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home:diseases:sarcoidosis [05.23.2019] – [Evidence of infectious cause] sallieqhome:diseases:sarcoidosis [09.14.2022] (current) – external edit 127.0.0.1
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 ====== Sarcoidosis ====== ====== Sarcoidosis ======
  
-Sarcoidosis or sarc is a multisystem disorder characterized by granuloma, ball-like encapsulations of phagocytic cells driven by microbes. Sarcoidosis is often called the "great masquerader" as there may be several atypical or nonspecific presentations – including not just the lungs but the brain, lymph glands, spleen, liver, skin and heart among others.(({{pubmed>long:15103279}})) +Sarcoidosis or sarc is a multisystem disorder characterized by granuloma, ball-like encapsulations of phagocytic cells driven by microbes. Sarcoidosis is often called the "great masquerader" as there may be several atypical or nonspecific presentations – including not just the lungs but the brain, lymph glands, spleen, liver, skin and heart among others.(({{pmid>long:15103279}})) 
  
-An infectious etiology of sarcoidosis has long been suspected. Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.(({{pubmed>long:17560303}}))+An infectious etiology of sarcoidosis has long been suspected. Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.(({{pmid>long:17560303}}))
  
-Sarcoidosis was the first disease treated by the Marshall Protocol.(({{pubmed>long:15246025}})) The FDA's Office of Orphan Products Development [[home:publications:applications_orphan_status|has conferred]] orphan drug status on several MP medications.+Sarcoidosis was the first disease treated by the Marshall Protocol.(({{pmid>long:15246025}})) The FDA's Office of Orphan Products Development [[home:publications:applications_orphan_status|has conferred]] orphan drug status on several MP medications.
  
  
 ===== Evidence of infectious cause===== ===== Evidence of infectious cause=====
  
-Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.(({{pubmed>long:17560303}}))+Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.(({{pmid>long:17560303}}))
  
 [[https://sarcoidosisnews.com/2017/02/15/study-confirms-bacteria-that-causes-tuberculosis-also-involved-in-sarcoidosis/|Tuberculosis-causing Bacteria Linked to Sarcoidosis, Study Confirms [[https://sarcoidosisnews.com/2017/02/15/study-confirms-bacteria-that-causes-tuberculosis-also-involved-in-sarcoidosis/|Tuberculosis-causing Bacteria Linked to Sarcoidosis, Study Confirms
-Link]]  (({{pubmed>long:28159576}}))+Link]]  (({{pmid>long:28159576}}))
 ==== History of conflicting results ==== ==== History of conflicting results ====
  
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-An infectious etiology of sarcoidosis has long been suspected and investigated, sometimes with inconsistent results. For example, the histologic similarity of sarcoidosis to //Mycobacterium tuberculosis// (see discussion of [[#granuloma|granuloma]] below) infection led to the "extensive" evaluation of this organism as a possible etiologic factor.(({{pubmed>long:7617973}})) The findings have been mixed with some investigators finding evidence of //M. tuberculosis//(({{pubmed>long:1373786}})) (({{pubmed>long:1349051}})) and some failing to confirm this work.(({{pubmed>long:1586060}})) (({{pubmed>long:8542146}})) (({{pubmed>long:9310026}})) (({{pubmed>long:10193375}})) (({{pubmed>long:10408488}})) In their 1996 review of mycobacteria's possible role in sarcoidosis, Zumla and James list 15 studies evaluating a mycobacterial cause of sarcoidosis, only three of which were negative.(({{pubmed>long:17560303}})) +An infectious etiology of sarcoidosis has long been suspected and investigated, sometimes with inconsistent results. For example, the histologic similarity of sarcoidosis to //Mycobacterium tuberculosis// (see discussion of [[#granuloma|granuloma]] below) infection led to the "extensive" evaluation of this organism as a possible etiologic factor.(({{pmid>long:7617973}})) The findings have been mixed with some investigators finding evidence of //M. tuberculosis//(({{pmid>long:1373786}})) (({{pmid>long:1349051}})) and some failing to confirm this work.(({{pmid>long:1586060}})) (({{pmid>long:8542146}})) (({{pmid>long:9310026}})) (({{pmid>long:10193375}})) (({{pmid>long:10408488}})) In their 1996 review of mycobacteria's possible role in sarcoidosis, Zumla and James list 15 studies evaluating a mycobacterial cause of sarcoidosis, only three of which were negative.(({{pmid>long:17560303}})) 
  
-There appear to several reasons why researchers have failed to definitively link microbes to sarcoidosis in all cases. For one, even today researchers adhere to the antiquated model of disease set forth by Koch's postulates namely that a pathogen must be: found in all cases of the disease examined, prepared and maintained in a pure culture, capable of producing the original infection, even after several generations in culture, and retrievable from an inoculated animal and cultured again. For all their lingering influence, Koch's postulates never anticipated the era of the human metagenome in which thousands of difficult or impossible-to-culture species of bacteria – rather than just one – contribute to a single disease state. Indeed, the notion of a single causative agent is not in keeping with the worldwide distribution of sarcoidosis.(({{pubmed>long:17560303}})) Koch's century-old ideas have held science back from understanding how chronic disease occurs because they make no provision for these facts.+There appear to several reasons why researchers have failed to definitively link microbes to sarcoidosis in all cases. For one, even today researchers adhere to the antiquated model of disease set forth by Koch's postulates namely that a pathogen must be: found in all cases of the disease examined, prepared and maintained in a pure culture, capable of producing the original infection, even after several generations in culture, and retrievable from an inoculated animal and cultured again. For all their lingering influence, Koch's postulates never anticipated the era of the human metagenome in which thousands of difficult or impossible-to-culture species of bacteria – rather than just one – contribute to a single disease state. Indeed, the notion of a single causative agent is not in keeping with the worldwide distribution of sarcoidosis.(({{pmid>long:17560303}})) Koch's century-old ideas have held science back from understanding how chronic disease occurs because they make no provision for these facts.
  
  
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 The following types and species of bacteria have been found in patients with sarcoidosis, especially the granuloma: The following types and species of bacteria have been found in patients with sarcoidosis, especially the granuloma:
-  * L-form/cell wall deficient bacteria (({{pubmed>long:8711683}}))  (({{pubmed>long:6184266}}))  (({{pubmed>long:1067009}}))  +  * L-form/cell wall deficient bacteria (({{pmid>long:8711683}}))  (({{pmid>long:6184266}}))  (({{pmid>long:1067009}}))  
-  * mycoplasma (({{pubmed>long:8865408}})) +  * mycoplasma (({{pmid>long:8865408}})) 
-  * //Borrelia burgdorferi// (({{pubmed>long:1582344}})) (({{pubmed>long:8391908}})) (({{pubmed>long:9596840}})) (({{pubmed>long:9561361}}))  +  * //Borrelia burgdorferi// (({{pmid>long:1582344}})) (({{pmid>long:8391908}})) (({{pmid>long:9596840}})) (({{pmid>long:9561361}}))  
-  * //Mycobacterium//, in general (({{pubmed>long:11773116}}))  (({{pubmed>long:10472755}})); in one study (({{pubmed>long:12453366}})) //Mycobacterium// was found in the majority of sarcoidosis patients +  * //Mycobacterium//, in general (({{pmid>long:11773116}}))  (({{pmid>long:10472755}})); in one study (({{pmid>long:12453366}})) //Mycobacterium// was found in the majority of sarcoidosis patients 
-  * //Mycobacterium avium// (({{pubmed>long:8862592}})) +  * //Mycobacterium avium// (({{pmid>long:8862592}})) 
-  * //Mycobacterium tuberculosis//(({{pubmed>long:17088357}}))  (({{pubmed>long:16926652}})) (({{pubmed>long:16113515}})) (({{pubmed>long:10834540}}))  (({{pubmed>long:10418818}}))  +  * //Mycobacterium tuberculosis//(({{pmid>long:17088357}}))  (({{pmid>long:16926652}})) (({{pmid>long:16113515}})) (({{pmid>long:10834540}}))  (({{pmid>long:10418818}}))  
-  * //Propionibacterium acnes//(({{pubmed>long:18156583}})) (({{pubmed>long:15948792}}))  +  * //Propionibacterium acnes//(({{pmid>long:18156583}})) (({{pmid>long:15948792}}))  
-  * //Rickettsia helvetica//(({{pubmed>long:11930323}}))+  * //Rickettsia helvetica//(({{pmid>long:11930323}}))
  
-Mycobacterial and propionibacterial DNA have been found in the lymph nodes of Japanese and European patients with sarcoidosis.(({{pubmed>long:11773116}}))+Mycobacterial and propionibacterial DNA have been found in the lymph nodes of Japanese and European patients with sarcoidosis.(({{pmid>long:11773116}}))
  
  
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 A granuloma is a ball of immune cells associated with various disease states including sarcoidosis, Crohn's, and tuberculosis. (Hence, the term "granulomatous diseases.") The presence of noncaseating (no tissue death) granuloma of the lungs is the hallmark of sarcoidosis. In sarcoidosis, granuloma are most commonly found in the alveolar septa, the walls of bronchi, and the pulmonary arteries and veins.   A granuloma is a ball of immune cells associated with various disease states including sarcoidosis, Crohn's, and tuberculosis. (Hence, the term "granulomatous diseases.") The presence of noncaseating (no tissue death) granuloma of the lungs is the hallmark of sarcoidosis. In sarcoidosis, granuloma are most commonly found in the alveolar septa, the walls of bronchi, and the pulmonary arteries and veins.  
  
-At their core, granuloma contain cells from the innate immune system: macrophages and monocytes. Lymphocytes, which are a part of the adaptive or acquired immune system, tend to exist on the periphery or in latter stages of development.(({{pubmed>long:3486154}})) (({{pubmed>long:12540568}})) +At their core, granuloma contain cells from the innate immune system: macrophages and monocytes. Lymphocytes, which are a part of the adaptive or acquired immune system, tend to exist on the periphery or in latter stages of development.(({{pmid>long:3486154}})) (({{pmid>long:12540568}})) 
  
-Granulomas may represent an extreme form of innate immune dysfunction.(({{pubmed>long:12540568}})) The macrophages and monocytes in granuloma are infected by intracellular pathogens such as //Mycobacteria//. When infected, the internal chemistry of innate immune cells is altered such that these cells no longer undergo apoptosis (programmed cell death).(({{pubmed>long:16086183}})) Significant differences in the expression of apoptosis-related genes were found in peripheral blood of patients with acute onset sarcoidosis.(({{pubmed>long:11641969}}))+Granulomas may represent an extreme form of innate immune dysfunction.(({{pmid>long:12540568}})) The macrophages and monocytes in granuloma are infected by intracellular pathogens such as //Mycobacteria//. When infected, the internal chemistry of innate immune cells is altered such that these cells no longer undergo apoptosis (programmed cell death).(({{pmid>long:16086183}})) Significant differences in the expression of apoptosis-related genes were found in peripheral blood of patients with acute onset sarcoidosis.(({{pmid>long:11641969}}))
  
 Also, they cease to move towards chemical signals driving an immune response, instead aggregating in clumps. One other side effect of infected macrophages is the [[home:pathogenesis:vitamind:metabolism|dysregulation of the Vitamin D Receptor]], leading to the high levels of 1,25-D characteristic of chronic inflammatory diseases. Also, they cease to move towards chemical signals driving an immune response, instead aggregating in clumps. One other side effect of infected macrophages is the [[home:pathogenesis:vitamind:metabolism|dysregulation of the Vitamin D Receptor]], leading to the high levels of 1,25-D characteristic of chronic inflammatory diseases.
  
-In a number of diseases such as tuberculosis, leprosy, histoplasmosis, cryptococcosis, blastomycosis, coccidioidomycosis and syphilis, the formation of a granuloma is widely considered to be an indication of infection.(({{pubmed>long:14527294}})) Even so, many researchers continue to assume that certain chronic diseases such as sarcoidosis and Crohn's disease are not caused by infection even though they present with granuloma which are similar to those found in diseases known to be infectious.+In a number of diseases such as tuberculosis, leprosy, histoplasmosis, cryptococcosis, blastomycosis, coccidioidomycosis and syphilis, the formation of a granuloma is widely considered to be an indication of infection.(({{pmid>long:14527294}})) Even so, many researchers continue to assume that certain chronic diseases such as sarcoidosis and Crohn's disease are not caused by infection even though they present with granuloma which are similar to those found in diseases known to be infectious.
  
-In fact, the presence of granuloma are entirely consistent with an infectious disease. For example, a Japanese team showed that one could use //Propionibacterium acnes// in mice to induce lung granuloma mimicking sarcoidosis.(({{pubmed>long:20424662}})) The distinction between infectious and "non-infectious" granulomatous diseases, may be further complicated by reports such as those by Warrier who reported a case of cutaneous sarcoidosis, the histology of which showed tuberculoid granuloma.(({{pubmed>long:17656979}}))+In fact, the presence of granuloma are entirely consistent with an infectious disease. For example, a Japanese team showed that one could use //Propionibacterium acnes// in mice to induce lung granuloma mimicking sarcoidosis.(({{pmid>long:20424662}})) The distinction between infectious and "non-infectious" granulomatous diseases, may be further complicated by reports such as those by Warrier who reported a case of cutaneous sarcoidosis, the histology of which showed tuberculoid granuloma.(({{pmid>long:17656979}}))
  
-Some researchers have argued that, rather than be a host-protective structures formed to contain infection,(({{pubmed>long:14527294}}))  granuloma may be exploited to expand and disseminate an infection. A //Cell// paper explains how //Mycobacteria// implicated in tuberculosis may recruit new macrophages to, nascent granulomas.(({{pubmed>long:19135887}}))+Some researchers have argued that, rather than be a host-protective structures formed to contain infection,(({{pmid>long:14527294}}))  granuloma may be exploited to expand and disseminate an infection. A //Cell// paper explains how //Mycobacteria// implicated in tuberculosis may recruit new macrophages to, nascent granulomas.(({{pmid>long:19135887}}))
  
 ==== Other evidence ==== ==== Other evidence ====
  
-  * **Difficulty distinguishing sarcoidosis from tuberculosis** – Although they have identified a signature that distinguishes healthy individuals from sarcoidosis or tuberculosis patients, the biosignatures of both diseases are nevertheless very similar. Gupta //et al.// write that differential diagnosis between the two is "very challenging."(({{pubmed>long:22759770}})) According to the [[http://www.mpg.de/5771449/biosignatures_tuberculosis_sarcoidosis|Max Planck Institute]], it is almost impossible to distinguish between tuberculosis and sarcoidosis with just a single signature. A set of different biosignatures is better suited for distinguishing in a first step between diseased and healthy individuals and, in a further step, between the specific diseases. +  * **Difficulty distinguishing sarcoidosis from tuberculosis** – Although they have identified a signature that distinguishes healthy individuals from sarcoidosis or tuberculosis patients, the biosignatures of both diseases are nevertheless very similar. Gupta //et al.// write that differential diagnosis between the two is "very challenging."(({{pmid>long:22759770}})) According to the [[https://www.mpg.de/5771449/biosignatures_tuberculosis_sarcoidosis|Max Planck Institute]], it is almost impossible to distinguish between tuberculosis and sarcoidosis with just a single signature. A set of different biosignatures is better suited for distinguishing in a first step between diseased and healthy individuals and, in a further step, between the specific diseases. 
-  * **Disease appearing in scars** – There are several case reports of sarcoidosis lesions forming within scars, which are especially susceptible to infection. That these granuloma often take long periods of time to be realized corresponds with the growth rate of the slow-growing chronic pathogens which the Marshall Pathogenesis implicates in chronic disease.(({{pubmed>long:17243430}})) According to one report, a patient developed sarcoid granuloma fully 50 years after his initial injury.(({{pubmed>long:19094856}})) Sorabee //et al// write(({{pubmed>long:15640432}})) that in addition to reactivation of scars obtained from previous wounds, scar sarcoidosis has been reported at the sites of previous intramuscular injections, blood donation venepuncture sites, scars of herpes zoster,(({{pubmed>long:10086879}})) sarcoidosis on ritual scarification,(({{pubmed>long:2917808}})) and at the sites of allergen extracts for desensitisation.(({{pubmed>long:1458650}}))  +  * **Disease appearing in scars** – There are several case reports of sarcoidosis lesions forming within scars, which are especially susceptible to infection. That these granuloma often take long periods of time to be realized corresponds with the growth rate of the slow-growing chronic pathogens which the Marshall Pathogenesis implicates in chronic disease.(({{pmid>long:17243430}})) According to one report, a patient developed sarcoid granuloma fully 50 years after his initial injury.(({{pmid>long:19094856}})) Sorabee //et al// write(({{pmid>long:15640432}})) that in addition to reactivation of scars obtained from previous wounds, scar sarcoidosis has been reported at the sites of previous intramuscular injections, blood donation venepuncture sites, scars of herpes zoster,(({{pmid>long:10086879}})) sarcoidosis on ritual scarification,(({{pmid>long:2917808}})) and at the sites of allergen extracts for desensitisation.(({{pmid>long:1458650}}))  
-  * **[[home:pathogenesis:transmission|Transmission of disease through blood, bone marrow, organs or other tissues]]** – Organs and tissue from sarcoidosis patients have been known to cause sarcoidosis in the transplanted recipients.(({{pubmed>long:12002380}})) (({{pubmed>long:7951107}})) (({{pubmed>long:11607780}})) +  * **[[home:pathogenesis:transmission|Transmission of disease through blood, bone marrow, organs or other tissues]]** – Organs and tissue from sarcoidosis patients have been known to cause sarcoidosis in the transplanted recipients.(({{pmid>long:12002380}})) (({{pmid>long:7951107}})) (({{pmid>long:11607780}})) 
-  * **Disease prevalence of small communities in close contact** – A number of studies of unrelated people shows that mere proximity seems to be enough to transmit chronic disease. A case-controlled study of residents of the Isle of Man found that 40 percent of people with sarcoidosis had been in contact with a person known to have the disease, compared with 1 to 2 percent of the control subjects.(({{pubmed>long:16844727}})) Another study reported three cases of sarcoidosis among ten firefighters who apprenticed together.(({{pubmed>long:8214953}}))   +  * **Disease prevalence of small communities in close contact** – A number of studies of unrelated people shows that mere proximity seems to be enough to transmit chronic disease. A case-controlled study of residents of the Isle of Man found that 40 percent of people with sarcoidosis had been in contact with a person known to have the disease, compared with 1 to 2 percent of the control subjects.(({{pmid>long:16844727}})) Another study reported three cases of sarcoidosis among ten firefighters who apprenticed together.(({{pmid>long:8214953}}))   
-  * **[[home:pathogenesis:familial_aggregation|Familial aggregation]] of the same disease** –  A number of studies have shown that spouses have a greater chance of developing the same disease as their partners - a phenomenon that can best be explained if familial aggregation has an infectious cause. One study of sarcoidosis found that among the 215 study participants who had been diagnosed with sarcoidosis, there were five husband-and-wife couples that both had the disease, an incidence 1,000 times greater than could be expected by chance.(({{pubmed>long:17684288}})) In an analysis of 706 patients and 10,862 first-degree relatives, the 2001 ACCESS study quantified the increased risk relatives of sarcoidosis have in acquiring the illness.(({{pubmed>long:11739139}})) According to the analysis, first-degree relatives of sarcoidosis patients have a 3.8 times greater risk of having sarcoidosis themselves, with siblings having the greatest risk. +  * **[[home:pathogenesis:familial_aggregation|Familial aggregation]] of the same disease** –  A number of studies have shown that spouses have a greater chance of developing the same disease as their partners - a phenomenon that can best be explained if familial aggregation has an infectious cause. One study of sarcoidosis found that among the 215 study participants who had been diagnosed with sarcoidosis, there were five husband-and-wife couples that both had the disease, an incidence 1,000 times greater than could be expected by chance.(({{pmid>long:17684288}})) In an analysis of 706 patients and 10,862 first-degree relatives, the 2001 ACCESS study quantified the increased risk relatives of sarcoidosis have in acquiring the illness.(({{pmid>long:11739139}})) According to the analysis, first-degree relatives of sarcoidosis patients have a 3.8 times greater risk of having sarcoidosis themselves, with siblings having the greatest risk. 
-  * **Kveim reaction** – The mKatG protein, a mycobacterial protein, was detected in sarcoidosis tissues and, when injected into sarcoidosis tissues has been shown to induce an adaptive immune response in a subgroup of patients with sarcoidosis.(({{pubmed>long:17684291}}))+  * **Kveim reaction** – The mKatG protein, a mycobacterial protein, was detected in sarcoidosis tissues and, when injected into sarcoidosis tissues has been shown to induce an adaptive immune response in a subgroup of patients with sarcoidosis.(({{pmid>long:17684291}}))
  
  
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 Patients with autoimmune disease often show inconsistent signs of autoimmune reactivity. Patients with autoimmune disease often show inconsistent signs of autoimmune reactivity.
  
-Kanchwala //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.((Kanchwala, A., B. Barna, et al. (2009). [[http://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Deficiencies of cathelicidin and vitamin D accompany disease severity in sarcoidosis]].)) Wiken //et al.// showed that there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome (a type of acute sarcoidosis).(({{pubmed>long:20813038}})) Note that TLR2 (which the Marshall Pathogenesis theorizes is downregulated in autoimmune disease states) is expressed by the VDR. +Kanchwala //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.((Kanchwala, A., B. Barna, et al. (2009). [[https://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Deficiencies of cathelicidin and vitamin D accompany disease severity in sarcoidosis]].)) Wiken //et al.// showed that there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome (a type of acute sarcoidosis).(({{pmid>long:20813038}})) Note that TLR2 (which the Marshall Pathogenesis theorizes is downregulated in autoimmune disease states) is expressed by the VDR. 
  
 ===== Data ===== ===== Data =====
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-No definitive laboratory test diagnostic of sarcoidosis has been identified. For example, sarcoidosis is not diagnosed by the presence of certain antibodies as there usually are none.(({{pubmed>long:8620732}}))+No definitive laboratory test diagnostic of sarcoidosis has been identified. For example, sarcoidosis is not diagnosed by the presence of certain antibodies as there usually are none.(({{pmid>long:8620732}}))
  
-In the absence of a single agreed upon etiologic agent, sarcoidosis often remains a diagnosis of exclusion, although a typical presentation may strongly suggest the diagnosis. The diagnosis of sarcoidosis is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and exclusion of other granulomatous diseases (e.g. Crohn's) capable of producing a similar histologic or clinical picture. Note that sarcoidosis is sometimes confused with benign or malignant cancerous tumors.(({{pubmed>long:16168469}})) Patients should make their doctors aware of any previous sarcoidosis diagnosis (even if only suspected) so sarcoidosis can be investigated as a possible cause of any lumps or tumors. +In the absence of a single agreed upon etiologic agent, sarcoidosis often remains a diagnosis of exclusion, although a typical presentation may strongly suggest the diagnosis. The diagnosis of sarcoidosis is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and exclusion of other granulomatous diseases (e.g. Crohn's) capable of producing a similar histologic or clinical picture. Note that sarcoidosis is sometimes confused with benign or malignant cancerous tumors.(({{pmid>long:16168469}})) Patients should make their doctors aware of any previous sarcoidosis diagnosis (even if only suspected) so sarcoidosis can be investigated as a possible cause of any lumps or tumors. 
  
  
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     * **FEV1** – ???     * **FEV1** – ???
   * **angiotensin converting enzyme (ACE)** – ACE is made by cells in the granulomas.  However, ACE levels are not always elevated in those with the disease.      * **angiotensin converting enzyme (ACE)** – ACE is made by cells in the granulomas.  However, ACE levels are not always elevated in those with the disease.   
-  * **tuberculin skin test** – The tuberculin [[http://www.nlm.nih.gov/medlineplus/ency/article/003384.htm|tine test]] is the test administered most frequently to screen for tuberculosis, which like sarcoidosis, is a granulomatous disorder. +  * **tuberculin skin test** – The tuberculin [[https://www.nlm.nih.gov/medlineplus/ency/article/003384.htm|tine test]] is the test administered most frequently to screen for tuberculosis, which like sarcoidosis, is a granulomatous disorder. 
-  * **x-rays and CT scans** – Several imaging technologies are used to show the hallmarks of sarcoidosis in lung tissue. A chest x-ray offers a single scan of the chest while a chest CT relies on [[http://en.wikipedia.org/wiki/Computed_axial_tomography|x-ray radiation in higher doses]] than a standard x-ray but allows better pictures of the lung. A CT scan will use a contrast material, typically iodine, to provide superior image quality This may be pose a risk to patients who have renal insufficiency. Usual precautions are to drink plenty of water before and after a CT. These imaging technologies may show granulomas, which appear as a shadow, or enlarged lymph glands in the chest. A staging system is used to classify chest x-rays taken to detect sarcoidosis.+  * **x-rays and CT scans** – Several imaging technologies are used to show the hallmarks of sarcoidosis in lung tissue. A chest x-ray offers a single scan of the chest while a chest CT relies on [[https://en.wikipedia.org/wiki/Computed_axial_tomography|x-ray radiation in higher doses]] than a standard x-ray but allows better pictures of the lung. A CT scan will use a contrast material, typically iodine, to provide superior image quality This may be pose a risk to patients who have renal insufficiency. Usual precautions are to drink plenty of water before and after a CT. These imaging technologies may show granulomas, which appear as a shadow, or enlarged lymph glands in the chest. A staging system is used to classify chest x-rays taken to detect sarcoidosis.
     * Stage 0 is a normal chest x-ray.     * Stage 0 is a normal chest x-ray.
     * Stage 1 is a chest x-ray with enlarged lymph nodes but otherwise clear lungs.     * Stage 1 is a chest x-ray with enlarged lymph nodes but otherwise clear lungs.
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-  * **corticosteroids** – There are no studies which show that glucocoritcoids (corticosteroids) improve long-term prognosis in the treatment of illness. Van den Bosch and Grutters write(({{pubmed>long:16946094}})), "Remarkably, despite over 50 years of use, there is no proof of long-term (survival) benefit from corticosteroid treatment." The 2003 NIH ACCESS study(({{pubmed>long:14620163}})), the largest and most ambitious to date, validates that these drugs are ineffective for sarcoidosis patients, even for a time period as short as two years.  For even short periods of time, steroid use can become genuinely addictive. Research shows that any kind of short-term symptomatic improvement from corticosteroid use does not last, and that over the longer term, use of the drugs entales a litany of side effects. For their own safety, patients on the Marshall Protocol (MP) must [[home:othertreatments:corticosteroids:weaningoffsteroids|wean off]] of them as opposed to discontinuing them outright. +  * **corticosteroids** – There are no studies which show that glucocoritcoids (corticosteroids) improve long-term prognosis in the treatment of illness. Van den Bosch and Grutters write(({{pmid>long:16946094}})), "Remarkably, despite over 50 years of use, there is no proof of long-term (survival) benefit from corticosteroid treatment." The 2003 NIH ACCESS study(({{pmid>long:14620163}})), the largest and most ambitious to date, validates that these drugs are ineffective for sarcoidosis patients, even for a time period as short as two years.  For even short periods of time, steroid use can become genuinely addictive. Research shows that any kind of short-term symptomatic improvement from corticosteroid use does not last, and that over the longer term, use of the drugs entales a litany of side effects. For their own safety, patients on the Marshall Protocol (MP) must [[home:othertreatments:corticosteroids:weaningoffsteroids|wean off]] of them as opposed to discontinuing them outright. 
-  * **[[home:othertreatments:antitnf|TNF-alpha inhibitors]]** – Tumor necrosis factor-alpha or TNF-alpha is a cytokine critical for effective immune surveillance.(({{pubmed>long:16331857}})) TNF-alpha inhibitors, also known as TNF blockers, anti-TNF drugs or TNF-alpha antagonists, are drugs which interfere with the body's production of TNF-alpha.(({{pubmed>long: 18387510}})) Anti-TNF drugs are expensive, ineffective at treating chronic disease and have a number of adverse effects such as increase risk of serious infection such as mycobacterial infection.(({{pubmed>long:16705109}})) (({{pubmed>long:12614731}}))+  * **[[home:othertreatments:antitnf|TNF-alpha inhibitors]]** – Tumor necrosis factor-alpha or TNF-alpha is a cytokine critical for effective immune surveillance.(({{pmid>long:16331857}})) TNF-alpha inhibitors, also known as TNF blockers, anti-TNF drugs or TNF-alpha antagonists, are drugs which interfere with the body's production of TNF-alpha.(({{pmid>long: 18387510}})) Anti-TNF drugs are expensive, ineffective at treating chronic disease and have a number of adverse effects such as increase risk of serious infection such as mycobacterial infection.(({{pmid>long:16705109}})) (({{pmid>long:12614731}}))
   * **[[home:othertreatments:steroid_inhalers|inhalers, steroid]]** – Steroid inhalers suppress the innate immune response and delay progress on the MP. MP patients taking steroid inhalers should work with their physicians to switch drugs such as a [[home:othertreatments:bronchodilator_inhalers|bronchiodilator inhaler]].   * **[[home:othertreatments:steroid_inhalers|inhalers, steroid]]** – Steroid inhalers suppress the innate immune response and delay progress on the MP. MP patients taking steroid inhalers should work with their physicians to switch drugs such as a [[home:othertreatments:bronchodilator_inhalers|bronchiodilator inhaler]].
 ==== Lung transplantation ==== ==== Lung transplantation ====
 In the face of end-stage pulmonary sarcoidosis, many pulmonologists advise patients to consider lung transplantation. While a number of patients with advanced forms of sarcoidosis (including many who need supplemental oxygen) have done well on the MP, lung transplantation for sarcoidosis is problematic for several reasons.  In the face of end-stage pulmonary sarcoidosis, many pulmonologists advise patients to consider lung transplantation. While a number of patients with advanced forms of sarcoidosis (including many who need supplemental oxygen) have done well on the MP, lung transplantation for sarcoidosis is problematic for several reasons. 
  
-A lung transplant fails to address the underlying cause, and, as a result, disease reoccurrence is not uncommon. A Danish study showed that lungs implanted in sarcoid patients are reinfected with granulomas five months later (reinfection was determined to come from the recipient patient)(({{pubmed>long:16135738}})) while another study showed recurrent sarcoidosis occurred as late as 56 months after the procedure.(({{pubmed>long:9741371}})) +A lung transplant fails to address the underlying cause, and, as a result, disease reoccurrence is not uncommon. A Danish study showed that lungs implanted in sarcoid patients are reinfected with granulomas five months later (reinfection was determined to come from the recipient patient)(({{pmid>long:16135738}})) while another study showed recurrent sarcoidosis occurred as late as 56 months after the procedure.(({{pmid>long:9741371}})) 
  
-According to several observational studies, the median survival time of sarcoidosis patients after they receive a transplant has been reported to be about 4.7 years(({{pubmed>long:19134524}})) – about [[http://www.ustransplant.org/csr/current/Centers/TransplantCenters.aspx?organ=Lung|half]] that of other major transplanted organ recipients. +According to several observational studies, the median survival time of sarcoidosis patients after they receive a transplant has been reported to be about 4.7 years(({{pmid>long:19134524}})) – about [[https://www.ustransplant.org/csr/current/Centers/TransplantCenters.aspx?organ=Lung|half]] that of other major transplanted organ recipients. 
  
 Finally, any quality of life during time following transplant is limit. To ward off tissue rejection and survive several years, patients must take a cocktail of anti-rejection and immunosuppressive drugs, classes of drugs which entale a number of side effects.  Finally, any quality of life during time following transplant is limit. To ward off tissue rejection and survive several years, patients must take a cocktail of anti-rejection and immunosuppressive drugs, classes of drugs which entale a number of side effects. 
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 <mainarticle> [[home:pathogenesis:vitamind:metabolism|Metabolism of vitamin D and the Vitamin D Receptor]]</article> <mainarticle> [[home:pathogenesis:vitamind:metabolism|Metabolism of vitamin D and the Vitamin D Receptor]]</article>
  
-Under most normal conditions, serum levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-D), are constant throughout the year (no variability due to sun exposure),(({{pubmed>long:19444938}})) but there is no such tight biochemical regulation in at least some chronic inflammatory diseases such as sarcoidosis. Patients with sarcoidosis tend to have high levels of 1,25-D. As the article [[home:pathogenesis:vitamind:metabolism|Metabolism of vitamin D and the Vitamin D Receptor]] explains, these high levels may be a direct outcome of microbes' effect on slowing activity of the VDR. It is also an indication of innate immune dysfunction.+Under most normal conditions, serum levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-D), are constant throughout the year (no variability due to sun exposure),(({{pmid>long:19444938}})) but there is no such tight biochemical regulation in at least some chronic inflammatory diseases such as sarcoidosis. Patients with sarcoidosis tend to have high levels of 1,25-D. As the article [[home:pathogenesis:vitamind:metabolism|Metabolism of vitamin D and the Vitamin D Receptor]] explains, these high levels may be a direct outcome of microbes' effect on slowing activity of the VDR. It is also an indication of innate immune dysfunction.
  
-It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but this process happens outside those organs – not coincidentally, at the very sites where patients report symptoms of chronic disease. High levels of 1,25-D and the enzyme which leads to the production of 1,25-D, 1 α-hydroxylase, have been found at various locations where the human body needs a strong host defense.(({{pubmed>long:18981129}})) Zehnder //et al// found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients where sarcoidosis patients tend to have disease symptoms.(({{pubmed>long:11158062}})) They write: +It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but this process happens outside those organs – not coincidentally, at the very sites where patients report symptoms of chronic disease. High levels of 1,25-D and the enzyme which leads to the production of 1,25-D, 1 α-hydroxylase, have been found at various locations where the human body needs a strong host defense.(({{pmid>long:18981129}})) Zehnder //et al// found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients where sarcoidosis patients tend to have disease symptoms.(({{pmid>long:11158062}})) They write: 
  
 <blockquote> In particular, the expression of 1α-OHase [1 α-hydroxylase] by activated macrophages and epidermal keratinocytes [skin cells] suggests a role for 1,25(OH)2D3 [1,25-D] as an immunomodulatory and/or antiproliferative hormone. </blockquote>  <blockquote> In particular, the expression of 1α-OHase [1 α-hydroxylase] by activated macrophages and epidermal keratinocytes [skin cells] suggests a role for 1,25(OH)2D3 [1,25-D] as an immunomodulatory and/or antiproliferative hormone. </blockquote> 
  
-A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases. Kavathia //et al.// found that in patients with sarcoidosis, those with high serum levels of 1,25-D have more pronounced chronic treatment needs.(({{pubmed>long:20071158}}))+A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases. Kavathia //et al.// found that in patients with sarcoidosis, those with high serum levels of 1,25-D have more pronounced chronic treatment needs.(({{pmid>long:20071158}}))
  
  
 ===== Calcium metabolism ===== ===== Calcium metabolism =====
  
-Hypercalcemia (excess levels of calcium in the blood) and hypercalciuria (excessive urinary calcium excretion) are frequently associated with the granulomatous diseases. Prevalence data suggests that 30 to 50 percent of patients with sarcoidosis have hypercalciuria and 10 to 20 percent have hypercalcemia.(({{pubmed>long:2673772}})) (({{pubmed>long:8620732}})) Until recently, some researchers suggested that these processes were caused by high levels of 1,25-D.(({{pubmed>long:10782361}})) (({{pubmed>long:10363752}}))  As a result, patients with granulomatous disease are [[http://emedicine.medscape.com/article/436343-overview|widely cautioned]] to limit sunlight exposure and vitamin D ingestion – recommendations that are generally not offered to patients with other chronic inflammatory diseases. Even pro-vitamin D advocates such as Michael Holick, M.D. have issued such cautions for high-dose supplementation of vitamin D in granulomatous diseases.(({{pubmed>long:17634462}}))+Hypercalcemia (excess levels of calcium in the blood) and hypercalciuria (excessive urinary calcium excretion) are frequently associated with the granulomatous diseases. Prevalence data suggests that 30 to 50 percent of patients with sarcoidosis have hypercalciuria and 10 to 20 percent have hypercalcemia.(({{pmid>long:2673772}})) (({{pmid>long:8620732}})) Until recently, some researchers suggested that these processes were caused by high levels of 1,25-D.(({{pmid>long:10782361}})) (({{pmid>long:10363752}}))  As a result, patients with granulomatous disease are [[https://emedicine.medscape.com/article/436343-overview|widely cautioned]] to limit sunlight exposure and vitamin D ingestion – recommendations that are generally not offered to patients with other chronic inflammatory diseases. Even pro-vitamin D advocates such as Michael Holick, M.D. have issued such cautions for high-dose supplementation of vitamin D in granulomatous diseases.(({{pmid>long:17634462}}))
  
-However, according to the Marshall Pathogenesis, any essential discrepancy in calcium/VDR metabolism between the granulomatous and non-granulomatous diseases is limited. The prevalence data suggests as much. Not everyone who has sarcoidosis gets hypercalcemia, and a large number of patients with other diseases such as breast and lung cancers are at risk for the condition.(({{pubmed>long:1460860}})) Further, in many diseases for which hypercalcemia is not suspected, the condition tends to go [[http://emedicine.medscape.com/article/240681-overview|underdiagnosed]].+However, according to the Marshall Pathogenesis, any essential discrepancy in calcium/VDR metabolism between the granulomatous and non-granulomatous diseases is limited. The prevalence data suggests as much. Not everyone who has sarcoidosis gets hypercalcemia, and a large number of patients with other diseases such as breast and lung cancers are at risk for the condition.(({{pmid>long:1460860}})) Further, in many diseases for which hypercalcemia is not suspected, the condition tends to go [[https://emedicine.medscape.com/article/240681-overview|underdiagnosed]].
  
-Consistent with its classically understood role in maintaining bone health, the Vitamin D Receptor does appear to play at least some direct role in calcium regulation: a 2010 paper showed that the VDR signals stem cells responsible for osteoblast (bone-building) activity.(({{pubmed>long:20813899}})) But, researchers have since emphasized the role of estrogens and the estrogen receptor in maintaining bone health.(({{pubmed>long:19751412}})) In a 2007 study in //Cell//, Nakamura and colleagues showed that, in a female mouse model, removing estrogen receptor alpha in osteoblasts demonstrated that estrogen directly induces osteoclast apoptosis.(({{pubmed>long:17803905}})) The loss of estrogen among women at menopause may play some role in this process, but it is too soon to say this relationship is causal. Nakamura's work was done in otherwise healthy mouse cells rather than in human cells – which may be infected by pathogens. If such cells were infected, supplementation with estrogen would not address the underlying disease process.+Consistent with its classically understood role in maintaining bone health, the Vitamin D Receptor does appear to play at least some direct role in calcium regulation: a 2010 paper showed that the VDR signals stem cells responsible for osteoblast (bone-building) activity.(({{pmid>long:20813899}})) But, researchers have since emphasized the role of estrogens and the estrogen receptor in maintaining bone health.(({{pmid>long:19751412}})) In a 2007 study in //Cell//, Nakamura and colleagues showed that, in a female mouse model, removing estrogen receptor alpha in osteoblasts demonstrated that estrogen directly induces osteoclast apoptosis.(({{pmid>long:17803905}})) The loss of estrogen among women at menopause may play some role in this process, but it is too soon to say this relationship is causal. Nakamura's work was done in otherwise healthy mouse cells rather than in human cells – which may be infected by pathogens. If such cells were infected, supplementation with estrogen would not address the underlying disease process.
  
 ===== Incidence and prevalence ===== ===== Incidence and prevalence =====
  
-An analysis of the 2001 ACCESS study challenged the widely held stereotype that the American patients most often affected by sarcoidosis are African-Americans and under 40.(({{pubmed>long:11734441}}))+An analysis of the 2001 ACCESS study challenged the widely held stereotype that the American patients most often affected by sarcoidosis are African-Americans and under 40.(({{pmid>long:11734441}}))
  
  
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 ===== Commonly involved organs ===== ===== Commonly involved organs =====
  
-Sarcoidosis can affect any organ, initially presenting with one or more of the following abnormalities (in order of frequency according to the 2001 ACCESS study, which used data collected by pulmonologists).(({{pubmed>long:11739139}}))+Sarcoidosis can affect any organ, initially presenting with one or more of the following abnormalities (in order of frequency according to the 2001 ACCESS study, which used data collected by pulmonologists).(({{pmid>long:11739139}}))
  
  
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   * **crackles** – Crackles, crepitations, or rales are the clicking, rattling, or crackling noises that may be made by one or both lungs of a human with a respiratory disease during inhalation.   * **crackles** – Crackles, crepitations, or rales are the clicking, rattling, or crackling noises that may be made by one or both lungs of a human with a respiratory disease during inhalation.
   * **diffuse interstitial lung disease** –  A group of lung disorders in which the deep lung tissues become swollen and scarred. Caused by swelling and scarring of the air sacs (alveoli) and their supporting structures (the interstitium). This leads to reduced levels of oxygen in the blood.   * **diffuse interstitial lung disease** –  A group of lung disorders in which the deep lung tissues become swollen and scarred. Caused by swelling and scarring of the air sacs (alveoli) and their supporting structures (the interstitium). This leads to reduced levels of oxygen in the blood.
-  * **Eosinophilic pneumonia** is characterized by a large number of eosinophils in the lungs, usually in the absence of an infectious disease. Eosinophils are one of the white blood cells and are classified as a granulocyte. (({{pubmed>long:28705588}}))  +  * **Eosinophilic pneumonia** is characterized by a large number of eosinophils in the lungs, usually in the absence of an infectious disease. Eosinophils are one of the white blood cells and are classified as a granulocyte. (({{pmid>long:28705588}}))  
-  * **hyperinflation** – Hyperinflation is sometimes called “air trapping” and may be helped by measures such as [[http://www.olivija.com/exercise/|pursed lip breathing]]. Pursed lip breathing can help release air trapped in the lungs and can help relieve the feeling of shortness of breath, if it's due to hyperinflation. In some cases, supplemental oxygen might be useful in overcoming hyperinflation. This [[http://www.medscape.com/viewarticle/518312|Medscape article]] (registration required) discusses how supplemental oxygen facilitates lung emptying. +  * **hyperinflation** – Hyperinflation is sometimes called “air trapping” and may be helped by measures such as [[https://www.olivija.com/exercise/|pursed lip breathing]]. Pursed lip breathing can help release air trapped in the lungs and can help relieve the feeling of shortness of breath, if it's due to hyperinflation. In some cases, supplemental oxygen might be useful in overcoming hyperinflation. This [[https://www.medscape.com/viewarticle/518312|Medscape article]] (registration required) discusses how supplemental oxygen facilitates lung emptying. 
-  * **obstructive lung disease** – It's a little-recognized fact that sarcoidosis can cause PFTs results to indicate obstructive lung disease (sarcoidosis is considered a restrictive lung disease). This is because chest lymph nodes may become so enlarged they compress airways and/or granulomas themselves may obstruct airways. [[http://www.mayoclinic.com/invoke.cfm?id=AN00759|This article]] explains the difference between restrictive and obstructive lung disease.  +  * **obstructive lung disease** – It's a little-recognized fact that sarcoidosis can cause PFTs results to indicate obstructive lung disease (sarcoidosis is considered a restrictive lung disease). This is because chest lymph nodes may become so enlarged they compress airways and/or granulomas themselves may obstruct airways. [[https://www.mayoclinic.com/invoke.cfm?id=AN00759|This article]] explains the difference between restrictive and obstructive lung disease.  
-  * **pulmonary fibrosis** –  Formation or development of fibrous connective tissue in the lungs. Also called scarring, the creation of collagen allows the body to encase pathogens which have been missed by the immune system. Symptoms of pulmonary fibrosis include shortness of breath, a chronic dry cough, and chest discomfort. The angiotensin blockade (put into place by olmesartan) inhibits the formation of new fibrotic tissue. ALSO This study suggests that mast cells may contribute to the progression of pulmonary fibrosis.  (({{pubmed>long:    30808717}}))   +  * **pulmonary fibrosis** –  Formation or development of fibrous connective tissue in the lungs. Also called scarring, the creation of collagen allows the body to encase pathogens which have been missed by the immune system. Symptoms of pulmonary fibrosis include shortness of breath, a chronic dry cough, and chest discomfort. The angiotensin blockade (put into place by olmesartan) inhibits the formation of new fibrotic tissue. ALSO This study suggests that mast cells may contribute to the progression of pulmonary fibrosis.  (({{pmid>long:    30808717}}))   
-  * **pulmonary hypertension** – Abnormally high blood pressure in the  in the pulmonary artery, which connects the heart to the lungs. It makes the right side of the heart need to work harder than normal. PH is common in sarcoidosis.(({{pubmed>long:16227329}})) (({{pubmed>long:16198969}})) (({{pubmed>long:15863633}})) (({{pubmed>long:15449010}}))+  * **pulmonary hypertension** – Abnormally high blood pressure in the  in the pulmonary artery, which connects the heart to the lungs. It makes the right side of the heart need to work harder than normal. PH is common in sarcoidosis.(({{pmid>long:16227329}})) (({{pmid>long:16198969}})) (({{pmid>long:15863633}})) (({{pmid>long:15449010}}))
  
  
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 Lupus pernio is not another disease, nor is it related to lupus. Lupus pernio is a chronic plaquelike hardening of the face, usually appearing with violet discoloration of the cheeks, lips, nose, and ears. It can erode into cartilage or bone. Lupus pernio lesions can be permanently disfiguring and cause a patient to feel embarrassed, particularly since they may be noticeable on facial areas so visible to the public.  Lupus pernio is not another disease, nor is it related to lupus. Lupus pernio is a chronic plaquelike hardening of the face, usually appearing with violet discoloration of the cheeks, lips, nose, and ears. It can erode into cartilage or bone. Lupus pernio lesions can be permanently disfiguring and cause a patient to feel embarrassed, particularly since they may be noticeable on facial areas so visible to the public. 
  
-Sometimes lupus pernio lesions will have an appearance of small "beads" along their edge, especially if the sore is on the rim of the nose. Like some other cutaneous sarcoidosis lesions, lupus pernio can appear at sites of old scars or trauma(({{pubmed>long:8252776}})) as well as in the upper respiratory tract(({{pubmed>long:1013937}})) – both sites of which can be quite resistant to the standard immunosuppressive therapies. These lesions can occur when the nose, face or hands are exposed to cold or wind, so it's a good idea for patients with sacroidosis to keep these areas protected from wind and cold. Avoiding exposure to bright lights is also an important preventative measure. Lupus pernio is said to be the skin lesion most characteristic (a diagnostic indicator) of sarcoidosis(({{pubmed>long:17041433}})), but not all sarcoidosis patients have these skin lesions.+Sometimes lupus pernio lesions will have an appearance of small "beads" along their edge, especially if the sore is on the rim of the nose. Like some other cutaneous sarcoidosis lesions, lupus pernio can appear at sites of old scars or trauma(({{pmid>long:8252776}})) as well as in the upper respiratory tract(({{pmid>long:1013937}})) – both sites of which can be quite resistant to the standard immunosuppressive therapies. These lesions can occur when the nose, face or hands are exposed to cold or wind, so it's a good idea for patients with sacroidosis to keep these areas protected from wind and cold. Avoiding exposure to bright lights is also an important preventative measure. Lupus pernio is said to be the skin lesion most characteristic (a diagnostic indicator) of sarcoidosis(({{pmid>long:17041433}})), but not all sarcoidosis patients have these skin lesions.
  
  
 === Erythema nodosum (subcutaneous nodules) === === Erythema nodosum (subcutaneous nodules) ===
  
-Erythema nodosum are raised red, tender nodular lesions, generally but not exclusively on the anterior surface of the lower part of the leg. These lesions do not represent granulomatous involvement of the skin. Rather, the histopathology is primarily that of a panniculitis (inflammation of the fatty layer under the skin), with cellular inflammation and edema of the deep dermis and subcutaneous tissue. The presence of erythema nodosum is commonly observed in other infectious diseases such as tuberculosis.(({{pubmed>long:15307561}}))+Erythema nodosum are raised red, tender nodular lesions, generally but not exclusively on the anterior surface of the lower part of the leg. These lesions do not represent granulomatous involvement of the skin. Rather, the histopathology is primarily that of a panniculitis (inflammation of the fatty layer under the skin), with cellular inflammation and edema of the deep dermis and subcutaneous tissue. The presence of erythema nodosum is commonly observed in other infectious diseases such as tuberculosis.(({{pmid>long:15307561}}))
  
  
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-The reported frequency of ocular manifestations for sarcoidosis varies according to the source and group studied, but may be as high as 70%.(({{pubmed>long:18021432}}))  In the eye, the common sites of involvement are the skin of eyelid, conjunctiva, uveal tract, retina, optic nerve and lacrimal gland.(({{pubmed>long:11217257}})) Common symptoms of ocular sarcoidosis include:+The reported frequency of ocular manifestations for sarcoidosis varies according to the source and group studied, but may be as high as 70%.(({{pmid>long:18021432}}))  In the eye, the common sites of involvement are the skin of eyelid, conjunctiva, uveal tract, retina, optic nerve and lacrimal gland.(({{pmid>long:11217257}})) Common symptoms of ocular sarcoidosis include:
   * uveitis – Swelling and irritation of the uvea, the middle layer of the eye. Most common is anterior uveitis, however, over a quarter of patients will have inflammation at the posterior of the eye, including retinitis pars planitis. according to the Cleveland Clinic, "Complications of uveitis may include glaucoma, cataract, abnormal blood vessel growth, fluid within the retina and vision loss."   * uveitis – Swelling and irritation of the uvea, the middle layer of the eye. Most common is anterior uveitis, however, over a quarter of patients will have inflammation at the posterior of the eye, including retinitis pars planitis. according to the Cleveland Clinic, "Complications of uveitis may include glaucoma, cataract, abnormal blood vessel growth, fluid within the retina and vision loss."
   * Sjogren's (Sicca) – Sjogren's and sarcoidosis are both described in the standard literature as a collection of symptoms. Sjogren's is known to be related to diseases such as rheumatoid arthritis, sarcoidosis, lupus, scleroderma and polymyositis. Many sarcoidosis patients manifest the same symptoms as described in Sjogren's syndrome (dry eyes and mouth, decreased tears and saliva, and resulting dental caries). Sjogren's is reportedly seen in about half of patients.   * Sjogren's (Sicca) – Sjogren's and sarcoidosis are both described in the standard literature as a collection of symptoms. Sjogren's is known to be related to diseases such as rheumatoid arthritis, sarcoidosis, lupus, scleroderma and polymyositis. Many sarcoidosis patients manifest the same symptoms as described in Sjogren's syndrome (dry eyes and mouth, decreased tears and saliva, and resulting dental caries). Sjogren's is reportedly seen in about half of patients.
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   * dry eyes – may require natural tears or other lubricants   * dry eyes – may require natural tears or other lubricants
   * cataracts   * cataracts
-  * conjunctiva(({{pubmed>long:15512984}}))+  * conjunctiva(({{pmid>long:15512984}}))
  
 Some asymptomatic patients still have active inflammation. Initially asymptomatic patients with ocular sarcoidosis can eventually develop blindness. Therefore, it is recommended that all patients with sarcoidosis receive a dedicated ophthalmologic examination. Some asymptomatic patients still have active inflammation. Initially asymptomatic patients with ocular sarcoidosis can eventually develop blindness. Therefore, it is recommended that all patients with sarcoidosis receive a dedicated ophthalmologic examination.
  
-Columbia University researcher Emil Wirotsko identified cell wall deficient bacteria – which he described as "mollicute-like organisms" – in the vitreous fluid of sarcoidal eyes.(({{pubmed>long:2801045}})) He further showed that the introduction of these microbes into mouse model effectively reproduced the chronic inflammatory process and granuloma that are the hallmark of sarcoidosis.+Columbia University researcher Emil Wirotsko identified cell wall deficient bacteria – which he described as "mollicute-like organisms" – in the vitreous fluid of sarcoidal eyes.(({{pmid>long:2801045}})) He further showed that the introduction of these microbes into mouse model effectively reproduced the chronic inflammatory process and granuloma that are the hallmark of sarcoidosis.
  
  
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 Lymph nodes play a vital role in the body's ability to fight off microbes. During an infection, the lymph nodes can expand due to intense B-cell proliferation in the germinal centers, a condition commonly referred to as "swollen glands." Lymphadenopathy refers to "disease of the lymph nodes." It is, however, almost synonymously used with "swollen or enlarged lymph nodes." Lymphadenopathy can occur anywhere there are lymph node, but especially the neck, armpits, groin, or chest. Enlarged or tender glands can often be detected by low-tech means: visually or by palpation. Lymph nodes deep in the groin or beneath the ribs in the chest can be monitored with imaging such as chest x-ray, CT or PET scan.  Lymph nodes play a vital role in the body's ability to fight off microbes. During an infection, the lymph nodes can expand due to intense B-cell proliferation in the germinal centers, a condition commonly referred to as "swollen glands." Lymphadenopathy refers to "disease of the lymph nodes." It is, however, almost synonymously used with "swollen or enlarged lymph nodes." Lymphadenopathy can occur anywhere there are lymph node, but especially the neck, armpits, groin, or chest. Enlarged or tender glands can often be detected by low-tech means: visually or by palpation. Lymph nodes deep in the groin or beneath the ribs in the chest can be monitored with imaging such as chest x-ray, CT or PET scan. 
  
-Like any sarcoidosis symptom, lymphadenopathy may flare with immunopathology, resulting in enlarged and/or tender lymph nodes. The increase in the size of lymph nodes is consistent with an immunostimulatory therapy such as the Marshall Protocol. However, in later stages of sarcoidosis the lymph nodes shrink as their functionality decreases. This may be because they become too damaged to function. It is not unusual for lymph nodes to be calcified in sarcoidosis patients.(({{pubmed>long:8617038}})) +Like any sarcoidosis symptom, lymphadenopathy may flare with immunopathology, resulting in enlarged and/or tender lymph nodes. The increase in the size of lymph nodes is consistent with an immunostimulatory therapy such as the Marshall Protocol. However, in later stages of sarcoidosis the lymph nodes shrink as their functionality decreases. This may be because they become too damaged to function. It is not unusual for lymph nodes to be calcified in sarcoidosis patients.(({{pmid>long:8617038}})) 
  
  
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 <relatedarticle>  [[home:othertreatments:massage|Massage and other manipulation therapies]]</article> <relatedarticle>  [[home:othertreatments:massage|Massage and other manipulation therapies]]</article>
  
-Massage can increase lymphatic flow(({{pubmed>long:2250109}})) as can osteopathic manipulation.(({{pubmed>long:16314677}})) Patients seeking this kind of therapy should look for therapists competent in techniques to help the lymphatic system and familiar with the needs of patients with chronic illness.+Massage can increase lymphatic flow(({{pmid>long:2250109}})) as can osteopathic manipulation.(({{pmid>long:16314677}})) Patients seeking this kind of therapy should look for therapists competent in techniques to help the lymphatic system and familiar with the needs of patients with chronic illness.
  
  
 ====Liver==== ====Liver====
  
-Sarcoidosis of the liver is not uncommon.(({{pubmed>long:8036338}}))  According to [[http://www.medscape.com/viewarticle/405532_4|Richard W Goodgame, MD]], "The prevalence of hepatic granulomas in sarcoidosis is 65%. In a study of 100 patients with hepatic sarcoidosis, the majority of patients were asymptomatic and had normal abdominal examinations." +Sarcoidosis of the liver is not uncommon.(({{pmid>long:8036338}}))  According to [[https://www.medscape.com/viewarticle/405532_4|Richard W Goodgame, MD]], "The prevalence of hepatic granulomas in sarcoidosis is 65%. In a study of 100 patients with hepatic sarcoidosis, the majority of patients were asymptomatic and had normal abdominal examinations." 
  
-The angtiotensin receptor blocker olmesartan has been shown to reduce liver fibrosis(({{pubmed>long:19303015}})) and aid liver healing.(({{pubmed>long:12871826}})) Some patients with sarcoidosis of the liver are mistakenly told they have "fatty liver disease" or cirrhosis.+The angtiotensin receptor blocker olmesartan has been shown to reduce liver fibrosis(({{pmid>long:19303015}})) and aid liver healing.(({{pmid>long:12871826}})) Some patients with sarcoidosis of the liver are mistakenly told they have "fatty liver disease" or cirrhosis.
  
 ====Spleen==== ====Spleen====
  
-The reported frequency of splenomegaly, enlargement or inflammation of the spleen, in sarcoidosis has ranged from 1% to 40%.(({{pubmed>long:8532960}}))+The reported frequency of splenomegaly, enlargement or inflammation of the spleen, in sarcoidosis has ranged from 1% to 40%.(({{pmid>long:8532960}}))
  
 ====Neurologic (neurosarcoidosis)==== ====Neurologic (neurosarcoidosis)====
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 Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to sarcoidosis involving the central nervous system (brain and spinal cord). It can have many manifestations, but abnormalities of the cranial nerves (a group of twelve nerves supplying the head and neck area) are the most common. It may develop acutely, subacutely, and chronically. Approximately 5-10% of people with sarcoidosis of other organs develop central nervous system involvement. Only 1% of people with sarcoidosis will have neurosarcoidosis alone without involvement of any other organs. Diagnosis can be difficult, with no test apart from biopsy being completely reliable. Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to sarcoidosis involving the central nervous system (brain and spinal cord). It can have many manifestations, but abnormalities of the cranial nerves (a group of twelve nerves supplying the head and neck area) are the most common. It may develop acutely, subacutely, and chronically. Approximately 5-10% of people with sarcoidosis of other organs develop central nervous system involvement. Only 1% of people with sarcoidosis will have neurosarcoidosis alone without involvement of any other organs. Diagnosis can be difficult, with no test apart from biopsy being completely reliable.
  
-Psychiatric problems occur in 20% of cases; many different disorders have been reported, e.g. depression and psychosis. Peripheral neuropathy has been reported in up to 15% of cases of neurosarcoidosis.(({{pubmed>long:17636138}}))+Psychiatric problems occur in 20% of cases; many different disorders have been reported, e.g. depression and psychosis. Peripheral neuropathy has been reported in up to 15% of cases of neurosarcoidosis.(({{pmid>long:17636138}}))
  
 === Managing neurological symptoms === === Managing neurological symptoms ===
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 ====Cardiac==== ====Cardiac====
  
-According to a 2003 study of Dutch patients, 30% of people with sarcoidosis suffer from chest pain.(({{pubmed>long:12737278}})) A similar proportion of sarcoidosis patients were found to have cardiac involvement upon autopsy.(({{pubmed>long:12360650}})) A third paper found that perhaps 50% of sarcoidosis patients have cardiac involvement that is not diagnosed(({{pubmed>long:9608713}})).+According to a 2003 study of Dutch patients, 30% of people with sarcoidosis suffer from chest pain.(({{pmid>long:12737278}})) A similar proportion of sarcoidosis patients were found to have cardiac involvement upon autopsy.(({{pmid>long:12360650}})) A third paper found that perhaps 50% of sarcoidosis patients have cardiac involvement that is not diagnosed(({{pmid>long:9608713}})).
  
-While it is true that chest pain can be due to cardiac involvement,(({{pubmed>long:15316439}})) it may simply be due to other problems brought on by sarcoidosis such as enlarged lymph nodes which can cause pressure, crowding and pain in the chest.+While it is true that chest pain can be due to cardiac involvement,(({{pmid>long:15316439}})) it may simply be due to other problems brought on by sarcoidosis such as enlarged lymph nodes which can cause pressure, crowding and pain in the chest.
  
 All sarcoidosis patients are cautioned to assume they may have unrecognized cardiac involvement and to control their level of immunopathology accordingly. All sarcoidosis patients are cautioned to assume they may have unrecognized cardiac involvement and to control their level of immunopathology accordingly.
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   * **Heerfordt's syndrome** – also referred to as uveoparotid fever, Heerfordt-Mylius syndrome, Heerfordt-Waldenström syndrome, and Waldenström’s uveoparotitis, is a rare manifestation of sarcoidosis. The symptoms include inflammation of the eye (uveitis), swelling of the parotid gland, chronic fever, and in some cases, palsy of the facial nerves.   * **Heerfordt's syndrome** – also referred to as uveoparotid fever, Heerfordt-Mylius syndrome, Heerfordt-Waldenström syndrome, and Waldenström’s uveoparotitis, is a rare manifestation of sarcoidosis. The symptoms include inflammation of the eye (uveitis), swelling of the parotid gland, chronic fever, and in some cases, palsy of the facial nerves.
-  * **mouth** – Symptoms of sarcoidosis involvement in the mouth include: sores on or swelling of the face, tongue, mouth, gums or inside the cheeks,(({{pubmed>long:16456999}})) (({{pubmed>long:16610265}})) (({{pubmed>long:9127377}})) (({{pubmed>long:10761605}})) gingivitis,(({{pubmed>long:3134086}})) too much or more commonly too little saliva, (({{pubmed>long:15759458}})) and gum disease and increased dental cavities. Biopsy of the mouth often leads to diagnosis. +  * **mouth** – Symptoms of sarcoidosis involvement in the mouth include: sores on or swelling of the face, tongue, mouth, gums or inside the cheeks,(({{pmid>long:16456999}})) (({{pmid>long:16610265}})) (({{pmid>long:9127377}})) (({{pmid>long:10761605}})) gingivitis,(({{pmid>long:3134086}})) too much or more commonly too little saliva, (({{pmid>long:15759458}})) and gum disease and increased dental cavities. Biopsy of the mouth often leads to diagnosis. 
-  * **nails** – Onycholysis, the loosening of lifting of the nail, is common in sarcoidosis. Several researchers describe this manifestation.(({{pubmed>long:19467377}})) (({{pubmed>long:10575159}})) (({{pubmed>long:7648885}})) +  * **nails** – Onycholysis, the loosening of lifting of the nail, is common in sarcoidosis. Several researchers describe this manifestation.(({{pmid>long:19467377}})) (({{pmid>long:10575159}})) (({{pmid>long:7648885}})) 
-  * **sleep apnea** – Sleep apnea is the temporary absence of breathing during sleep. Sarcoidosis patients have a higher incidence of sleep apnea than the general population.(({{pubmed>long:9186990}})) Sarcoidosis itself can cause obstuctive sleep apnea due to the fact that sarcoid inflammation and granulomas can obstruct upper airway passages. In addition, use of the common therapy for relieving sarcoidosis symptoms: Prednisone, which is a corticosteroid, usually results in significant weight gain – which itself contributes to sleep apnea. +  * **sleep apnea** – Sleep apnea is the temporary absence of breathing during sleep. Sarcoidosis patients have a higher incidence of sleep apnea than the general population.(({{pmid>long:9186990}})) Sarcoidosis itself can cause obstuctive sleep apnea due to the fact that sarcoid inflammation and granulomas can obstruct upper airway passages. In addition, use of the common therapy for relieving sarcoidosis symptoms: Prednisone, which is a corticosteroid, usually results in significant weight gain – which itself contributes to sleep apnea. 
  
  
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 sarcoidosis, bladder cancer sarcoidosis, bladder cancer
  
-Read the [[http://bacteriality.com/2008/07/18/interview24/|interview]]+Read the [[https://bacteriality.com/2008/07/18/interview24/|interview]]
  
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 diabetes, sarcoidosis, irritable bowel syndrome diabetes, sarcoidosis, irritable bowel syndrome
  
-Read the [[http://bacteriality.com/2008/06/19/interview22/|interview]]+Read the [[https://bacteriality.com/2008/06/19/interview22/|interview]]
  
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 sarcoidosis of the heart, coronary artery disease, atrial fibrillation sarcoidosis of the heart, coronary artery disease, atrial fibrillation
  
-Read the [[http://bacteriality.com/2008/01/18/interview15/|interview]]+Read the [[https://bacteriality.com/2008/01/18/interview15/|interview]]
  
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 sarcoidosis, cat scratch fever, restless leg syndrome sarcoidosis, cat scratch fever, restless leg syndrome
  
-Read the [[http://bacteriality.com/2007/11/19/interview13/|interview]]+Read the [[https://bacteriality.com/2007/11/19/interview13/|interview]]
  
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 sarcoidosis sarcoidosis
  
-Read the [[http://bacteriality.com/2007/11/17/interview11/|interview]]+Read the [[https://bacteriality.com/2007/11/17/interview11/|interview]]
  
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 sarcoidosis, rheumatoid arthritis sarcoidosis, rheumatoid arthritis
  
-Read the [[http://bacteriality.com/2008/06/03/interview21/|interview]]+Read the [[https://bacteriality.com/2008/06/03/interview21/|interview]]
  
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 sarcoidosis (Heerfordt's Syndrome), uveitis sarcoidosis (Heerfordt's Syndrome), uveitis
  
-Read the [[http://bacteriality.com/2007/11/19/interview12|interview]]+Read the [[https://bacteriality.com/2007/11/19/interview12|interview]]
  
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 sarcoidosis sarcoidosis
  
-Read the [[http://bacteriality.com/2007/11/04/interview7/|interview]]+Read the [[https://bacteriality.com/2007/11/04/interview7/|interview]]
  
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 sarcoidosis, fibromyalgia, chronic fatigue syndrome (CFS) sarcoidosis, fibromyalgia, chronic fatigue syndrome (CFS)
  
-Read the [[http://bacteriality.com/2007/11/08/interview8//|interview]]+Read the [[https://bacteriality.com/2007/11/08/interview8//|interview]]
  
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 neurosarcoidosis, systemic sarcoidosis; spasticity, myasthenia, CNS dysfunction, joint pain, pulmonary, splenic and cardiac involvement neurosarcoidosis, systemic sarcoidosis; spasticity, myasthenia, CNS dysfunction, joint pain, pulmonary, splenic and cardiac involvement
  
-Read the [[http://bacteriality.com/2008/03/02/interview17/|interview]]+Read the [[https://bacteriality.com/2008/03/02/interview17/|interview]]
  
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 ===== Read more ===== ===== Read more =====
  
-  * [[http://bacteriality.com/2008/08/09/berniemac/|Bernie Mac didn’t have to die – pervasive misconceptions about sarcoidosis]]+  * [[https://bacteriality.com/2008/08/09/berniemac/|Bernie Mac didn’t have to die – pervasive misconceptions about sarcoidosis]]
  
 {{tag>disease}} {{tag>disease}}
  
  
 +<nodisp>
 ===== Notes and comments ===== ===== Notes and comments =====
  
 huh ! link removed from gif huh ! link removed from gif
- Source: [[http://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Kanchwala et al.]]}}]+ Source: [[https://meeting.chestpubs.org/cgi/content/abstract/136/4/127S-a|Kanchwala et al.]]}}]
  
-[[http://www.clevelandclinic.org/eye/patient_info/uveitis.asp|Cleveland Clinic]]+[[https://www.clevelandclinic.org/eye/patient_info/uveitis.asp|Cleveland Clinic]]
  
 smoking reduces risk smoking reduces risk
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 <blockquote>The Etiologic Agent of SarcoidosisWhat If There Isn’t One? <blockquote>The Etiologic Agent of SarcoidosisWhat If There Isn’t One?
  
-http://chestjournal.chestpubs.org/content/124/1/6.full+https://chestjournal.chestpubs.org/content/124/1/6.full
 </blockquote> </blockquote>
-===== References =====+===== References =====</nodisp> 
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