0:00 In this video, we're going to talk about dress syndrome, which stands for drug 0:13 reaction 0:14 with ease inophilia and systemic symptoms. 0:18 It's a potentially life-threatening drug-induced hypersensitivity reaction that 0:23 occurs two to 0:24 six weeks of commencing a new drug. 0:29 It is characterized by skin eruption, looking like a more biloform rash, hemat 0:35 ological abnormalities 0:37 such as atypical lymphocytosis, ease inophilia, hence the name, and internal 0:47 organ involvement, 0:49 including the lungs, liver, kidneys, as well as other organs not mentioned. 0:57 The pathogenesis involves a delayed hypersensitivity reaction to a drug, and is 1:01 more characteristic 1:03 of a Type IV hypersensitivity reaction, where the T cells, the immune cells, 1:08 play an important 1:09 role. 1:10 There is also evidence of reactivation of dormant viruses during the infection, 1:14 such 1:15 as Epstein-Bavirus, EBV, and human herpes virus, 6 and human herpes virus 7. 1:24 The latency between drug exposure and onset of symptoms is considerably longer 1:29 in dress 1:29 than in most drug eruptions. 1:32 The clinical presentation includes fever, malays, lymphadenopathy, or around 1:39 the body, 1:40 and eruption of a more biloform rash that evolves differently but occupies more 1:46 than 50% of 1:47 the body's surface area, and here is an example of someone with a more biloform 1:57 rash. 1:58 People with dress can also develop swelling of the face called facial edema, 2:02 and so dress 2:03 is sometimes mistaken for an allergic reaction, like anaphylaxis. 2:10 Other features depend on organ involvement, so we have lung involvement in 2:15 dress, and 2:15 this is quite nonspecific but can include pleural effusion, as well as pneumon 2:22 itis. 2:23 Liver involvement is common and is usually asymptomatic with some liver derang 2:27 ement, however 2:29 other features can include jaundice and hepatomegaly, and worse liver failure. 2:34 Kidney involvement can also include acute interstitial nephritis. 2:41 The cause in culprit is usually a new drug, commenced two to six weeks prior to 2:46 the manifestation 2:48 of symptoms. 2:49 Any drug can really cause dress, but the most common drugs known to cause 2:54 include antiapeleptics 2:56 such as carbamazepine, lomatrogen, phenotone, as well as alopyranol. 3:01 Other drugs include antipsychotics, sulfonomides such as sulfosalazine, as well 3:07 as vancomycin. 3:12 Let's talk about the pathophysiology of dress in a bit more detail. 3:16 There's a lot of theories behind this, and different causes each geology as to 3:21 how they 3:22 immune system responds to a drug. 3:26 There's a metabolism to haptogenic form theory, and it's where a drug is known 3:33 as a prohaptin, 3:34 and when it's metabolized by the liver, it becomes a haptin. 3:38 A haptin, which is usually safe, does not do much. 3:43 But it may bind to certain proteins, termed carrier proteins from different 3:48 parts of 3:49 our body. 3:51 Now when they bind, they form a haptin carrier protein complex, and this 3:56 complex can now 3:58 be detected by antigen-presenting cells, such as macrophages. 4:02 The antigen-presenting cells will express, will pick this complex up, and then 4:08 express 4:09 a component of this protein-habton complex on an MHC class 2 molecule. 4:15 Similarly, circulating B cells, which are also antigen-presenting cells, can 4:21 bind and 4:22 detect this haptin carrier protein complex, take it in, process it, and then 4:27 express its 4:28 component on a MHC class 2 molecule as well. 4:36 Antigen-presenting cells travel to the lymph nodes, where they then activate T 4:41 helper cells. 4:42 Now T helper cells are CD4 cells, because they contain the CD4 receptor, which 4:46 together 4:47 with the T cell receptor, help identify the MHC class 2 molecule, as well as 4:53 the component 4:55 of the drug peptide. 4:58 The T helper cells are activated by interleukin-12, telling it to become T 5:06 helper 1 cells. 5:08 The T helper 1 cells are triggered by interleukin-12, and they're further 5:12 differentiation and 5:13 activity by interleukin-2, which are released by the T helper cells themselves. 5:20 T helper 1 cells stimulate the cell-mediated immune response, by activating mac 5:25 rophages 5:26 with interferon gamma and TNF alpha. 5:31 Macrophages, which are activated, are primed to attack the haptin protein 5:35 complex, presented 5:37 by the antigen-presenting cell initially. 5:39 Now, this haptin carrier protein complex can be anywhere in the body. 5:44 Regardless, the activated macrophage will attack, and as a side effect, causes 5:50 tissue 5:50 inflammation in various areas of the body, via TNF alpha, interleukin-1, and 5:55 interleukin-6. 5:58 T helper 1 cells promote the cell-mediated immune response, by also stimulating 6:02 T-killer 6:03 cells, also known as CD8 T cells. 6:06 CD8 T cells target cells which have interacted with the drug peptide, and will 6:11 kill it, essentially 6:12 further causing inflammation, tissue inflammation, as a side effect. 6:17 This mounting of immune response is what happens in Dres syndrome. 6:22 The first theory we looked at was one called the metabolism of haptogenic form. 6:29 There's also another theory called the direct haptogen theory, whereby the drug 6:34 is not metabolized, 6:36 but it's carried by a carrier protein directly. 6:40 The carrier protein drug complex is identified again by antigen-presenting 6:44 cells mentioned 6:45 earlier, such as the circulating B cells, the monocytes, the macrophages, and 6:50 this will 6:51 again trigger the cascade of events we talked about, leading to T helper 1 cell 6:57 activation. 6:58 The final theory is the PI theory, standing for the pharmacological interaction 7:04 with 7:04 immune receptors theory. 7:07 The PI theory, or concept, postulates that some drugs that lack haptogen 7:15 characteristic 7:15 can bind directly and reversibly to immune receptors, and thereby stimulate the 7:21 cells. 7:22 Here, you can see that a drug binds directly onto the T cell receptor. 7:28 The T helper cell can then be stimulated, or the drug binds to MHC class II 7:35 receptors 7:36 directly, which in turn will stimulate T helper cells via interleukin-12. 7:43 The immune response mounted from the drug will cause tissue inflammation to 7:47 different 7:48 areas of the body, including organs such as the liver, kidneys, and lungs. 7:55 Unique to Dres is that the immune response mounted can trigger the reactivation 8:00 of dormant viruses, 8:02 such as Epstein-Bau virus and human herpes virus. 8:06 The theory here is that the cytokines produced in the inflammatory response, 8:12 such as TNF 8:13 alpha, interleukin-1, and interleukin-6, will stimulate the immune response. 8:19 Some viruses actually stay dormant in these immune cells, so when the immune 8:22 cells get 8:23 stimulated, the virus becomes reactivated. 8:29 The other idea is that antigen-presenting cells, such as B cells, can have 8:32 latent viruses inside 8:33 them chilling out. 8:35 The hapton carrier protein complex we learned about earlier is recognized by 8:39 the antigen-presenting 8:40 cell. 8:41 The antigen-presenting cell is stimulated, and the virus particles that were 8:48 latent inside 8:49 them can be reactivated. 8:52 Thus, the antigen-presenting cell will incorporate part of the virus particles 8:58 with it, expressing 8:59 it on an MHC class 1 molecule together with the drug peptide. 9:05 The stimulated antigen-presenting cell, such as the B cell, will activate the 9:10 latent Epstein-Bau 9:11 virus and human herpes virus. 9:14 The B cell that is expressing the MHC class 1 molecule will be recognized by 9:20 the T-killer 9:21 cell via the CD8 T-cell receptor. 9:26 And thus, the T-killer cell will be stimulated and will attack this V-cell, and 9:31 also will 9:32 cause further tissue information. 9:38 One of the clinical features of dress we have learned is lymphocytosis, 9:42 elevated lymphocytes 9:44 in the blood. 9:45 Lymphocytes specifically T lymphocytes, as we have learned, play a key role in 9:49 the pathophysiology 9:50 of dress. 9:53 The T-helper cells and T-killer cells are known to produce a special interleuk 10:03 in-5. 10:04 And interleukin-5 is a key cytokine for e-cinephyl survival, proliferation, and 10:10 activation. 10:11 So a lot of interleukin-5, secreted by these lymphocytes, will cause e-cinephyl 10:17 ia, a hallmark 10:19 of dress, and plays a key role in the pathophysiology as well. 10:23 E-cinephyls are circulating granulocytes, involved in the host defense, 10:27 normally against 10:28 parasites, bacteria, viruses, as well as in allergic reactions. 10:33 In dress, e-cinephyls infiltrate different organs because of chemokines, which 10:39 attract 10:39 them into these sites. 10:41 Here, the e-cinephyls release their granules, which cause damage to the tissue. 10:47 Thus in the liver, hepatocytes, it can lead to hepatitis, or worse liver 10:52 failure. 10:53 In the cardiomyocytes of the heart, it can lead to myocarditis, and the most 10:58 dangerous 10:59 involvement in dress patients is caused by hot e-cinephyl damage. 11:05 In the pulmonary system, the release of these granules can lead to interstitial 11:09 pneumonitis, 11:10 in the kidneys, interstitial nephritis, and in the skin, you get the 11:16 development of a 11:17 more biliform rash. 11:18 Again, the e-cinephyls infiltrate these organs because these organs release 11:24 chemokines, such 11:25 as eotaxin and tach, which attract the e-cinephyls to the area. 11:29 So that was the overall pathophysiology of dress, and the different theories as 11:34 to how 11:35 the immune response become activated and mounted. 11:39 The most important challenge in dress syndrome is early recognition of the 11:43 condition and 11:44 immediate withdrawal of the offending drug, failing to do so often proves 11:49 crucial, leading 11:50 to unwarranted morbidity and mortality. 11:54 It also involves steroids, topical steroids for mild skin manifestations, or 11:59 more commonly 12:01 high-dose oral or intravenous steroids with organ involvement or critically ill 12:08 people. 12:09 Intravenous immunoglobulin is a possible alternative. 12:14 Steroids are usually weaned over a course of six to eight weeks. 12:19 So in summary, dress is a delayed hypersensitivity reaction to a drug that was 12:25 commenced two 12:26 to six weeks prior to symptomology. 12:31 Treatment involves steroids.
