostaurin. TKI acting on many different tyrosine kinases, approved by FDA and EMA for advanced mastocytosis
Imatinib. Can have effect in rare cases without mutation in KIT(D816V)
Masitinib. Is being tested in trials. Not approved.
Midostaurin - 60% respond.
Avapritinib in trials; currently being tested but showing promise in reduction of tryptase levels.Allogeneic stem cell transplantation has been used in rare cases with aggressive systemic mastocytosis in patients deemed to be fit for the procedure.

Other
Treatment with ultraviolet light can relieve skin symptoms, but may increase the risk of skin cancer.

Prognosis
Patients with indolent systemic mastocytosis have a normal life expectancy. The prognosis for patients with advanced systemic mastocytosis differs depending on type of disease with MCL being the most serious form with short survival.

Epidemiology
The true incidence and prevalence of mastocytosis is unknown, but mastocytosis generally has been considered to be an "orphan disease"; orphan diseases affect 200,000 or fewer people in the United States. Mastocytosis, however, often may be misdiagnosed, as it typically occurs secondary to another condition, and thus may occur more frequently than assumed.[

Research
National Institute of Allergy and Infectious Diseases scientists have been studying and treating patients with mastocytosis for several years at the National Institutes of Health (NIH) Clinical Center.Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production </s>