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"abstract": "BACKGROUND\nWe report a rare case of optic neuropathy following dacryocystorhinostomy (DCR) in a 57-year-old female patient with May-Hegglin anomaly.\n\n\nMETHODS\nThe patient was presented with sudden onset of vision loss for the left eye after DCR under general anesthesia. Her best corrected visual acuity was light perception in the left eye. Relative afferent pupillary defect was detected in her left eye. Magnetic resonance imaging of the orbit revealed an hyperintensity at the intra-orbital segment of the left optic nerve on T2-weighted image and Flair image. The patient was diagnosed with acute postoperative optic neuropathy and treated with methylprednisolone. Although her vision partially improved, she was left with a visual field defect in the left eye.\n\n\nCONCLUSIONS\nIn patients with hematologic diseases, postoperative vision loss can occur following even minor surgery under general anesthesia, such as DCR. Therefore, preoperative counseling regarding the risk of visual loss should be given to high-risk patients.",
"affiliations": "Department of Ophthalmology, School of Medicine, Kosin University, #34 Amnam-dong. Seo-gu, Busan, 602-702, South Korea.;Department of Ophthalmology, College of Medicine, Gyeongsang National University, Gyeongsang National University Changwon Hospital, 121, Samjeongja-ro, Changwon, Gyeongsangnam-do, 51476, South Korea.;Department of Ophthalmology, College of Medicine, Gyeongsang National University, Gyeongsang National University Changwon Hospital, 121, Samjeongja-ro, Changwon, Gyeongsangnam-do, 51476, South Korea.;Department of Ophthalmology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20, Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, 50612, South Korea. pearlsj@hanmail.net.",
"authors": "Lee|Seung Uk|SU|;Huh|Hyoun Do|HD|;Cho|Hyun Kyung|HK|;Kim|Su Jin|SJ|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12886-020-01433-w",
"fulltext": "\n==== Front\nBMC Ophthalmol\nBMC Ophthalmol\nBMC Ophthalmology\n1471-2415 BioMed Central London \n\n1433\n10.1186/s12886-020-01433-w\nCase Report\nA case report of optic neuropathy following dacryocystorhinostomy in a 57-year-old female patient with May-Hegglin anomaly\nLee Seung Uk seung28@hanmail.net 1 Huh Hyoun Do h-h-d@hanmail.net 2 Cho Hyun Kyung hkcho@hanmail.net 2 Kim Su Jin pearlsj@hanmail.net 34 1 grid.411144.50000 0004 0532 9454Department of Ophthalmology, School of Medicine, Kosin University, #34 Amnam-dong. Seo-gu, Busan, 602-702 South Korea \n2 grid.256681.e0000 0001 0661 1492Department of Ophthalmology, College of Medicine, Gyeongsang National University, Gyeongsang National University Changwon Hospital, 121, Samjeongja-ro, Changwon, Gyeongsangnam-do 51476 South Korea \n3 Department of Ophthalmology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20, Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do 50612 South Korea \n4 grid.412591.a0000 0004 0442 9883Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan-si, 50612 South Korea \n19 4 2020 \n19 4 2020 \n2020 \n20 15914 1 2020 13 4 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nWe report a rare case of optic neuropathy following dacryocystorhinostomy (DCR) in a 57-year-old female patient with May-Hegglin anomaly.\n\nCase presentation\nThe patient was presented with sudden onset of vision loss for the left eye after DCR under general anesthesia. Her best corrected visual acuity was light perception in the left eye. Relative afferent pupillary defect was detected in her left eye. Magnetic resonance imaging of the orbit revealed an hyperintensity at the intra-orbital segment of the left optic nerve on T2-weighted image and Flair image. The patient was diagnosed with acute postoperative optic neuropathy and treated with methylprednisolone. Although her vision partially improved, she was left with a visual field defect in the left eye.\n\nConclusions\nIn patients with hematologic diseases, postoperative vision loss can occur following even minor surgery under general anesthesia, such as DCR. Therefore, preoperative counseling regarding the risk of visual loss should be given to high-risk patients.\n\nKeywords\nDacryocystorhinostomyMay-Hegglin anomalyOptic neuropathyissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nWe report a rare case of an optic neuropathy following dacryocystorhinostomy (DCR) in a 57-year-old female patient with May-Hegglin anomaly. Generally speaking, a DCR surgery is a very common and safe procedure that is conducted successfully throughout the world. In its positive context, a DCR can improve the subjective symptoms and the quality of life of patients with nasolacrimal duct obstructions [1]. However, it is noted that rare complications can occur, including hemorrhage, infection, cerebrospinal fluid leakage, and damage to the medial rectus or superior oblique muscle [2]. Ischemic optic neuropathy (ION) has been documented after a non-complex cataract surgery, uncomplicated pars plana vitrectomy (PPV), and non-ocular surgery, such as with a spinal or cardiac surgery [3–6]. The retinal arterial occlusion (RAO), cortical blindness, acute glaucoma, and choroidal and vitreous hemorrhage have been reported as causes of perioperative vision loss (POVL) after a non-ophthalmic surgery [7–10]. However, the instance of an optic neuropathy following DCR has not yet been reported. Here we report a case of acute postoperative optic neuropathy following DCR in a patient previously diagnosed with May-Hegglin anomaly (MHA).\n\nCase presentation\nA 57-year-old female presented with vision loss in the left eye during the restoration of consciousness after endoscopic DCR surgery for the left eye. In this case, the DCR surgery was performed under general anesthesia. Notably, 2 ml of 1% lidocaine with 1:100,000 epinephrine was injected into the axilla of the middle turbinate and the frontal process of the maxilla using a dental syringe. In this case, the neurosurgical patties soaked in 2 ml of 1:1000 epinephrine were inserted between the inferior turbinate and the nasal septum and in the middle meatus to achieve topical decongestion. In the process of making mucosal flap and incision, the patient had a higher bleeding tendency than was noted with other patients, and a suction diathermy was used meticulously for the incidence of hemostasis. For this reason, it did not lead to a major bleeding in this case.\n\nThe patient’s medical history was notable for thrombocytopenia and MHA. Upon review, the patient denied temporal headache, pain, or flashes. When tested, the patient’s best-corrected visual acuity (BCVA) was 20/20 in the right eye and light perception in the left eye. Her intraocular pressure (IOP) was 14 mmHg in the right eye and 16 mmHg in the left eye. Her visual field test result was normal for the right eye. However, the test could not be conducted for the left eye due to the incidence of poor vision. When tested with the swinging flashlight maneuver, a relative afferent pupillary defect was found in the left eye of the patient. Her extraocular movements were noted as being full and painless. However, mild periorbital bruising and swelling were detected in the left eye. Additionally, there was mild maxillary sinusitis noted as well. However, it was shown there was no underlying disease in the other sinuses. On the funduscopic examination, there were no obvious abnormal findings in the macula of either eye. The use of a fluorescent angiography did not reveal leakage or a filling defect at the disc. The baseline testing included blood tests to evaluate syphilis, systemic lupus erythematosus, and neuromyelitis optica. Her erythrocyte sedimentation rate and C-reactive protein results were noted as normal. Her pre-operative platelet count was 61 × 103/mm3. A chest x-ray was performed to evaluate sarcoidosis. She was transfused with six units of platelets preoperatively, which increased her platelet count to 123 × 103/mm3. No other cause of optic neuropathy was found in this evaluation.\n\nThe pattern visual evoked potential revealed delayed P100 latency (Fig. 1). Her electroretinogram showed normal electrical activity in the retina. The magnetic resonance imaging (MRI) of the orbit revealed a focal hyperintensity within the intra-orbital segment of the left optic nerve on the T2-weighted image (T2-WI) and flair image. At evaluation, the MRI showed an enhancement on the T1 post-contrast imaging (Fig. 2). It did not show any demyelinating disease in the brain. The patient was diagnosed with left optic neuropathy and treated with 1 g/day of intravenous methylprednisolone for 3 days, followed by 1 mg/kg/day of oral prednisone with subsequent dose tapering. It is noted that the patient’s BCVA improved to 20/30 after the treatment. Although her vision improved, she was left with a visual field defect in the left eye.\nFig. 1 Pattern visual evoked potential (VEP) revealing delay of P100 latency and decreased amplitude\n\nFig. 2 Axial images of brain MRI (a, b and c: T2-weighted image (T2-WI), Flair images, and T1 post contrast images, respectively). Coronal images of brain MRI (d, e and f: T2-WI, Flair images, and T1 post contrast images, respectively). T2-WI (d) revealing hyperintensity in the intra-orbital segment of the left optic nerve (arrow). T1 post contrast images (f) revealing enhancement in the same level (arrow)\n\n\n\nDiscussion and conclusions\nPerioperative vision loss (POVL) is a rare but devastating consequence of ocular or non-ocular surgery. To this end, the nonarteritic anterior ischemic optic neuropathy (NAION) after cataract surgery or PPV has been reported to result from increased intraocular pressure (IOP), raised intra-orbital pressure from a retrobulbar anesthetic, face-down position, systemic peri-operative hypotension, or a combination of these factors [3, 4, 11, 12]. For this reason, the causes of visual impairment in patients undergoing non-ocular surgery under general anesthesia can be categorized into three main types: ION, retinal vascular occlusion, and cortical vision loss due to a perioperative stroke. The particularly high incidence of ION after coronary artery bypass grafts might be due to an increased blood viscosity caused by induced hypothermia, leading to a watershed injury to the optic nerve head [13–15]. The IOP may also play a role in these cases, because IOP spikes have been demonstrated when bypass circulation begins and the IOP may remain elevated for days after surgery. ION following spinal fusion is most commonly associated with posterior ischemic optic neuropathy (PION) [5]. Ischemia in PION involves the portion of the optic nerve perfused by the small vessels of a pial capillary plexus between the orbital apex posteriorly and the point at which the central retinal artery enters the nerve at its mid-point. As noted, prone positioning can decrease venous outflow by increasing intra-abdominal and intrathoracic pressure, raise IOP, and decrease perfusion pressure of the optic nerve head [16].\n\nIn the present case, the patient was diagnosed with MHA, a rare hematological disorder. MHA is characterized by various degrees of thrombocytopenia, giant platelets, and basophilic, cytoplasmic inclusion bodies in the granulocytes [17, 18]. Here, thrombocytopenia occurs in approximately 50% of the patients with MHA. Likewise, the clinical manifestations vary and range from mild bleeding not requiring specific treatment to severe bleeding episodes following trauma or surgery that require the administration of blood products [17, 18]. To the author’s knowledge, there are no guidelines for preoperative prophylaxis in MHA patients. In general, a platelet count of ≥50 × 109/L is recommended for safe procedures [18]. The present patient experienced neither spontaneous hemorrhage nor other complications before. She was transfused with platelets before the DCR surgery to prevent complications which were associated with bleeding.\n\nThe possible differential diagnoses of this patient included traumatic optic neuropathy, compressive optic neuropathy, inflammatory optic neuropathy, anterior ischemic optic neuropathy (AION), and PION. During the surgery, there was more bleeding tendency than expected, but hemostasis was well done, in order that there was not much bleeding and there were no other problems noted. Since the pupillary reaction was observed during operation, we could rule out direct trauma to the optic nerve by needle. Additionally, as the IOP may be elevated as the injected local anesthetic material passes to the retrobulbar area, or retrobulbar bleeding occurs by needle injury, or the eyeball was pressed inadvertently by the surgeon or assistant, this may play a factor or a role in the occurring AION. However, on funduscopic examination, there was no optic disc edema or peripapillary hemorrhage. The patient’s visual acuity was improved with methylprednisolone. Thus, the possibility of an ION is low. The optic nerve may have been damaged by adrenaline-induced vasospasm, but this is less likely because the concentration and amount of adrenaline were used the same as usual surgery. Bleeding during surgery might have temporarily resulted in hypoperfusion and ischemia to the optic nerve head. Also, the existence of a PION due to hypotension seems to be the most likely cause of this event.\n\nIn this case, despite pre-operative platelet transfusion and uncomplicated surgery, the patient developed vision loss, presumably due to posterior ischemic optic neuropathy. Her underlying hematologic abnormality might have increased the risk of bleeding and caused optic neuropathy. In patients with hematologic diseases, postoperative vision loss can occur following even minor surgery under general anesthesia, such as a DCR. Therefore, preoperative counseling regarding the risk of POVL should be given to high-risk patients, and appropriate prevention should be conducted to minimize the advent of any unanticipated events that can cause devastating visual morbidity.\n\nAbbreviations\nDCRDacryocystorhinostomy\n\nIONIschemic optic neuropathy\n\nPPVPars plana vitrectomy\n\nRAORetinal arterial occlusion\n\nPOVLPerioperative vision loss\n\nMHAMay-hegglin anomaly\n\nBCVABest-corrected visual acuity\n\nIOPIntraocular pressure\n\nMRIMagnetic resonance imaging\n\nNAIONNonarteritic anterior ischemic optic neuropath\n\nPIONPosterior ischemic optic neuropathy\n\nAIONAnterior ischemic optic neuropathy\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThis study was not presented at any other paper.\n\nAuthors’ contributions\nKSJ and LSU is responsible for acquisition of the clinical information and writing up of the manuscript. HHD and CHK is responsible for acquisition of the clinical information and reviewing the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo funding was received for this research.\n\nAvailability of data and materials\nAll data have been presented within the manuscript and in the form of images.\n\nEthics approval and consent to participate\nInformed consent was obtained from all individual participants included in the study.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest, or other equity interest, or non-financial interest in the subject matter or materials discussed in this manuscript.\n==== Refs\nReferences\n1. Sipkova Z Vonica O Olurin O Obi EE Pearson AR Assessment of patient-reported outcome and quality of life improvement following surgery for epiphora Eye (Lond) 2017 31 12 1664 1671 10.1038/eye.2017.120 28622317 \n2. Bernal-Sprekelsen M, Alobid I, Miret JM. Complications of Endoscopic DCR. In: Weber RK, Keerl R, Schaefer SD, Della Rocca RC, editors. Atlas of Lacrimal Surgery, 1st ed. New York: Springer Science & Business Media; 2007. p. 87–90.\n3. Moradi A Kanagalingam S Diener-West M Miller NR Post-cataract surgery optic neuropathy: prevalence, incidence, temporal relationship and fellow eye involvement Am J Ophthalmol 2017 175 3 183 193 10.1016/j.ajo.2016.10.008 27984025 \n4. Cunha LP Cunha LV Costa CF Monteiro ML Nonarteritic anterior ischemic optic neuropathy following pars plana vitrectomy for macular hole treatment: case report Arq Bras Oftalmol 2016 79 5 342 345 10.5935/0004-2749.20160098 27982219 \n5. Lee LA Roth S Posner KL Cheney FW Caplan RA Newman NJ Domino KB The American Society of Anesthesiologists Postoperative Visual Loss Registry: analysis of 93 spine surgery cases with postoperative visual loss Anesthesiology 2006 105 4 652 659 10.1097/00000542-200610000-00007 17006060 \n6. Rubin DS Parakati I Lee LA Moss HE Joslin CE Roth S Perioperative visual loss in spine fusion surgery: ischemic optic neuropathy in the United States from 1998 to 2012 in the nationwide inpatient sample Anesthesiology 2016 125 3 457 464 10.1097/ALN.0000000000001211 27362870 \n7. Biousse V Nahab F Newman NJ Management of acute retinal ischemia: follow the guidelines! Ophthalmology 2018 125 10 1597 1607 10.1016/j.ophtha.2018.03.054 29716787 \n8. Biousse V Newman NJ Ischemic optic neuropathies N Engl J Med 2015 372 25 2428 2436 10.1056/NEJMra1413352 26083207 \n9. De la Garza-Ramos R Samdani AF Sponseller PD Ain MC Miller NR Shaffrey CI Sciubba DM Visual loss after corrective surgery for pediatric scoliosis: incidence and risk factors from a nationwide database Spine J 2016 16 4 516 522 10.1016/j.spinee.2015.12.031 26769351 \n10. Gayat E Gabison E Devys JM Case report: bilateral angle closure glaucoma after general anesthesia Anesth Analg 2011 112 1 126 128 10.1213/ANE.0b013e3182009ad6 21081770 \n11. Luscavage LE Volpe NJ Liss R Posterior ischemic optic neuropathy after uncomplicated cataract extraction Am J Ophthalmol 2001 132 3 408 409 10.1016/S0002-9394(01)00955-2 11530058 \n12. Bansal AS Hsu J Garg SJ Sivalingam A Vander JF Moster M Maguire JI Regillo CD Optic neuropathy after vitrectomy for retinal detachment: clinical features and analysis of risk factors Ophthalmology 2012 119 11 2364 2370 10.1016/j.ophtha.2012.06.002 22840420 \n13. Holy SE Tsai JH McAllister RK Smith KH Perioperative ischemic optic neuropathy: a case control analysis of 126,666 surgical procedures at a single institution Anesthesiol 2009 110 2 246 253 \n14. Berg KT Harrison AR Lee MS Perioperative visual loss in ocular and nonocular surgery Clin Ophthalmol 2010 24 4 531 546 \n15. Nuttall GA Garrity JA Dearani JA Abel MD Schroeder DR Mullany CJ Risk factors for ischemic optic neuropathy after cardiopulmonary bypass: a matched case/control study Anesth Analg 2001 93 6 1401 1416 10.1097/00000539-200112000-00012 \n16. Cheng MA Todorov A Tempelhoff R McHugh T Crowder CM Lauryssen C The effect of prone positioning on intraocular pressure in anesthetized patients Anesthesiol 2001 95 6 1351 1355 10.1097/00000542-200112000-00012 \n17. Balduini CL Pecci A Savoia A Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias Br J Haematol 2011 154 2 161 174 10.1111/j.1365-2141.2011.08716.x 21542825 \n18. Althaus K Greinacher A MYH9-related platelet disorders Semin Thromb Hemost 2009 35 2 189 203 10.1055/s-0029-1220327 19408192\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2415",
"issue": "20(1)",
"journal": "BMC ophthalmology",
"keywords": "Dacryocystorhinostomy; May-Hegglin anomaly; Optic neuropathy",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D003608:Dacryocystorhinostomy; D005260:Female; D006319:Hearing Loss, Sensorineural; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009900:Optic Nerve; D009901:Optic Nerve Diseases; D013921:Thrombocytopenia; D014792:Visual Acuity; D014794:Visual Fields",
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"other_id": null,
"pages": "159",
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"pubdate": "2020-04-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "A case report of optic neuropathy following dacryocystorhinostomy in a 57-year-old female patient with May-Hegglin anomaly.",
"title_normalized": "a case report of optic neuropathy following dacryocystorhinostomy in a 57 year old female patient with may hegglin anomaly"
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"abstract": "We describe a case report of hypertensive crisis induced by a combination of amphetamine and Marwitt's Kidney Pills. Diagnosis was delayed because of nonspecific physical findings including chest pain, abdominal pain, coughing, and diarrhea. This was confounded by puzzling physical examination findings, including green-colored urine and fingernails. Diagnosis was aided with point-of-care ultrasound, which presented a picture of acute cardiac insufficiency, pulmonary congestion, and bilateral effusions. Laboratory values on admission indicated acute multiorgan injury. Detailed patient history revealed chronic consumption of \"Kidney,\" an over-the-counter drug available in Thailand with the primary ingredient methylene blue and used for a myriad of renal and genitourinary conditions. The patient also had a history of amphetamine use, which ultimately initiated his acute presentation.",
"affiliations": "Department of Emergency Medicine, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Department of Emergency Medicine, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Department of Emergency Medicine, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Division of Internal Medicine 'D', Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Cardiac Intensive Care Unit, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Department of General Intensive Care, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.;Division of Internal Medicine 'D', Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.",
"authors": "Trotzky|Daniel|D|;Pachys|Gal|G|;Zarror|Amir|A|;Mosery|Jonathan|J|;Cohen|Aya|A|;Shaheen|Khieralla|K|;Kalmanovich|Eran|E|;Ilgiyaev|Eduard|E|;Goltsman|Galina|G|",
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"fulltext": "\n==== Front\nJ Am Coll Emerg Physicians Open\nJ Am Coll Emerg Physicians Open\n10.1002/(ISSN)2688-1152\nEMP2\nJournal of the American College of Emergency Physicians Open\n2688-1152\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/emp2.12539\nEMP212539\nCase Report\nToxicology\nThe green man enigma: Unique presentation of toxicology in the emergency department\nTROTZKY et al.\nTrotzky Daniel MD 1\nPachys Gal MD 1\nZarror Amir MD 2\nMosery Jonathan MA 2\nCohen Aya 1 ayaco@shamir.gov.il\n\nShaheen Khieralla MD 3\nKalmanovich Eran MD 4\nIlgiyaev Eduard MD 5\nGoltsman Galina MD 3\n1 Department of Emergency Medicine, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n2 Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n3 Division of Internal Medicine 'D', Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n4 Cardiac Intensive Care Unit, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Zerifin, Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n5 Department of General Intensive Care, Shamir Medical Center (formerly Assaf Harofeh Medical Center), Israel, affiliated with the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel\n* Correspondence\nAya Cohen, Department of Emergency Medicine, Shamir Medical Center (Assaf Harofeh Medical Center), Zerifin 70300, Israel.\nEmail: ayaco@shamir.gov.il\n\n05 9 2021\n10 2021\n2 5 10.1002/emp2.v2.5 e1253903 8 2021\n23 5 2021\n04 8 2021\n© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nWe describe a case report of hypertensive crisis induced by a combination of amphetamine and Marwitt's Kidney Pills. Diagnosis was delayed because of nonspecific physical findings including chest pain, abdominal pain, coughing, and diarrhea. This was confounded by puzzling physical examination findings, including green‐colored urine and fingernails. Diagnosis was aided with point‐of‐care ultrasound, which presented a picture of acute cardiac insufficiency, pulmonary congestion, and bilateral effusions. Laboratory values on admission indicated acute multiorgan injury. Detailed patient history revealed chronic consumption of “Kidney,” an over‐the‐counter drug available in Thailand with the primary ingredient methylene blue and used for a myriad of renal and genitourinary conditions. The patient also had a history of amphetamine use, which ultimately initiated his acute presentation.\n\namphetamine\ngreen fingernails\ngreen urine\nhypertensive crisis\n“Kidney”–Marwitt's Kidney Pills\nmethylene blue\npoint‐of‐care ultrasound\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:05.09.2021\nTrotzkyD, PachysG, ZarrorA, et al. The green man enigma: Unique presentation of toxicology in the emergency department. JACEP Open. 2021;2 :e12539. 10.1002/emp2.12539\n\nFunding and support: By JACEP Open policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.\n\nSupervising Editor: Karl Sporer, MD.\n==== Body\npmc1 CLINICAL RECORD\n\nA 41‐year‐old citizen from Thailand with an unclear history of a kidney illness presented to our emergency department (ED) in Israel with nonspecific chest pain, abdominal pain, coughing, and diarrhea. The preliminary clinical picture at a private outpatient clinic showed generally apathy and weakness. The language barrier made ascertaining a precise history of patient illness difficult; a medical history was later obtained over the phone through a translator from the Embassy of Thailand in Israel. The patient had a history of genitourinary complaints and was taking Marwitt's Kidney Pills, an over‐the‐counter supplement available at the time in Thailand. It was determined that the patient had been well until 3 days before his admission, at which point he suddenly developed chest pain with coughing and intermittent nonspecific abdominal pain. The development of symptoms coincided with his acute use of “Ice,” an illegal substance predominantly composed of amphetamine.\n\nOn presentation to our ED, the patient appeared ill and rapidly deteriorated. An electrocardiogram (ECG) demonstrated normal axis, sinus tachycardia of 116 beats, ST‐elevation in lead V3, and biphasic T‐wave in leads V1 and V2. Vital signs on arrival were a pulse of 116 beats per minute, blood pressure of 210/112, and oxygen saturation of 99% in room air. Physical examination findings were notable for bilateral clubbing in the fingers and bilateral edema of the lower extremities. The patient's fingernails were noted to have a distinct green hue (see Figure 1). The color could not be scratched off or removed.\n\nFIGURE 1 Patient's physical examination notable findings\n\nAfter the detection of these odd physical findings, ED staff were equipped in full personal protective equipment as the etiology of his condition may have been an infectious organism or attributed to an environmental exposure. The patient was attached to a monitor, 2 large‐bore intravenous cannulas were placed, blood cultures were taken, and 0.9% NaCl 1000 mL (normal saline) was administered.\n\nA second ECG performed in the ED showed P‐wave inversions in leads V2 and V3, a prolonged QTc interval of 472 milliseconds, poor R‐wave progression through V1 to V5, and T‐wave inversionsin leads V2 and V4, and augmented Vector Left (aVL). Point‐of‐care ultrasound (POCUS) in the ED showed poor cardiac contractility, no focal akinesia, and a mitral valve without flick to the left ventricle wall. Chest ultrasound demonstrated the presence of bilateral B‐lines, a classic finding indicative of pulmonary congestion. Furthermore, no peritoneal fluid was identified on the right upper quadrant and left upper quadrant views, but a positive spine sign indicated pleural effusions. A chest X‐ray confirmed a pleural effusion in the right lobe with bilateral perihilar consolidations and pulmonary congestion. At this stage, a presumptive diagnosis of cardiogenic pulmonary edema was made.\n\nA Foley catheter was inserted, and odd, green‐colored urine was noted (Figure 2). Urinalysis showed the presence of nitrites, proteins, erythrocytes, and leukocytes. A urine toxicology screen, which tested for amphetamine, Δ‐9‐tetrahydrocannabinol, cocaine, opioids, and phencyclidine, was negative, although in retrospect, we could not determine why. Cell microscopy was not performed. Blood work is shown in Table 1. A follow‐up POCUS in the ED demonstrated hydronephrosis with no visible evidence of obstructive stones as well as an ejection fraction between 20% and 25%, with a significant decrease in left ventricle function, intermediate mitral insufficiency, and minimal pericardial effusion.\n\nFIGURE 2 Green‐colored urine\n\nTABLE 1 Selected laboratory values from time of admission\n\n\tPatient laboratory value\tNormal value\t\nTroponin\t0.1 ng/mL\t<0.013 ng/mL\t\nCreatinine\t2.45 mg/dL\t0.70–1.20 mg/dL\t\nUrea\t78 mg/dL\t20–45 mg/dL\t\nPotassium\t6.2 mmol/L\t3.5–5 mmol/L\t\nC‐reactive protein\t15 mg/L\t<10 mg/L\t\nAmylase\t142 U/L\t23–85 U/L\t\nLipase\t63 U/L\t0–160 U/L\t\nJohn Wiley & Sons, Ltd.\n\nIn the ED, treatment was initiated with bisoprolol, hydralazine, amlodipine, Isoket (isosorbide mononitrate), and furosemide. Within a few hours, the patient had significantly improved urine output, and his blood pressure had dropped to between 140 and 100 systolic.\n\nA few hours after admission, a more detailed patient history was ascertained through a translator. The patient admitted to regularly taking an over‐the‐counter drug called Marwitt's Kidney Pills, which he purchased in Thailand for an unspecified “chronic kidney problem” (see Figure 3). It is probable that the patient had an underlying renal disease as evidenced by elevated creatinine, which may have explained his use of “Kidney,” then a readily available and widely used drug for kidney problems. In the ED, the patient had proteinuria, and we suspected rapidly progressive glomerulonephritis or hemolytic uremic syndrome, most likely attributed to drug use. It appears that this drug is no longer available for sale, either over the counter or through a prescription in Thailand.\n\nFIGURE 3 Herbal supplement called “Marwitt's Kidney Pills”\n\nThe patient arrived at the ICU with hyperkalemia of 6.2 mmol/L and was treated with kayexalate. Repeat blood tests showed a maximum troponin of 1 ng/mL and repeat troponin levels between 1 and 0.9 ng/mL, with no rise or fall of troponin as is expected in acute coronary syndrome.\n\nOn day 4, the patient underwent a myocardial perfusion scan that showed no evidence of significant myocardial ischemia. A decrease in left ventricular contraction after dipyridamole injection may indicate a non‐ischemic cardiomyopathy. A repeat echocardiogram demonstrated a significant improvement in global cardiac function with an increased ejection fraction of 40%.\n\nOn day 14, the patient was hemodynamically stable with a blood pressure of 121/69. Although the patient's creatinine level remained as high as 2.1 mg/dL, his urine output and color improved steadily. At discharge, the patient was instructed to abstain from consuming “Ice” in the future, in any form. It was also recommended that he stop taking Marwitt's Kidney Pills, the over the counter drug. Follow‐ups with cardiac, pulmonary, and renal specialists were recommended.\n\n2 DISCUSSION\n\nIn our case report, accurate diagnosis was complicated by an incomplete patient history and rare clinical features. The patient's hypertension along with unique dermatologic findings initially prompted us to suspect a connective tissue disorder or other systemic diseases. We looked for further evidence of vasculitis, systemic sclerosis, or an infectious agent. Rheumatological factors were tested including anti‐nuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), Rh antibodies, Complement system antibodies, antitopoisomerase I antibodies (anti‐SCL‐70), anti‐centromere and anti‐dsDNA antibodies. All of these test results were negative. An extensive infectious and immunological serological test was taken, including hepatitis, rickettsia, brucella, Q‐fever, chlamydia, gonorrhea, syphilis, Epstein‐Barr virus (EBV), cytomegalovirus (CMV), and tuberculosis (TB). These test results also all came back negative.\n\nIndeed, during the patient's time in the ICU, his creatinine level was between 2.4 and 3.25 mg/dL. His baseline creatinine was not known. An underlying renal condition can most probably explain his chronic hypertension. Furthermore, the patient's use of Marwitt's Kidney Pills can explain many of his atypical findings, including discoloring of the nails and urine as well as thickened skin, particularly of the upper extremities.1\n\nA consultation with a team of doctors and pharmacists from Thailand confirmed the drug's biochemical and clinical profile and commonly seen adverse effects. Marwitt's Kidney Pills are a common over‐the‐counter medicine in Thailand and often taken for a myriad of urinary problems. It contains methylene blue, a metabolite of which can cause methemoglobinemia, although we found no evidence of this in our patient. A common adverse effect of this drug is color change in urine, and in our patient specifically, nail beds as well, although we have not found other similar reported cases of a color change in nail beds.2 This adverse effect, although typically surprising to the patient and medical care team, is usually reversible when medication usage is stopped.\n\nThe patient's presentation in hypertensive crisis demanded further investigation. The patient's chronic renal disease could not explain his acute deterioration with significant heart failure. Use of POCUS aided in surveillance of cardiac function and ejection fraction. An ophthalmologist evaluation did not reveal acute fundus changes, and in conjunction with the absence of left ventricular hypertrophy, reduced the probability of hypertensive heart disease, acute coronary syndrome, or acute myocarditis.\n\nThe patient admitted that in the week before his admission, he had consumed large quantities of alcohol and used a drug called “Ice,” which he consumed both intravenously and through inhalation. The primary active ingredient of “Ice” is methamphetamine, although there are often various other compounds added unbeknownst to the users. Although a urine toxicology screen in our ED came back negative for amphetamines, a study in 2019 suggested that emergency clinicians should not rely on the results of urine drug screens to diagnose patients with methamphetamine or amphetamine toxicity as the results of these tests are preliminary and are subject to many external variables that can affect the results. We, therefore, concluded that his acute presentation in hypertensive crisis was caused by his recent use of amphetamine.\n\nPatient care was focused on managing his hypertension and acute presentation of heart and renal failure. The patient's hypertensive crisis resolved shortly after arriving in the ED with appropriate treatment as mentioned previously, including β‐blockers, calcium‐channel blockers, and nitrates. His heart and renal failure stabilized within a few days with supportive treatment. Many other findings associated with his drug use would improve naturally with time after the cessation of use.3\n\n3 CONCLUSION\n\nTo summarize, we identified 2 distinct processes that contributed to our patient's clinical presentation. First, his acute use and abuse of “Ice,” the amphetamine stimulant that triggered a hypertensive crisis and may have caused a reversible cardiomyopathy, although we did not find a direct link. His underlying renal condition may have predisposed him to a rapid decline into a hypertensive crisis. POCUS in the ED provided immediate cardiac and hemodynamic indications in this dynamic patient with an unclear history and aided our clinical work‐up. Despite the odd clinical picture, POCUS allowed us to rapidly “rule out” life‐threatening pathologies associated with hypertensive crisis and aortic dissection, such as focal myocardial akinesia. This permitted early pharmacologic and fluid interventions and helped further focus the diagnosis workup in a patient with unique and seemingly unrelated clinical findings.\n\nSecond, we determined that the patient's unique clinical findings, including discoloration of urine and nails, were caused by his use of Marwitt's Kidney Pills and its active ingredient of methylene blue. We were unfamiliar with this drug and its effects until this presentation.\n\nTogether, these 2 parallel clinical developments created a unique patient presentation that required us to methodically and sequentially move through a differential diagnosis and use many resources at our disposal in the ED, such as POCUS, to exclude life‐threatening causes.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 PrakashS, SainiS, MullickP, PawarM. Green urine: a cause for concern?. J Anesthesiol Clin Pharmacol. 2017;33 (1 ):128‐130.\n2 WiersingaWJ, LimmathurotsakulD, ChengAC. Turning green with shock. Neth J Med. 2009;67 :291‐294.19687527\n3 CruickshankCC, DyerKR. A review of the clinical pharmacology of methamphetamine. Addiction. 2009;104 :1085‐1099.19426289\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2688-1152",
"issue": "2(5)",
"journal": "Journal of the American College of Emergency Physicians open",
"keywords": "amphetamine; green fingernails; green urine; hypertensive crisis; methylene blue; point‐of‐care ultrasound; “Kidney”–Marwitt's Kidney Pills",
"medline_ta": "J Am Coll Emerg Physicians Open",
"mesh_terms": null,
"nlm_unique_id": "101764779",
"other_id": null,
"pages": "e12539",
"pmc": null,
"pmid": "34505114",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "19426289;19687527;28413291",
"title": "The green man enigma: Unique presentation of toxicology in the emergency department.",
"title_normalized": "the green man enigma unique presentation of toxicology in the emergency department"
} | [
{
"companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2021-06280",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE"
},
... |
{
"abstract": "Topiramate, an anticonvulsant used for prophylaxis of migraines and epilepsy, is commonly associated with adverse effects of cognitive dulling and fatigue. Chest pain is a potential adverse effect that to our knowledge has not been reported with the use of topiramate.\nWe present the case of a 38-year-old female with a seizure disorder who experienced chest pain after the first dose of topiramate. On day 1, she presented to the emergency department, was admitted, and over the course of 3 days had a chest X-ray, electrocardiogram (ECG), and echocardiogram, and her vitals, basic metabolic panel, complete blood counts, troponin, and d-dimer levels were monitored. The chest pain improved when the topiramate was held. No identifiable causes of chest pain were apparent, other than the topiramate.\nThe Naranjo probability scale was utilized to determine the causality of topiramate. The resulting score of 3 indicates that it is possible that the chest pain was due to the topiramate.\nThis report demonstrates an example of a patient who experienced chest pain possibly caused by the initiation of topiramate. The objective of this case report is to increase the awareness of chest pain as an adverse effect of topiramate.",
"affiliations": "1 Department of Pharmacy Practice, Western New England University College of Pharmacy and Health Sciences, Springfield, MA, USA.;2 Western New England University College of Pharmacy and Health Sciences, Springfield, MA, USA.;1 Department of Pharmacy Practice, Western New England University College of Pharmacy and Health Sciences, Springfield, MA, USA.;1 Department of Pharmacy Practice, Western New England University College of Pharmacy and Health Sciences, Springfield, MA, USA.",
"authors": "Ostroff|Jared L|JL|;LeClair Barnet|Jessica N|JN|;Ostroff|Marissa L|ML|;Laskey|Corey S|CS|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190017753922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "32(2)",
"journal": "Journal of pharmacy practice",
"keywords": "adverse drug event; antiepileptic drugs; chest pain; topiramate",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002637:Chest Pain; D064420:Drug-Related Side Effects and Adverse Reactions; D004636:Emergency Service, Hospital; D004827:Epilepsy; D005260:Female; D006760:Hospitalization; D006801:Humans; D000077236:Topiramate",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "236-239",
"pmc": null,
"pmid": "29355072",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Topiramate-Induced Chest Pain: A Case Report.",
"title_normalized": "topiramate induced chest pain a case report"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK032465",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABACAVIR SULFATE\\DOLUTEGRAVIR SODIUM\\LAMIVUDIN... |
{
"abstract": "BACKGROUND\nThe function reported after arm transplantation is deemed beneficial relative to the marked disability that upper arm amputation causes.\n\n\nOBJECTIVE\nWe report a 51-year-old man with a Disabilities of the Arm, Shoulder and Hand (DASH) score of 75.83 who underwent bilateral arm transplantation in October 2015.\n\n\nMETHODS\nThe right arm was transplanted at the glenohumeral joint level, including transplantation of the humeral head, joint capsule, and rotator cuff ligaments and tendons. Additionally, neurorrhaphies were performed at the origin of the terminal branches of the brachial plexus, including the axillary and musculocutaneous nerves. Therefore, this was considered a total arm transplantation. The left arm was transplanted at the transhumeral level, with complete transplantation of the biceps and triceps brachii, and terminolateral neurorrhaphy of the donor musculocutaneous nerve to the receptor radial nerve. A maintenance triple immunosuppression scheme was administered, with tacrolimus levels kept at 10 ng/mL.\n\n\nRESULTS\nAt 18 months post-transplantation, the intrinsic musculature in the left hand showed electrical registry, DASH score was 67.5, Carroll test score was 28 in both extremities, Hand Transplant Score System was 67.5 in the right extremity and 77.5 in the left extremity, and Short Form-36 score was 96.1. The patient was healthy, with restored body integrity. He could lift medium-sized weightless objects, eat and go to the bathroom by himself, drink liquids with bimanual grasp, swim, dress almost independently, and drive.\n\n\nCONCLUSIONS\nThe functional evolution of the patient was similar to previously reported transplanted arms, even though the right arm transplant involved the glenohumeral joint and axillary and musculocutaneous nerve repair.",
"affiliations": "Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México. Electronic address: iglesias@drmartiniglesias.com.;Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Transplant Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Laboratory of Clinical Neurophysiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Anesthesiology Department, Hospital Gea Gonzalez, Secretaria de Salud, Ciudad de México, México.;Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Radiology and Imaging Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Radiology and Imaging Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Psychiatry Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Infectology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Infectology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Physical Medicine and Rehabilitation, México City, México.;Dermatology Department, Instituto Nacional de Ciencias Médicas y Nutrición, México City, México.;Transplant Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Dermatology Department, Hospital Gea Gonzalez, Secretaria de Salud, Ciudad de México, México.;Neurology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Endocrinology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.;Ocular Ultrasound Service, Asociación para Evitar la Ceguera en México, IAP, Ciudad de México, México.",
"authors": "Iglesias|M|M|;Ramírez-Berumen|M|M|;Butrón|P|P|;Alberú-Gómez|J|J|;Salazar-Hernández|F|F|;Macias-Gallardo|J|J|;Leal-Villalpando|R P|RP|;Zamudio-Bautista|J|J|;Acosta|V|V|;Jauregui|L|L|;Hernández-Campos|A|A|;Espinosa-Cruz|V|V|;Vázquez-Lamadrid|J|J|;González-Sánchez|J|J|;Cuellar-Rodriguez|J|J|;Sierra-Madero|J G|JG|;Gaytan-Cervantes|R|R|;Contreras-Barbosa|S|S|;Navarro-Lara|A|A|;Guzman-Gonzalez|J|J|;Domínguez-Cherit|J|J|;Vilatoba|M|M|;Toussaint-Caire|S|S|;Vega-Boada|F|F|;Gómez-Pérez|F J|FJ|;Mayorquin-Ruiz|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.12.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000203:Activities of Daily Living; D000671:Amputation; D001132:Arm; D001917:Brachial Plexus; D004185:Disability Evaluation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D016377:Organ Transplantation; D011184:Postoperative Period; D020127:Recovery of Function; D012782:Shoulder; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "950-958",
"pmc": null,
"pmid": "29555246",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Functional Outcomes 18 Months After Total and Midarm Transplantation: A Case Report.",
"title_normalized": "functional outcomes 18 months after total and midarm transplantation a case report"
} | [
{
"companynumb": "MX-ASTELLAS-2018US015356",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "Sunitinib is an oral multitargeted tyrosine kinase inhibitor that was newly approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Although generally well tolerated, common side effects of sunitinib have been reported, with an important and well-recognized example being hypothyroidism. Although the exact mechanism of sunitinib-induced hypothyroidism is unclear, some authors have suggested sunitinib might induce hypothyroidism by the blockade of iodine uptake, destructive thyroiditis and inhibition of peroxidase activity. In these studies autoimmune-mediated hypothyroidism could not be demonstrated as an etiological factor. We herein report the case of a 71-year-old woman diagnosed as metastatic renal cell carcinoma with severe autoimmune hypothyroidism associated with sunitinib after 10 months of treatment. To the best of our knowledge, this is the first report that shows sunitinib may induce autoimmune thyroiditis. Further clinical and experimental studies with larger patient groups are required to verify the findings of the present study. Routine monitoring of thyroid autoantibodies including antithyroglobulin and antithyroid peroxidase antibodies and thyroid ultrasonography are recommended during the treatment of sunitinib-induced hypothyroidism.",
"affiliations": "Department of Oncology, School of Medicine, Hacettepe University, Sihhiye Ankara, Turkey. mdbabacan@mynet.com",
"authors": "Babacan|T|T|;Sevinc|A|A|;Akarsu|E|E|;Balakan|O|O|",
"chemical_list": "D000906:Antibodies; D007211:Indoles; D011758:Pyrroles; D013954:Thyroglobulin; D007453:Iodide Peroxidase; D000077210:Sunitinib",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000337086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "58(2)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000368:Aged; D000906:Antibodies; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007211:Indoles; D007453:Iodide Peroxidase; D007680:Kidney Neoplasms; D011758:Pyrroles; D000077210:Sunitinib; D013954:Thyroglobulin; D013967:Thyroiditis, Autoimmune; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "142-5",
"pmc": null,
"pmid": "22584361",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sunitinib-induced autoimmune thyroiditis in a patient with metastatic renal cell carcinoma: a case report.",
"title_normalized": "sunitinib induced autoimmune thyroiditis in a patient with metastatic renal cell carcinoma a case report"
} | [
{
"companynumb": "TR-PFIZER INC-2012124978",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAutoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis and data is limited in the paediatric population. We aim to describe in detail a cohort of paediatric patients with AIP including their presentation, investigations that led to their diagnosis, management and long-term follow up.\n\n\nMETHODS\nWe retrospectively reviewed the data of 6 patients diagnosed with AIP over an 10-year period. Data including demographics, clinical information, laboratory parameters, serological markers, radiological and histological findings as well as longitudinal follow up were collected.\n\n\nRESULTS\nOut of the six patients, one was diagnosed with definitive Type 1 AIP, two with definitive Type 2 AIP, two with probable Type 2 AIP and one with suspected Type 2 AIP. Median time of follow up was 3.9 years (range 2.6-10.1). 4 patients had pancreatic biopsies with 2 of these patients showing granulocytic epithelial lesions (GELs). 4 patients received steroids and two of them developed ulcerative colitis. Azathioprine was commenced on the patient with Type 1 AIP to help her wean off steroids that caused significant side effects on her. Only two patients developed exocrine insufficiency.\n\n\nCONCLUSIONS\nThe long term follow up of our cohort of paediatric AIP shows good prognosis. More follow up data on patients with AIP is needed to help further characterize and define the disease.",
"affiliations": "Paediatric Liver, GI & Nutrition Centre and MowatLabs, King's College Hospital NHS Foundation Trust, London, UK.;Institute of Liver Studies, King's College London, London, UK.;Institute of Liver Studies, King's College London, London, UK.;Institute of Liver Studies, King's College London, London, UK.;Department of Radiology, King's College Hospital NHS Foundation Trust, London, UK.;Paediatric Liver, GI & Nutrition Centre and MowatLabs, King's College Hospital NHS Foundation Trust, London, UK.;Paediatric Liver, GI & Nutrition Centre and MowatLabs, King's College Hospital NHS Foundation Trust, London, UK.;Paediatric Liver, GI & Nutrition Centre and MowatLabs, King's College Hospital NHS Foundation Trust, London, UK; Institute of Liver Studies, King's College Hospital, Faculty of Life Sciences & Medicine at King's College Hospital, London, UK. Electronic address: t.grammatikopoulos@nhs.net.",
"authors": "Lee|Huey Miin|HM|;Deheragoda|Maesha|M|;Harrison|Phil|P|;Devlin|John|J|;Sellars|Maria|M|;Hadzic|Nedim|N|;Dhawan|Anil|A|;Grammatikopoulos|Tassos|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1016/j.pan.2018.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1424-3903",
"issue": "19(1)",
"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Autoimmune pancreatitis; Children; Diagnosis; Granulocyte epithelial lesion; Immunoglobulin G subclass 4",
"medline_ta": "Pancreatology",
"mesh_terms": "D000293:Adolescent; D001327:Autoimmune Diseases; D002648:Child; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D010195:Pancreatitis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100966936",
"other_id": null,
"pages": "169-176",
"pmc": null,
"pmid": "30455055",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Autoimmune pancreatitis in children: A single centre experience in diagnosis, management and long term follow up.",
"title_normalized": "autoimmune pancreatitis in children a single centre experience in diagnosis management and long term follow up"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1013616",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Disulfiram (tetraethylthiuram disulfide) has been used for the treatment of alcohol dependence. An axonal sensory-motor polyneuropathy with involvement of cranial pairs due to disulfiram is exceedingly rare. The authors report a unique case of an extremely severe axonal polyneuropathy involving cranial nerves that developed within weeks after a regular dosage of 500mg/day disulfiram. To the authors best knowledge, such a severe and rapidly-progressive course has never been described with disulfiram dosages of only 500mg/day.",
"affiliations": "Neurology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Porto, Portugal. Electronic address: telma.cristiana.santos@gmail.com.;Neurology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Porto, Portugal.;Neurology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Porto, Portugal.",
"authors": "Santos|Telma|T|;Martins Campos|António|A|;Morais|Hugo|H|",
"chemical_list": "D000427:Alcohol Deterrents; D004221:Disulfiram",
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"abstract": "The Neuroleptic Malignant Syndrome (NMS) is a medical emergency of infrequent presentation in the emergency department, which is associated with the use of psychiatric drugs, such as typical and atypical antipsychotics. Our case addresses a 55-year-old patient diagnosed with undifferentiated schizophrenia for 10 years, who had been receiving clozapine and clonazepam as part of their treatment. This patient presents the symptoms of Neuroleptic Malignant Syndrome without fever, which improves with treatment especially with the withdrawal of clozapine. In the absence of fever and clinical improvement, the patient is considered to have an atypical presentation of this disease.",
"affiliations": "Emergency Department, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia.;Emergency Department, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia.;Emergency Department, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia.",
"authors": "Leonardo|Quevedo-Florez|QF|0000-0002-7655-7548;Juliana|Granada-Romero|GR|;Fernando|Camargo-Arenas Juan|CJ|",
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"fulltext": "\n==== Front\nCase Rep Emerg MedCase Rep Emerg MedCRIEMCase Reports in Emergency Medicine2090-648X2090-6498Hindawi Publishing Corporation 10.1155/2017/2174379Case ReportAtypical Neuroleptic Malignant Syndrome Associated with Use of Clozapine http://orcid.org/0000-0002-7655-7548Leonardo Quevedo-Florez \n*\nJuliana Granada-Romero Fernando Camargo-Arenas Juan Emergency Department, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia*Quevedo-Florez Leonardo: leonardo.quevedof@gmail.comAcademic Editor: Oludayo A. Sowande\n\n2017 20 2 2017 2017 217437921 9 2016 31 12 2016 10 1 2017 Copyright © 2017 Quevedo-Florez Leonardo et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The Neuroleptic Malignant Syndrome (NMS) is a medical emergency of infrequent presentation in the emergency department, which is associated with the use of psychiatric drugs, such as typical and atypical antipsychotics. Our case addresses a 55-year-old patient diagnosed with undifferentiated schizophrenia for 10 years, who had been receiving clozapine and clonazepam as part of their treatment. This patient presents the symptoms of Neuroleptic Malignant Syndrome without fever, which improves with treatment especially with the withdrawal of clozapine. In the absence of fever and clinical improvement, the patient is considered to have an atypical presentation of this disease.\n==== Body\n1. Introduction\nThe Neuroleptic Malignant Syndrome (NMS) is a medical emergency of rare presentation in a service. Its appearance is associated with the use of a group of drugs frequently used in psychiatry, within which the less frequent ones in developing this disease are atypical antipsychotics such as clozapine. This disease is a fatal syndrome that, despite its clinical symptoms, which is easily recognizable by having a classic presentation, occasionally does not present all the described characteristics; this ignorance and low clinical suspicion lead to delayed diagnosis that can result in progression and fatal outcomes like death.\n\n2. Case\nThis is a 55-year-old male patient institutionalized in a psychiatric clinic 10 years ago, diagnosed with undifferentiated schizophrenia in management with clozapine 500 mg day and clonazepam 6 drops a day, admitted to the emergency room due to altered state of consciousness, disorientation, and decreased production of language, associated with rigidity, with no other symptoms, for one week (37.2°C). Physical examination revealed diaphoretic ingress, tachycardic, afebrile, semidry mucous membranes, disoriented, disintegrated thought, hypoprosexic, bradylaliac, glabellar reflex present, with generalized rigidity, and mild tremor in the upper limbs.\n\nParaclinical exams at admittance are reported in Table 1, EKG is taken with only abnormality QTc 500 msec, simple skull CT scan within normal limits; given the alterations of consciousness associated with increased CPK and stiffness, a NMS diagnosis was made; patient is taken to the resuscitation area, initiating management with Ringers Lactate 2 cc/kg with target urine output of 2 cc/kg/hour, Lorazepam 2 mg orally every 8 hrs, and Bromocriptine 2.5 mg every 12 hours, monitoring thermal curve hourly, daily renal function monitoring, daily CPK control, and urine output.\n\nPatient presents adequate evolution of symptoms of admittance, with complete disappearance of muscle stiffness, improved state of consciousness, no episodes of hyperthermia during hospitalization, with adequate urine output, and decreased CPK without compromise of renal function (Table 2) so that counter-referral to a psychiatric clinic where it was being handled was made.\n\n3. Discussion\nThe Neuroleptic Malignant Syndrome (NMS) was first described in 1960 [1, 2]; it has a low incidence (0.5 to 3%) in patients with use of neuroleptic drugs [3], having an increased risk with typical antipsychotic drugs versus atypical antipsychotics, with mortality reaching 10% [4, 5]. The pathophysiological mechanism is not precise. It is believed to be the result of altered dopamine transmission and, in some cases, it has a direct effect on skeletal muscle [6].\n\nThere is a blockage of the dopaminergic pathways, explaining the development of signs and symptoms of this syndrome as parkinsonism, rigidity, tremor, autonomic dysfunction, hyperthermia, and instability of cardiorespiratory parameters [7]. The two pathogenic mechanisms are as follows: the first mechanism is reduction of dopaminergic signals as a result of acute withdrawal or withdrawal of dopaminergic agents [6]; the other mechanism is by blocking the dopamine signal with the use of medications such as metoclopramide and neuroleptics [8]. The increase in epinephrine and serotonin contributes to the alteration in the transmission of dopamine [9], contributing to hyperthermia and rigidity [6]. There is rhabdomyolysis and muscle damage especially with the use of chlorpromazine and fluphenazine [10].\n\nThe defining characteristics of NMS are hyperthermia, motor symptoms, altered mental status, and autonomic instability; the first two constitute the clinical marker of the syndrome.\n\nEarly symptoms are tachycardia, arrhythmias, hypotension, and cardiac arrest. 50–80% of patients have muscle stiffness, mainly in the form of lockjaw. Hyperthermia usually occurs later and in final phases pulmonary edema and cerebral and disseminated intravascular coagulation occur [11, 12].\n\nThe diagnosis is made by combining clinical and laboratory findings, using the criteria of DSM-V [13] and Levenson [14].\n\nDespite different meta-analysis, there is no consensus that has standardized treatment; suspending the dopaminergic blocking agent or initiating the suspended agonist, hydration, decrease in temperature, correction of electrolyte abnormalities, thromboprophylaxis, and drug treatment as dopamine agonists (bromocriptine as first choice) are suggested, as well as muscle relaxants such as dantrolene. In some cases, ventilatory support or dialysis is suggested until the patient regains cardiorespiratory and renal functions and presents CPK concentrations of <1,000 U/L functions.\n\nAssociated acute renal failure is considered the most serious complication [15] and it is an independent predictor of mortality [16]; this is due to the intense rhabdomyolysis, deposit of myoglobin in the renal tubules, and dehydration, which occurs in about 16% of cases [17] with a mortality of 50% [18].\n\n4. Conclusion\nNMS is an uncommon and lethal neurological disorder [19], attributed to the administration of typical antipsychotics [2, 6, 8, 20, 21] and less commonly to the atypical antipsychotics, like clozapine [5], which has a direct dopaminergic effect but in less proportion than typical antipsychotics especially in D2 receptors. However, clozapine has an effect over serotoninergic pathways that stimulate the 5-HT1A receptor (5-hydroxytryptamine) causing recirculation of gamma amino butyric acid in the nucleus accumbens leading to the inhibition of the dopaminergic neurons [22], related to the development of the disease. There are also some described cases in which the medication relates with stiffness and fever but less frequently [12, 23].\n\nIn our particular case, this diagnosis was considered, since it had rigidity, altered state of consciousness, dysautonomia, and elevation of CPK, with a predisposing pharmacological condition, based on the clinical criteria of DSM-V and Levenson, without different drug consumption in the last 10 years of treatment, evolving appropriately with benzodiazepine, hydration, and withdrawal of clozapine, after 5 days of treatment initiation. The patient may have benefited from the use of dantrolene which was not administered because of the nonavailability of this drug in the institution.\n\nHowever, we emphasize the absence of hyperthermia, since its maximum temperature registered was 37.3°C, fever being one of the typical criteria found in this syndrome [24] considering it as an atypical variant [25].\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nTable 1 \tResult\tControl\t\nLeucocytes (103)\t7,2\t5.0–10\t\nNeutrophils (%)\t63,9\t45–70\t\nLymphocytes (%)\t23\t20–45\t\nHemoglobin (gr/dl)\t15,9\t11–16,5\t\nHematocrit (%)\t46\t42–52\t\nPlatelets (103)\t224.9\t150–450\t\nVSG (mm/hour)\t21\t0–20\t\nPCR (mg/dl)\t1,2\t<2\t\nGlycemia\t95\t65–110\t\nSodium (mEq/l)\t140\t137–145\t\nPotassium (mEq/l)\t3,4\t3,6–5\t\nChlorine (mEq/l)\t110\t98–107\t\nCreatine kinase (CPK) (U/l)\t12446\t0–50\t\nCreatinine (mg/dl)\t0,88\t0,52–1,3\t\nUreic nitrogen (mg/dl)\t24,5\t7,0–20\t\nTable 2 \tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\t\nCreatine kinase (CPK)\t12,446 U/l\t11,778 U/l\t9,046 U/l\t8,300 U/l\t2,762 U/l\t2,245 U/l\t\nCreatinine (mg/dl)\t0,84\t0,81\t0,64\t0,71\t0,64\t0,63\t\nTemperatures\t36,4–37,1°C\t36,5–37°C\t36,7–37,1°C\t36,5–37°C\t36,4–37,3°C\t36,6–37°C\t\nUrine output\t1,3 cc/kg/hour\t2,4 cc/kg/hour\t2,8 cc/kg/hour\t2,0 cc/kg/hour\t1,8 cc/kg/hour\t2,0 cc/kg/hour\n==== Refs\n1 Delay J. Pichot P. Lemperiere T. Elissalde B. Peigne F. A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses Annales Médico-Psychologiques 1960 118 1 145 152 2-s2.0-72849161152 13815606 \n2 Strawn J. R. Keck P. E. Jr. Caroff S. N. Neuroleptic malignant syndrome The American Journal of Psychiatry 2007 164 6 870 876 10.1176/appi.ajp.164.6.870 2-s2.0-34248395553 17541044 \n3 Maheshwari M. Shankaragouda B. H. Savadkar A. Vaishnav S. Haloperidol induced neurolept malignant syndrome complicated by right ventricular myocardial infarction Indian Medical Gazette 2013 79 80 \n4 Chopra M. P. Prakash S. S. Raguram R. The neuroleptic malignant syndrome: an Indian experience Comprehensive Psychiatry 1999 40 1 19 23 10.1016/s0010-440x(99)90071-8 2-s2.0-0032957998 9924872 \n5 Trollor J. N. Chen X. Sachdev P. S. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs CNS Drugs 2009 23 6 477 492 10.2165/00023210-200923060-00003 2-s2.0-66749158086 19480467 \n6 Borja B. Borja C. S. Gade S. Psychiatric emergencies in the geriatric population Clinics in Geriatric Medicine 2007 23 2 391 400 10.1016/j.cger.2007.01.001 2-s2.0-34247180806 17462524 \n7 Heiman-Patterson T. D. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant Medical Clinics of North America 1993 77 2 477 492 10.1016/s0025-7125(16)30265-6 2-s2.0-0027404697 8095087 \n8 Reeves R. R. Mack J. E. Torres R. A. Neuroleptic malignant syndrome during a change from haloperidol to risperidone Annals of Pharmacotherapy 2001 35 6 698 701 10.1345/aph.10137 2-s2.0-0035018959 11408988 \n9 Spivak B. Maline D. I. Vered Y. Prospective evaluation of circulatory levels of catecholamines and serotonin in neuroleptic malignant syndrome Acta Psychiatrica Scandinavica 2000 102 3 226 230 10.1034/j.1600-0447.2000.102003226.x 2-s2.0-0033836815 11008859 \n10 Dosi R. Ambaliya A. Joshi H. Patell R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary BMJ Case Reports 2014 2014 10.1136/bcr-2014-204154 2-s2.0-84964314029 \n11 Rozman C. Elsevier España S. A. Trastornos por el calor y el frío Farreras-Rozman. Medicina Interna 2012 17th Elsevier 2426 2433 \n12 Trollor J. N. Chen X. Chitty K. Sachdev P. S. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics British Journal of Psychiatry 2012 201 1 52 56 10.1192/bjp.bp.111.105189 2-s2.0-84863570344 22626633 \n13 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2013 5th Arlington, Va, USA American Psychiatric Publishing DSM-V \n14 Levenson J. L. Neuroleptic malignant syndrome American Journal of Psychiatry 1985 142 10 1137 1145 10.1176/ajp.142.10.1137 2-s2.0-0022370639 2863986 \n15 Sanai T. Matsui R. Hirano T. Successful treatment of six patients with neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure Renal Failure 2006 28 1 51 55 10.1080/08860220500461252 2-s2.0-32644470053 16526319 \n16 Shalev A. Hermesh H. Munitz H. Mortality from neuroleptic malignant syndrome Journal of Clinical Psychiatry 1989 50 1 18 25 2-s2.0-0024494998 \n17 Shalev A. Munitz H. The neuroleptic malignant syndrome: agent and host interaction Acta Psychiatrica Scandinavica 1986 73 4 337 347 10.1111/j.1600-0447.1986.tb02694.x 2-s2.0-0022469535 2873715 \n18 Korzets Z. Zeltzer E. Bernheim J. Acute renal failure in the setting of the neuroleptic malignant syndrome Nephrology Dialysis Transplantation 1996 11 5 885 886 10.1093/oxfordjournals.ndt.a027422 2-s2.0-0029960909 \n19 Bhanushali M. J. Tuite P. J. The evaluation and management of patients with neuroleptic malignant syndrome Neurologic Clinics 2004 22 2 389 411 10.1016/j.ncl.2003.12.006 2-s2.0-1642298049 15062519 \n20 Smith F. A. Wittmann C. W. Stern T. A. Medical complications of psychiatric treatment Critical Care Clinics 2008 24 4 635 656 10.1016/j.ccc.2008.05.004 2-s2.0-53449098848 18929938 \n21 Ananth J. Parameswaran S. Gunatilake S. Burgoyne K. Sidhom T. Neuroleptic malignant syndrome and atypical antipsychotic drugs Journal of Clinical Psychiatry 2004 65 4 464 470 10.4088/JCP.v65n0403 2-s2.0-2442436578 15119907 \n22 Nagaoka I. Sasa M. Yamawaki S. 5-HT(1A) receptor-mediated inhibition of nucleus accumbens neurons activated by stimulation of parafascicular nucleus of thalamus Psychopharmacology 1998 135 3 230 235 10.1007/s002130050504 2-s2.0-0031594548 9498725 \n23 Karagianis J. L. Phillips L. C. Hogan K. P. LeDrew K. K. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature Annals of Pharmacotherapy 1999 33 5 623 630 10.1345/aph.18286 2-s2.0-0032985192 10369628 \n24 Farver D. K. Neuroleptic malignant syndrome induced by atypical antipsychotics Expert Opinion on Drug Safety 2003 2 1 21 35 10.1517/14740338.2.1.21 2-s2.0-0042385014 12904122 \n25 Schneiderhan M. E. Marken P. A. An atypical course of neuroleptic malignant syndrome Journal of Clinical Pharmacology 1994 34 4 325 334 10.1002/j.1552-4604.1994.tb02001.x 2-s2.0-0028217274 8006200\n\n",
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"abstract": "Amiodarone is an antiarrhythmic medication that can adversely effect various organs including lungs, thyroid gland, liver, eyes, skin, and nerves. The risk of adverse effects increases with high doses and prolonged use. We report a 54-year-old female who presented with multiorgan toxicity after 8 months of low dose (200 mg/day) amiodarone treatment. The findings of confocal microscopy due to amiodarone-induced keratopathy are described. Amiodarone may cause multiorgan toxicity even at lower doses and for shorter treatment periods.",
"affiliations": "Department of Cardiology, Central Hospital, Bayrakli, Izmir, Turkey.;Department of Dermatology, Ege University Medical Faculty, Bornova, Izmir, Turkey.;Department of Ophthalmology, Ege University Medical Faculty, Bornova, Izmir, Turkey.;Department of Cardiology, Central Hospital, Bayrakli, Izmir, Turkey.;Department of Cardiology, Central Hospital, Bayrakli, Izmir, Turkey.;Department of Dermatology, Ege University Medical Faculty, Bornova, Izmir, Turkey.",
"authors": "Turk|Ugur|U|;Turk|Bengu Gerceker|BG|;Yılmaz|Suzan Guven|SG|;Tuncer|Esref|E|;Alioğlu|Emin|E|;Dereli|Tugrul|T|",
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"fulltext": "\n==== Front\nMiddle East Afr J OphthalmolMiddle East Afr J OphthalmolMEAJOMiddle East African Journal of Ophthalmology0974-92330975-1599Medknow Publications & Media Pvt Ltd India MEAJO-22-25810.4103/0974-9233.154411Case ReportAmiodarone-Induced Multiorgan Toxicity with Ocular Findings on Confocal Microscopy Turk Ugur Turk Bengu Gerceker 1Yılmaz Suzan Guven 2Tuncer Esref Alioğlu Emin Dereli Tugrul 1Department of Cardiology, Central Hospital, Bayrakli, Izmir, Turkey1 Department of Dermatology, Ege University Medical Faculty, Bornova, Izmir, Turkey2 Department of Ophthalmology, Ege University Medical Faculty, Bornova, Izmir, TurkeyCorresponding Author: Dr. Suzan Guven Yılmaz, Department of Ophthalmology, Ege University Medical Faculty, TR - 35100 Bornova, Izmir, Turkey. E-mail: drsuzan2003@yahoo.comApr-Jun 2015 22 2 258 260 Copyright: © Middle East African Journal of Ophthalmology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Amiodarone is an antiarrhythmic medication that can adversely effect various organs including lungs, thyroid gland, liver, eyes, skin, and nerves. The risk of adverse effects increases with high doses and prolonged use. We report a 54-year-old female who presented with multiorgan toxicity after 8 months of low dose (200 mg/day) amiodarone treatment. The findings of confocal microscopy due to amiodarone-induced keratopathy are described. Amiodarone may cause multiorgan toxicity even at lower doses and for shorter treatment periods.\n\nAmiodaroneConfocal MicroscopyMultiorgan Toxicity\n==== Body\nINTRODUCTION\nAmiodarone is a class III antiarrhythmic agent that is efficacious against all types of tachyarrhythmias. This medication is primarily used for preventing paroxysmal and persistent episodes of atrial fibrillation. However, the duration if use is limited due to the adverse effects association with amiodarone.123 In this report, we present a case of persistent atrial fibrillation that developed symptomatic hypothyroidism, skin discoloration, hepatotoxicity and corneal vortex keratopathy after 8 months of amiodarone therapy.\n\nCASE REPORT\n54-year-old female was admitted to the outpatient cardiology clinic with paroxysmal palpitation episodes 8 months prior to presentation at our center. Holter-electrocardiogram recordings demonstrated episodes of paroxysmal atrial fibrillation. After comprehensive cardiac evaluation, amiodarone therapy was started at an initial dose of 200 mg/day. General malaise, cold intolerance and blue-gray discoloration of the skin were noticed 7 months later. Dermatologic examination revealed bluish discoloration on the nose and cheeks [Figure 1a]. On histopathology, perivascular brown-gray pigment granule laden histiocytes were observed in the superficial dermis. Laboratory tests indicated slightly elevated serum aminotransferase levels (aspartate aminotransferase 54 μ/l [<31], alanine aminotransferase 73 μ/l [<34]). Thyroid function tests indicated hypothyroidism (free T4, 0.51 ng/dL [reference range, 0.7–2.01]; and thyroid-stimulating hormone, 41.23 μIU/mL [reference range, 0.4–3.1]). The patient was referred to an ophthalmologist for potential eye toxicity.\n\nThe patient underwent a complete ophthalmologic examination including measurement of visual acuity (VA), slit-lamp biomicroscopy, applanation tonometry, and dilated fundus examination. VA was 20/20 in both eyes. The intraocular pressures were within normal limits and the fundus examination was unremarkable in both eyes. There was no afferent pupillary defect. Slit-lamp examination indicated vortex keratopathy in both eyes. Vortex keratopathy was classified based on the grading system proposed by Orlando et al.4 The right eye presented with grade 1 vortex keratopathy (characterized by a horizontal line in the inferior third of the cornea), the left eye presented with grade 4 (a whorl-like pattern with additional clumps of pigment) [Figure 1b and c]. Both eyes underwent confocal laser-scanning microscopy (CLSM), (Heidelberg Retina Tomograph, HRT II) equipped with the Rostock cornea module (Heidelberg Engineering GmbH, Heidelberg, Germany). CLSM revealed hyper-reflective intracellular inclusions in both corneas. Inclusions were observed in the epithelium, stroma, and subepithelial nerves in both eyes [Figure 1d-g]. These findings were more evident in the epithelial basal cell layers. In the left eye with advanced keratopathy (stages 4), bright microdots were also detectable within the posterior stroma. Due to the ocular, skin and thyroid toxicity of the drug, amiodarone therapy was stopped and the patient underwent radiofrequency ablation for atrial fibrillation. Serum aminotransferase levels returned to normal limits after cessation of amiodarone. Although the discoloration of the face and vortex keratopathy regressed, this side effect did not disappear during the 5 months follow-up period.\n\nFigure 1 (a) Blue-grey discoloration on the nose and central cheeks. Amiodarone-induced corneal opacities; (b) horizontal line in the inferior third of the cornea in the right eye, (c) whorl-like pattern of powdery, white, yellow or brown corneal deposits of the left eye. In vivo confocal microscopic images of hyperreflective intracellular inclusions of amiodarone keratopathy (d) in epithelial cells, (e) in basal epithelial cells, (f) in stroma, (g) no deposits in the endothelium\n\nDISCUSSION\nAmiodarone is an iodinated benzofuran derivative. It has been associated with toxicity affecting the lungs, thyroid gland, liver, eyes, skin, and nerves. The daily (400 mg/day) and cumulative dose (100 g) combined with the length of therapy is associated with the toxicity. However, toxic effects may also be observed at lower maintenance doses, as observed in our patient.123\n\nThe most common cutaneous adverse effect of amiodarone is photosensitivity. Photosensitivity develops in approximately 75% of the patients usually after 4 months of treatment. Photosensitivity may persist between 4 and 12 months after stopping amiodarone. Eight percent of patients can develop hyperpigmentation due to accumulation of amiodarone metabolites on skin exposed to regular sunlight after 20 months of use. The primary step for skin discoloration is cessation of amiodarone. The pigmentation usually resolves within 2 years after cessation of the drug.345\n\nThe ocular effect of amiodarone is vortex keratopathy creating a whorl-like pattern by producing lysosomal deposits in the basal epithelial layer.67 The whorl-like pattern which was firstly described by Fleischer in 1910 is characterized as powdery, white, yellow, or brown corneal opacities beneath the cornea apex.4 Amiodarone reaches the cornea via the tear film, aqueous humor, and limbal vasculature. The drug or its metabolites penetrate lysosomes and bind with cellular lipids, producing drug-induced lipidosis.7 In the eye lysosomal storage leads to typical side-effects. Vortex keratopathy is the most common (70–100%) ocular change caused by amiodarone.8 Although the most common findings are corneal, lens opacities and optic neuropathy have also been reported due to amiodarone.910 In the current cases, lens changes and retinal changes were not observed. Photophobia, colored rings around lights and ocular irritation are the common symptoms of patients with amiodarone-induced keratopathy.910 However the patient in this case report did not complain of any of these symptoms. Corneal changes secondary to systemic amiodarone can affect all corneal layers.6811 Our patient also had amiodarone-induced deposits within the corneal epithelium and stroma, but there were no deposits in the endothelial layer. The vision of this patient was not affected. Although corneal deposition is not an indication for drug cessation, patients receiving this medication should be monitored for symptoms related to corneal deposition and ocular toxicity.12\n\nThe iodine content of amiodarone effects thyroid functions ranging from mild changes to hypothyroidism or thyrotoxicosis. The frequency of hyperthyroidism and hypothyroidism is 2% and 6% respectively. In case of amiodarone-induced thyroid dysfunction, “dronedarone,” an iodine free variant of amiodarone is preferred.1 The patient in this case report complained of general malaise and cold intolerance. These symptoms may be attributed to hypothyroidism. Liver transaminase levels may be elevated in 0.6% of the patients. Amiodarone should be discontinued, if the liver enzymes are three times higher than normal limits.1 In our patient, liver enzymes were slightly elevated.\n\nCONCLUSION\nThis case indicates that multiorgan toxicity due to amiodarone may develop even with short-term use and a low maintenance dose. Hence amiodarone should be used at lowest possible doses. Laboratory studies including liver and thyroid functions should be checked every 6 months and ocular examination should be done regularly to detect ocular side effects to prevent irreversible ocular damages in patients taking amiodarone.\n\nSource of Support: Nil\n\nConflict of Interest: None.\n==== Refs\nREFERENCES\n1 Siddoway LA Amiodarone: Guidelines for use and monitoring Am Fam Physician 2003 68 2189 96 14677664 \n2 Harris L McKenna WJ Rowland E Holt DW Storey GC Krikler DM Side effects of long-term amiodarone therapy Circulation 1983 67 45 51 6291807 \n3 Rappersberger K Hönigsmann H Ortel B Tanew A Konrad K Wolff K Photosensitivity and hyperpigmentation in amiodarone-treated patients: Incidence, time course, and recovery J Invest Dermatol 1989 93 201 9 2754275 \n4 Orlando RG Dangel ME Schaal SF Clinical experience and grading of amiodarone keratopathy Ophthalmology 1984 91 1184 7 6514284 \n5 Yones SS O’Donoghue NB Palmer RA Menagé Hdu P Hawk JL Persistent severe amiodarone-induced photosensitivity Clin Exp Dermatol 2005 30 500 2 16045677 \n6 Hollander DA Aldave AJ Drug-induced corneal complications Curr Opin Ophthalmol 2004 15 541 8 15523201 \n7 D’Amico DJ Kenyon KR Ruskin JN Amiodarone keratopathy: Drug-induced lipid storage disease Arch Ophthalmol 1981 99 257 61 6258544 \n8 Uçakhan OO Kanpolat A Ylmaz N Ozkan M Amiodarone keratopathy: An in vivo confocal microscopy study 2005 31 148 57 \n9 Flach AJ Dolan BJ Sudduth B Weddell J Amiodarone-induced lens opacities Arch Ophthalmol 1983 101 1554 6 6626008 \n10 Gittinger JW Jr Asdourian GK Papillopathy caused by amiodarone Arch Ophthalmol 1987 105 349 51 3827710 \n11 Mäntyjärvi M Tuppurainen K Ikäheimo K Ocular side effects of amiodarone Surv Ophthalmol 1998 42 360 6 9493278\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-9233",
"issue": "22(2)",
"journal": "Middle East African journal of ophthalmology",
"keywords": "Amiodarone; Confocal Microscopy; Multiorgan Toxicity",
"medline_ta": "Middle East Afr J Ophthalmol",
"mesh_terms": "D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D003316:Corneal Diseases; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D018613:Microscopy, Confocal; D008875:Middle Aged; D009102:Multiple Organ Failure",
"nlm_unique_id": "101521797",
"other_id": null,
"pages": "258-60",
"pmc": null,
"pmid": "25949090",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14677664;6258544;6291807;6626008;6514284;16045677;2754275;9493278;15523201;16021002;3827710",
"title": "Amiodarone-induced multiorgan toxicity with ocular findings on confocal microscopy.",
"title_normalized": "amiodarone induced multiorgan toxicity with ocular findings on confocal microscopy"
} | [
{
"companynumb": "TR-MYLANLABS-2015M1015528",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": null,
... |
{
"abstract": "Spontaneous periodic hypothermia is a rare syndrome presenting with recurrent, centrally mediated hypothermia without an identifiable systemic cause or brain lesion. The case of an 88-year-old woman with recurrent hypothermia is reported. Despite intensive investigation, no other manifestations of hypothalamic or autonomic dysfunction were found. No corpus callosum lesion was seen on MRI. The patient was successfully treated with clomipramine chlorhydrate.\nPeriodic hypothermia in the elderly is a rare and possibly under-recognised syndrome.The causes of the syndrome remain unknown.Pharmacological trials have only been modestly successful.",
"affiliations": "Internal Medicine Unit, General Hospital, Ales, France.;Internal Medicine Unit, General Hospital, Ales, France.;Internal Medicine Unit, General Hospital, Ales, France.",
"authors": "Attout|Hassene|H|;Amichi|Sofia|S|;Belkheir|Youcef|Y|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001874",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n10.12890/2020_001874\n1874-1-16651-2-10-20200928\nArticles\nSpontaneous Periodic Hypothermia in the Elderly: A Rare or Under-Recognised Syndrome\nAttout Hassene Amichi Sofia Belkheir Youcef Internal Medicine Unit, General Hospital, Ales, France\n2020 \n28 9 2020 \n7 12 00187406 7 2020 13 7 2020 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseSpontaneous periodic hypothermia is a rare syndrome presenting with recurrent, centrally mediated hypothermia without an identifiable systemic cause or brain lesion. The case of an 88-year-old woman with recurrent hypothermia is reported. Despite intensive investigation, no other manifestations of hypothalamic or autonomic dysfunction were found. No corpus callosum lesion was seen on MRI. The patient was successfully treated with clomipramine chlorhydrate.\n\nLEARNING POINTS\nPeriodic hypothermia in the elderly is a rare and possibly under-recognised syndrome.\n\nThe causes of the syndrome remain unknown.\n\nPharmacological trials have only been modestly successful.\n\nPeriodic hypothermiaShapiro’s syndromeclomipramine\n==== Body\nINTRODUCTION\nSpontaneous periodic hypothermia (SPH), defined as a core temperature below 35°C, is rare and occurs in association with a range of brain pathologies, including congenital brain disease, and acquired traumatic, ischaemic, neoplastic or inflammatory mechanisms involving the hypothalamus. In 1969, Shapiro et al. described the first two cases of SPH associated with agenesis of the corpus callosum[1]. Since then, numerous cases of idiopathic recurrent hypothermia have been described without corpus callosum agenesis. Structural, epileptiform or biochemical abnormalities have been suggested as possible causes. However, the aetiology of SPH has not yet been elucidated.\n\nPharmacological trials to date have been only modestly successful. Anticonvulsant agents, clonidine, clomipramine and cyproheptadine appear the most likely successful treatments[2, 3].\n\nCASE DESCRIPTION\nAn 88-year-old woman presented to the emergency department with repeated episodes of hypothermia and confusion over a 4-year period. Her medical history included hypertension, hypothyroidism and colonic diverticular disease. Her regular medications were aspirin, furosemide and levothyroxine. The patient was a non-smoker and did not consume alcohol. There was no history of abnormal behaviour or seizures. Her family history was unremarkable.\n\nThe patient first’s episode of hypothermia occurred in April 2016. On each of her five admissions, her peripheral body temperature recorded on arrival ranged from 30°C to 34°C.\n\nDuring each episode, the patient presented with confusion, dysarthria and mild ataxia. No hyperhidrosis was noted. There was no seasonal or diurnal variation. On each occasion, the hypothermia, confusion and ataxia resolved within 3–5 days with only supportive therapy. Between episodes of hypothermia, the patient returned to normal function without complaints despite her advanced age.\n\nSeptic screening tests were consistently negative. Investigation of anterior pituitary, thyroid and adrenal cortical function was normal at baseline and during hypothermia events. All biochemistry tests were within normal limits. CSF study was also normal. No antibodies against neuronal cell-surface antigens were found. Other investigations, including thermoregulatory sweat testing and autonomic reflex screening, were unremarkable\n\nBrain MRI was carried out three times and showed only mild atrophy. The corpus callosum, hypothalamus and pituitary were normal. An EEG was performed during each episode without findings of seizures or focal abnormalities. A diagnosis of SPH was made.\n\nThe patient was treated with lamotrigine and levetiracetam for 12 months without any response. Finally, in February 2019, oral clomipramine 25 mg per day was initiated and the patient remains asymptomatic to date.\n\nDISCUSSION\nThermoregulation maintains the temperature of the human body at 37°C by a complex mechanism. Induced or accidental hypothermia may occur in multiple clinical settings and may be caused by metabolic disorders, endocrine disorders, malnutrition, drugs, dermal dysfunction, sepsis and CNS dysfunction [2, 4–6]. The results of a review of the national French pharmacovigilance database showed that nearly a quarter (153/614) of cases of drug-related hypothermia were attributed to psychotropic drugs, mainly neuroleptics[4].\n\nVery rarely, periodic hypothermia has been observed with agenesis of the corpus callosum (Shapiro’s syndrome), with CNS abnormalities affecting structures related to thermoregulation, and without an associated systemic disease or obvious brain lesion. Prodromal sweating was a feature of most cases [1–3].\n\nShapiro’s syndrome is characterized by spontaneous recurrent episodes of hypothermia, hyperhidrosis and corpus callosum (CC) agenesis. Less than 80 cases have been reported to date and the pathogenic mechanism as well as the prognosis of this syndrome is still debated. It was suggested that episodes of hypothermia were due to a paroxystic reset of the hypothalamic thermostat with a lower temperature set point[1].\n\nOur case is consistent with previously reported cases of SPH. In those cases, the periodicity of hypothermia attacks ranged from hours to years and episodes lasted from hours to weeks[2, 3]. In our case, Shapiro’s syndrome was excluded due to the age of patient and absence of corpus callosum agenesis. A degenerative or autoimmune process was also excluded.\n\nThere is general consensus among authors that an altered central thermoregulatory mechanism is the determining factor for the fluctuating body temperatures in both Shapiro’s syndrome and SPH. Some authors have postulated an epileptic basis for SPH on the basis of EEG changes and some responsiveness to anticonvulsant therapy. However, others have noted that several antiepileptic drug trials have failed, and argue that the EEG changes may be secondary to hypothermia[2,7]. Rodrigues et al. found a consistent abnormality in cerebral neurotransmitter levels in patients with SPH without corpus callosum agenesis[8]. Recently, Tambasco et al. highlighted that agenesis of the corpus callosum was seen in only 40% of cases reported in the literature [9].\n\nDrug therapy with clonidine, oxybutynin, carbamazepine, pizotifen, clomipramine and chlorpromazine has been successful in rare cases[4,7]. In our patient, treatment with anticonvulsants (levetiracetam, lamotrigine) was tried without any response. Eventually our patient was treated with low-dose clomipramine (25 mg/day) and after 18 months, she remains free from hypothermia attacks.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Shapiro WR Williams GH Plum F Spontaneous recurrent hypothermia accompanying agenesis of the corpus callosum Brain 1969 92 423 436 5790256 \n2 Blondin NA Diagnosis and management of periodic hypothermia Neurol Clin Pract 2014 4 1 26 32 29473588 \n3 Kloos RT Spontaneous periodic hypothermia Medicine (Baltimore) 1995 74 5 268 280 7565067 \n4 Bosacki C Hausfater P Koenig M Serratrice J Piette AM Cathebras P Spontaneous hypothermia: a series of ten cases, place of Shapiro’s syndrome Rev Med Interne 2005 26 8 615 623 15990200 \n5 Mayer U Aigner JM Klein HE Hypothermia caused by neuroleptics: 2 case reports and review of the literature Nervenarzt 1994 65 7 488 491 7800095 \n6 Hemelsoet DM De Bleecker JL Post-traumatic spontaneous recurrent hypothermia: a variant of Shapiro’s syndrome Eur J Neurol 2007 14 2 224 227 17250734 \n7 Walker BR Anderson JA Edwards CR Clonidine therapy for Shapiro’s syndrome Q J Med 1992 82 299 235 245 1631258 \n8 Rodrigues MM Lin J Arita JH De Castro Neto EF Scerni DA Cavalheiro EA Spontaneous periodic hypothermia and hyperhidrosis: a possible novel cerebral neurotransmitter disorder Dev Med Child Neurol 2011 53 378 380 21166673 \n9 Tambasco N Belcastro V Prontera P Nigro P Donti E Rossi A Shapiro’s syndrome: defining the clinical spectrum of the spontaneous paroxysmal hypothermia syndrome Eur J Paediatr Neurol 2014 18 453 457 24594427\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "7(12)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Periodic hypothermia; Shapiro’s syndrome; clomipramine",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001874",
"pmc": null,
"pmid": "33312996",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "7565067;17250734;5790256;15990200;7800095;29473588;1631258;21166673;24594427",
"title": "Spontaneous Periodic Hypothermia in the Elderly: A Rare or Under-Recognised Syndrome.",
"title_normalized": "spontaneous periodic hypothermia in the elderly a rare or under recognised syndrome"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1003074",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "Bevacizumab is a human monoclonal immunoglobulin G1 antibody to vascular endothelial growth factor indicated in several adult diseases. Emerging literature and expert opinion support the off-label use of intravitreal bevacizumab in the treatment of retinopathy of prematurity (ROP), a common disease process seen in premature neonates. One of the most common side effects of systemic therapy in adults is hypertension; however, this has not been well described in infants receiving bevacizumab for ROP. In this report, we review a case of a former 25-week premature infant treated for stage 3 ROP with administration of intravitreal bevacizumab. The immediate posttreatment course was uncomplicated; however, at 10 days posttreatment, he developed new-onset systemic hypertension. In addition, neuroimaging revealed new areas of vasogenic edema, which improved over time. To the best of our knowledge and after a review of the literature, neither of these effects has been described in neonates after intravitreal bevacizumab for ROP.",
"affiliations": "Departments of Pediatrics and gtwitty@ufl.edu.;Departments of Pediatrics and.;Radiology, University of Florida, Gainesville, Florida; and.;Department of Pharmacy, University of Florida Health Shands Hospital, Gainesville, Florida.;Departments of Pediatrics and.",
"authors": "Twitty|Grace|G|;Weiss|Michael|M|;Albayram|Mehmet S|MS|;O'Mara|Keliana|K|;Mowitz|Meredith E|ME|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-1814",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "145(1)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001921:Brain; D001929:Brain Edema; D006801:Humans; D006973:Hypertension; D007223:Infant; D007234:Infant, Premature; D058449:Intravitreal Injections; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D012178:Retinopathy of Prematurity; D014463:Ultrasonography; D066127:White Matter",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31806670",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypertension and Neuroimaging Changes After Bevacizumab for Retinopathy of Prematurity.",
"title_normalized": "hypertension and neuroimaging changes after bevacizumab for retinopathy of prematurity"
} | [
{
"companynumb": "US-AMGEN-USASP2019207599",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB-AWWB"
},
"drugadditional": "3",
... |
{
"abstract": "A shortage in organs for transplantation has led to the increased use of hepatitis C (HCV) infected donor organs for solid organ transplant recipients infected with HCV. However, the donor HCV genotype is not routinely checked or known prior to transplant. Here, we report 4 cases of genotype conversion after transplantation in patients receiving HCV infected donor organs. This change in genotype may potentially impact HCV progression as well as treatment choice for these patients.",
"affiliations": "Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA.;University of Maryland School of Pharmacy, Baltimore, MD, USA.;University of Maryland School of Pharmacy, Baltimore, MD, USA.;Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.;Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.",
"authors": "Adekunle|R|R|;Jonchhe|S|S|;Ravichandran|B|B|;Wilson|E|E|;Husson|J|J|http://orcid.org/0000-0001-8203-1019",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12925",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "genotype; hepatitis C; transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D064591:Allografts; D000998:Antiviral Agents; D046148:Donor Selection; D058625:End Stage Liver Disease; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006084:Graft Rejection; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D000072230:Sustained Virologic Response",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12925",
"pmc": null,
"pmid": "29797655",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis C genotype change after transplantation utilizing hepatitis C positive donor organs.",
"title_normalized": "hepatitis c genotype change after transplantation utilizing hepatitis c positive donor organs"
} | [
{
"companynumb": "US-PFIZER INC-2018391063",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.",
"affiliations": "Medical University of South Carolina - MUSC, Charleston, SC, USA.;Department of Pediatrics Cardiology, MUSC, Charleston, SC, USA.;Department of Pediatric Gastroenterology, MUSC, Charleston, SC, USA.;Department of Hematology/Oncology, MUSC, Charleston, SC, USA.;Department of Pediatric Nephrology, MUSC, Charleston, SC, USA.;Department of Pediatrics Cardiology, MUSC, Charleston, SC, USA.;Department of Pathology, MUSC, Charleston, SC, USA.;Department of Pediatrics Cardiology, MUSC, Charleston, SC, USA.;Department of Pathology, MUSC, Charleston, SC, USA.",
"authors": "Lewis|Kimberly|K|;Butts|Ryan|R|;Antonio Quiros|J|J|;Hudspeth|Michelle|M|;Twombley|Katherine|K|;Savage|Andrew|A|;Self|Sally|S|;Burnette|Ali|A|;Sun|Shaoli|S|",
"chemical_list": "C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12877",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(2)",
"journal": "Pediatric transplantation",
"keywords": "T lymphocytes; autoimmune enteropathy; heart transplant; sirolimus; solid organ transplantation; thymectomy",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001402:B-Lymphocytes; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors; D006333:Heart Failure; D016027:Heart Transplantation; D006505:Hepatitis; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007413:Intestinal Mucosa; D016884:Polyendocrinopathies, Autoimmune; D020123:Sirolimus; D013601:T-Lymphocytes; D016559:Tacrolimus; D013934:Thymectomy; D015854:Up-Regulation",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28097735",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient.",
"title_normalized": "autoimmune enteropathy and hepatitis in pediatric heart transplant recipient"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0087196",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugaddition... |
{
"abstract": "A young child with catastrophic neurological illness diagnosed as a rare variant of acute demyelinating encephalomyelitis (ADEM). She succumbed to her illness despite of aggressive and appropriate management. Malignant demyelinating encephalomyelitis should be considered in children who are refractory to the treatment of ADEM.",
"affiliations": "Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, India.;Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, India.;Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, India.;Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, India.;Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, India.",
"authors": "Kushwaha|Suman|S|;Gupta|Ashutosh|A|;Agarwal|Neha|N|;Chaturvedi|Sujata|S|;Jha|Deepak|D|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/aian.AIAN_52_17",
"fulltext": "\n==== Front\nAnn Indian Acad NeurolAnn Indian Acad NeurolAIANAnnals of Indian Academy of Neurology0972-23271998-3549Medknow Publications & Media Pvt Ltd India AIAN-20-31610.4103/aian.AIAN_52_17Case ReportHyper Acute Demyelinating Encephalomyelitis of Childhood: A Rare Entity Kushwaha Suman Gupta Ashutosh Agarwal Neha Chaturvedi Sujata Jha Deepak Department of Neurology, Pathology, Neurosurgery, Institute of Human Behaviour and Allied Sciences, New Delhi, IndiaAddress for correspondence: Dr. Suman Kushwaha, Institute of Human Behaviour and Allied Sciences, New Delhi - 110 095, India. E-mail: sumankushwaha@gmail.comJul-Sep 2017 20 3 316 318 Copyright: © 2006 - 2017 Annals of Indian Academy of Neurology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A young child with catastrophic neurological illness diagnosed as a rare variant of acute demyelinating encephalomyelitis (ADEM). She succumbed to her illness despite of aggressive and appropriate management. Malignant demyelinating encephalomyelitis should be considered in children who are refractory to the treatment of ADEM.\n\nAcute demyelinating encephalomyelitismalignantrefractorytreatment\n==== Body\nINTRODUCTION\nAcute disseminated encephalomyelitis (ADEM) is an acute widespread demyelinating condition usually affecting young adults and children. It usually follows an infection or vaccination causing demyelination in brain and spinal cord. Failure to identify a viral agent suggests that the inciting agents are unusual or cannot be recovered by standard laboratory test. Possibly, a complex interplay among cytokines, chemokines, and adhesion molecules is responsible for the cellular events of inflammatory encephalomyelitis. Management consist of immunomodulation targeted to suppress a presumed aberrant immune response to an infectious agent or a vaccination. Malignant variants of ADEM, represent 2% of cases with catastrophic rapid symptom progression, malignant brain edema, non-responsiveness to treatment and high mortality rates.\n\nCASE REPORT\nA 15-year-old female presented with short history of acute onset bilateral vision loss and left-sided hemiparesis of 7 days’ duration. These symptoms were preceded by a febrile illness 8–10 days back. The symptoms were sudden in onset and progressive in nature. There was no prior history of significant medical illness, drug or toxin exposure, and seizure or loss of consciousness. Personal and family history was noncontributory.\n\nOn admission, the initial evaluation, she was afebrile and her vitals were stable. The Glasgow coma scale was 15 with no signs of meningism. She had visual acuity limited to the perception of lights in both eyes. Fundoscopic examination and pupils were normal. Other cranial nerve examination was normal. Motor system examination showed 4/5 power in the left upper and lower limb with 5/5 on the right side. Deep tendon reflexes were exaggerated in all 4 limbs and planters equivocal on the right and extensor on the left. Routine hematological and biochemical investigations were normal. Cerebrospinal fluid (CSF) study revealed acellular aspirate with raised protein (53 mg/dl) and normal sugar levels. Magnetic resonance imaging (MRI) brain with contrast showed ill-defined T2 and fluid-attenuated inversion recovery (FLAIR) hyper intensity predominantly involving the subcortical white matter at the gray-white matter junction in the right frontal, bilateral parietal lobes with patchy restricted diffusion in these areas [Figure 1]. There was no blooming or parenchymal enhancement associated with these lesions. A diagnosis of postinfectious acute demyelinating encephalomyelitis (ADEM) was kept based on clinical history, evaluation and neuroimaging findings. The patient was started on 500 mg intravenous (IV) methylprednisolone pulse therapy followed by 40 mg of oral steroids.\n\nFigure 1 Magnetic resonance imaging brain showing – T2-weighted images showing bilateral white matter hyperintensity in parietal, temporal lobes\n\nOn further investigations, to rule out the cause of etiology for ADEM, screening for possible organism, i.e., herpes simplex (HSV), Enterovirus, tuberculosis, leptospira, chlamydia, Legionella, and dengue infection were done and found to be negative. Immunoglobulin M (IgM) for varicella zoster was mildly positive. HSV polymerase chain reaction was negative. ELISA for human immune deficiency virus (HIV) was nonreactive. Visual evoked potential was normal bilaterally. Electroencephalogram showed slow background without any spike and wave discharges. Routine chest X-ray and ultrasound abdomen were normal. Blood and urine cultures were negative, Malarial Parasite ELISA and IgM - Typhidot was negative. Her vasculitis profile was negative. CSF and serum were negative for antimeasles antibody.\n\nOn 3rd day, the patient had started deteriorating clinically despite steroid pulse therapy. She became confused and agitated. The clinical examination revealed bradycardia and increase blood pressure with decreasing level of consciousness has raised the suspicion of raised intracranial pressure (ICP). Injection mannitol 100 ml thrice daily added as a decompressive therapy. A serial MRI brain showed increase in lesional size and extent with widespread edema, increase in hyperintensities on T2 and FLAIR in the right frontal, left temporoparietal, and bilateral occipital lobes, distal body, and selenium of the corpus callosum. Effacement of the regional sulci was seen. There were patchy restricted diffusion and patchy contrast enhancement seen in involved regions of bilateral cerebral hemispheres [Figure 2]. Repeated screen for sepsis and other organ dysfunction were noncontributory. On day 7, patient's conscious level further declined, and she was electively ventilated. A study of aquaporin antibodies and oligoclonal bands was negative. The patient became comatose and started having intermittent decerebrate posturing with horizontal roving eye movements suggestive of widespread cerebral dysfunction. She was started on IVIgs (0.4 g/kg/day for 5 days). She did not improve, and meanwhile, a trephine biopsy of the brain was done from her lesion in the left parietal area on day 7.\n\nFigure 2 Magnetic resonance imaging brain T2 showing increase in lesion size and extent with widespread edema, increase in hyperintensities in the right frontal, left temporoparietal, and bilateral occipital lobes, distal body and selenium of the corpus callosum as compare to Figure 1\n\nThe biopsy showed extensive demyelinating changes confirming our diagnosis of demyelination possibly postinfectious [Figure 3]. As she was not recovering, cyclophosphamide IV (60–120 mg/m2/day) (1–2.5 mg/kg/day) was given to her. Despite optimal available medical treatment, the patient did not recover and became vegetative and finally succumb to her illness after 20 days of admission.\n\nFigure 3 (a) Histopathology showing hypocellular loose areas (H and E, ×200). (b) Prominent large astrocytes (H and E, ×200). (c) Perivascular lymphocytic collection (H and E, ×200). (d) Widespread myelin loss (Luxol Fast Blue, ×200), (e) Glial fibrillary acidic protein-positive astrocytes (×200). (f) Decrease in preserved axons (NeuroFilament Protein, ×200)\n\nDISCUSSION\nADEM is an immune-mediated inflammatory disorder that predominantly involves the white matter of the brain and spinal cord. It preferentially affects children and young adults with an estimated prevalence of 0.8 per 100,000.[12]\n\nThe clinical diagnosis of ADEM is made by the temporal relationship between the acute onset of the neurological deficit with encephalopathy following the history of febrile illness and vaccination. Only 5% of the ADEM cases are attributed to be due to immunization. The systematic symptoms begin 4–21 days after the febrile illness. The presentation of neurological deficit can be heterogeneous depending on the location of the white matter tracts involvement which can be seen on neuroimaging. Encephalopathy is characteristically found and progress rapidly with multiple neurological deficit. The severe phase of ADEM usually lasts for 2–4 weeks. Hyperacute or malignant variants of ADEM, which represent 2% of cases, are associated with rapid symptom onset and progression, malignant brain edema, and high mortality rates due to herniation of brain.[13] The acute onset and rapid progression of the of symptoms of our case resemble the clinical profile of hyperacute ADEM. Malignant disseminated encephalomyelitis and acute hemorrhagic leukoencephalitis (AHLE) may be a part of the spectrum of the central nervous system (CNS) demyelinating disease, the clinical differentiation is difficult. Autoimmune process is the basic pathology is in both. AHLE is a rare and fulminant demyelinating disease considered to be the most severe form of ADEM. AHLE is diagnosed with neuroimaging and presence of hemorrhage in biopsy findings. The closest differential diagnosis of white matter involvement is multiple sclerosis is being ruled out on evaluating the clinical profile and the neuroimaging which shows the lesions are asymmetric and typically spares the periventricular area which differentiates it from multiple sclerosis. The T2-weighted and FLAIR images define the white matter involvement in ADEM. The lesions are usually bilateral and multiple in deep cortical and subcortical areas. Lesions are asymmetrical and poorly defined, thalami and basal ganglia are frequently affected. Brain stem and spinal cord involvement are commonly seen.[45] CSF may be normal, but frequently it shows some changes. Typical CSF changes include increased pressure, lymphocytic pleocytosis (as much as 1000/mm3, sometimes polymorphonuclear leukocytosis initially), and raised protein (usually <1.0 mg/l).\n\nThe pathogenesis of ADEM is not completely understood, and it is considered to be an autoimmune response causing inflammation affecting the CNS secondary to the direct inoculation by the neurotropic pathogens. There are consistent findings of nonspecific febrile illness preceding the onset of the disease all over the world.[6] In developing countries, due to poor implementation of immunization programs and poor hygiene practices measles and other viral infections are still widely prevalent and account for frequent occurrences of postinfectious demyelinating diseases. ADEM in developing countries is much more frequent than reported. Viral infections such as measles, rubella, and mumps have been reported in the Indian studies.[78] Although our patient had a history of febrile illness, the screening for the common virus was negative. Numerous causative agents have been identified all over the world; some of them include Coronavirus, coxsackie virus, Cytomegalovirus, Epstein-Barr virus, HSV virus, hepatitis B virus, HIV, influenza, measles, rubella, and West Nile virus.[1] Failure to identify a viral agent suggests that the inciting agents are unusual or cannot be recovered by standard laboratory methods.[9]\n\nTreatment usually consists of supportive therapy and steroids. Initially, IV steroids (10–30 mg/kg/day up to maximum dose of 1 g/day) in acute phase followed by oral steroids tapered over 3–6 weeks. The patients usually respond to steroid therapy within few days to weeks. In cases where corticosteroids have failed to work, use of plasmapheresis or IVIG has been shown to produce dramatic improvement.[1011] Severe cases of ADEM require the combination of immunosuppression with cyclophosphamide and mitoxantrone.[312] The management of raised ICP consists of intubation and controlled ventilation, elevation of the head of the bed, administration of analgesics, sedatives, and paralytics, and IV mannitol (1 g/kg) with placement of an ICP monitor as done in our case. A group from mayo Keegan et al. recently reviewed 59 consecutive patients with plasma exchange for acute severe attacks of CNS demyelination at the Mayo clinic, and it was concluded that certain factors such as male sex, preserved reflexes, and early initiation of treatment were associated with improvements. Successfully treated patients improved rapidly after plasma exchange, and improvement was sustained. In some cases, cytotoxic agents have been used with success.[13] The mortality varies between 10% and 30%, with complete recovery in 50%. Poor prognosis is correlated with severity and abruptness of onset of the clinical syndrome as in our case who has fulminant course with rapid onset and progression of symptoms leading to raised intracranial tension and refractory to the standard timely treatment.\n\nOur patient's presentation with headache, irritability, and hemiparesis that had progressed to stupor, decerebrate rigidity, coma, respiratory failure, or death due to herniation from severe intracranial hypertension along with radiological and biopsy-proven evidence and nonresponse to the optimal treatment qualifies for the malignant variant of ADEM which is rarely been described.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Tenembaum S Chitnis T Ness J Hahn JS International Pediatric MS Study Group Acute disseminated encephalomyelitis Neurology 2007 68 16 Suppl 2 S23 36 17438235 \n2 Leake JA Albani S Kao AS Senac MO Billman GF Nespeca MP Acute disseminated encephalomyelitis in childhood: Epidemiologic, clinical and laboratory features Pediatr Infect Dis J 2004 23 756 64 15295226 \n3 Menge T Hemmer B Nessler S Wiendl H Neuhaus O Hartung HP Acute disseminated encephalomyelitis: An update Arch Neurol 2005 62 1673 80 16286539 \n4 Hynson JL Kornberg AJ Coleman LT Shield L Harvey AS Kean MJ Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children Neurology 2001 56 1308 12 11376179 \n5 Callen DJ Shroff MM Branson HM Li DK Lotze T Stephens D Role of MRI in the differentiation of ADEM from MS in children Neurology 2009 72 968 73 19038851 \n6 Tenembaum S Chamoles N Fejerman N Acute disseminated encephalomyelitis: A long-term follow-up study of 84 pediatric patients Neurology 2002 59 1224 31 12391351 \n7 Das K Basu S Mondal GP Das SK Roy T Mukerjee B Clinical spectrum of acute disseminated encephalomyelitis in relation to etiology and neuroimaging study Ann Indian Acad Neurol 2004 7 501 6 \n8 Murthy JM Yangala R Meena AK Jaganmohan Reddy J Acute disseminated encephalomyelitis: Clinical and MRI study from South India J Neurol Sci 1999 165 133 8 10450798 \n9 Murthy SN Faden HS Cohen ME Bakshi R Acute disseminated encephalomyelitis in children Pediatrics 2002 110 2 Pt 1 e21 12165620 \n10 Kanter DS Horensky D Sperling RA Kaplan JD Malachowski ME Churchill WH Jr Plasmapheresis in fulminant acute disseminated encephalomyelitis Neurology 1995 45 824 7 7723979 \n11 Pradhan S Gupta RP Shashank S Pandey N Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis J Neurol Sci 1999 165 56 61 10426148 \n12 Alexander M Murthy JM Acute disseminated encephalomyelitis: Treatment guidelines Ann Indian Acad Neurol 2011 14 Suppl 1 S60 4 21847331 \n13 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BG Plasma exchange for severe attacks of CNS demyelination: Predictors of response Neurology 2002 58 143 6 11781423\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-2327",
"issue": "20(3)",
"journal": "Annals of Indian Academy of Neurology",
"keywords": "Acute demyelinating encephalomyelitis; malignant; refractory; treatment",
"medline_ta": "Ann Indian Acad Neurol",
"mesh_terms": null,
"nlm_unique_id": "101273955",
"other_id": null,
"pages": "316-318",
"pmc": null,
"pmid": "28904469",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "17438235;10426148;16286539;11781423;10450798;21847331;19038851;12165620;15295226;7723979;11376179;12391351",
"title": "Hyper Acute Demyelinating Encephalomyelitis of Childhood: A Rare Entity.",
"title_normalized": "hyper acute demyelinating encephalomyelitis of childhood a rare entity"
} | [
{
"companynumb": "PHHY2017IN176998",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Radiation recall dermatitis (RRD) is an inflammatory reaction limited to previously irradiated areas and occurs following the subsequent administration of a drug. Herein, we present a patient with severe RRD associated with pain and necrosis.",
"affiliations": "Yamaguchi University Graduate School of Medicine, Ube, Japan.",
"authors": "Nakamura|Yoshitaka|Y|;Kurata|Yusuke|Y|;Matsumoto|Kishiko|K|;Nakamura|Akiko|A|;Muto|Masahiko|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "21(5)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D001707:Biopsy, Needle; D001943:Breast Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D011855:Radiodermatitis; D012867:Skin",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26295858",
"pubdate": "2015-05-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ulcerated erythematous plaque on the right breast localized to the previously irradiated area.",
"title_normalized": "ulcerated erythematous plaque on the right breast localized to the previously irradiated area"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1043434",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "The CD4 lymphocytes are an important part of the immune system. Besides HIV Infection, other conditions can cause a low CD4 count. We report the case of a 82-year-old female who presented with a markedly low CD4 count during a severe lower respiratory tract infection and respiratory failure without HIV infection. The total lymphocyte and the absolute CD4 counts are 255/mm³ and 109/mm³, respectively. Sputum and bronchial lavage fluid were both negative for acid-fast bacilli. The anti-HIV antibody test was negative.The blood culture was also negative. She had no history of diabetes, malnutrition or chronic kidney disease. Because pneumocystis jiroveci pneumonia could not be excluded, she was treated with a combination of clindamycin, dexamethasone, primaquine, meropenem and oseltamivir because of sulfamethoxazole drug allergy. One week later, she developed herpes simplex of her labia majora, so acyclovir was added. She had history of having a normal lymphocyte count during her routine yearly check-up. Her severe respiratory tract infection was associated with CD4 lymphocytopenia.",
"affiliations": null,
"authors": "Khamanarong|Naporn|N|;Insiripong|Somchai|S|",
"chemical_list": null,
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-1562",
"issue": "47(3)",
"journal": "The Southeast Asian journal of tropical medicine and public health",
"keywords": null,
"medline_ta": "Southeast Asian J Trop Med Public Health",
"mesh_terms": "D000369:Aged, 80 and over; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D005260:Female; D006801:Humans; D008231:Lymphopenia; D012141:Respiratory Tract Infections",
"nlm_unique_id": "0266303",
"other_id": null,
"pages": "503-5",
"pmc": null,
"pmid": "27405134",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "CD4 LYMPHOCYTOPENIA WITHOUT HIV INFECTION.",
"title_normalized": "cd4 lymphocytopenia without hiv infection"
} | [
{
"companynumb": "TH-IMPAX LABORATORIES, INC-2017-IPXL-01145",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
"drugadditio... |
{
"abstract": "Anti-VEGF therapy with Bevacizumab (BEV) is widely used in cases of relapsed high-grade glioma (HGG). Arterial hypertension is a known side effect of anti-VEGF therapy. 42 Patients with relapsed HGG were treated with BEV 10 mg/kg on days 1 and 15 of 28-day cycles in addition to treatment with 40 mg TMZ daily until disease progression, based on magnetic resonance imaging and/or worsening of clinical status. In a retrospective analysis, hypertensive side effects were evaluated as the primary endpoint, while survival information in addition to toxicity was analyzed as secondary endpoint. Grading which employs the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 detected hypertensive events with a significantly higher sensitivity than CTCAE version 3.0. The rate of severe hypertensive events observed as CTCAE ≥ °3 were 9.5 % in version 3.0 and 45.2 % in version 4.0. The results presented here indicate that CTCAE version 3.0 may underreport the incidence and grade of BEV-induced hypertension within clinical trials. As hypertension has not only long-term, but also severe short-term side effects, we suggest that arterial hypertension under BEV should be scored according to CTCAE version 4.0 to avoid clinically relevant hypertension-related adverse events in these patients.",
"affiliations": "Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University of Regensburg Medical School, Universitätsstraße 84, 93053, Regensburg, Germany.;Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University of Regensburg Medical School, Universitätsstraße 84, 93053, Regensburg, Germany.;Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University of Regensburg Medical School, Universitätsstraße 84, 93053, Regensburg, Germany.;Department of Neurosurgery, Regensburg University Hospital, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.;Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University of Regensburg Medical School, Universitätsstraße 84, 93053, Regensburg, Germany.;Department of Neuropathology, Regensburg University Hospital, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.;Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.;Department of Radiology, Regensburg University Hospital, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.;Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University of Regensburg Medical School, Universitätsstraße 84, 93053, Regensburg, Germany. peter.hau@ukr.de.",
"authors": "Bumes|Elisabeth|E|;Rzonsa|Sarah|S|;Hutterer|Markus|M|;Proescholdt|Martin|M|;Bogdahn|Ulrich|U|;Riemenschneider|Markus J|MJ|;Uhl|Martin|M|;Wendl|Christina|C|;Hau|Peter|P|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-015-2031-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "127(1)",
"journal": "Journal of neuro-oncology",
"keywords": "Bevacizumab; CTCAE; Glioblastoma; High-grade glioma; Hypertension; Temozolomide",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001932:Brain Neoplasms; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "191-200",
"pmc": null,
"pmid": "26721240",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": "23075631;23400732;20547589;21590689;23833308;20308655;22844129;24877084;19114704;21986775;20665891;21086192;20351338;21986722;24552318;24417499;19720927;25035291;19920819;11902515;20716591;21865400;20406901;21135282;21627340;20714900;24219539;22680781;18936738;24786444;21036490;19593660;23143192;21792866;22548369;20853132;19727565;15758009",
"title": "Adverse event grading following CTCAE v3.0 underestimates hypertensive side effects in patients with glioma treated with Bevacizumab.",
"title_normalized": "adverse event grading following ctcae v3 0 underestimates hypertensive side effects in patients with glioma treated with bevacizumab"
} | [
{
"companynumb": "DE-ROCHE-1689543",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nProtocol biopsies after renal transplantation are useful in detecting subclinical rejection. In earlier studies, the incidence of subclinical rejection was high among renal transplant recipients on a cyclosporine-based immunosuppression. However, recent data show that subclinical rejection is low under tacrolimus-based immunosuppression. This study evaluates the utility of 6-month protocol biopsy in renal transplant recipients under induction with rabbit antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids.\n\n\nMETHODS\n6-month protocol biopsies on 40 transplant recipients were analyzed for borderline and subclinical rejections. Allograft injury at biopsy was evaluated using the chronic allograft damage index score system (CADI) and was compared with initial scores obtained at implantation.\n\n\nRESULTS\nBorderline rejection was detected in 1 out of 40 patients. No case of subclinical rejection was detected at protocol biopsy. In 31 patients with corresponding implantation biopsies, mean CADI score increased from 1.1 +/- 1.4 to 2.8 +/- 2.1 at 6 months despite stable graft function. In the subgroup of patients with a 6-month CADI score of 2 or less (n = 11), graft function remained stable at 12 months post transplant (65.3 +/- 16.9 ml/min/1.73 m2 at 6 months vs. 65.2 +/- 16.7 ml/min/1.73 m2 at 12 months, p = 0.96). In contrast, allograft function declined significantly at 12 months in those with a 6-month CADI score of > 2 (n = 20) (64.3 +/- 13.5 ml/min/1.73 m2 at 6 months vs. 51 +/- 9.8 ml/min/1.73 m2 at 12 months, p = 0.0006).\n\n\nCONCLUSIONS\nWhile the incidence of borderline and subclinical is low under antilymphocyte antibody induction and tacrolimus-based immunosuppression, chronic allograft damage is highly prevalent at 6 months post transplantation. Our findings suggest that protocol biopsies under current immunosuppression may be more useful in the early detection of chronic allograft nephropathy (CAN).",
"affiliations": "Division of Hypertension and Renal Diseases, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA. ayango@lifespan.org",
"authors": "Yango|A|A|;Gohh|R|R|;Wang|L J|LJ|;Morrissey|P|P|;Shih|M|M|;Lowery|K|K|;Charpentier|K|K|;Gautam|A|A|;Mendonca|C|C|;Kumar|S|S|;Dworkin|L|L|;Monaco|A|A|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.5414/cnp70490",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "70(6)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D001706:Biopsy; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D015994:Incidence; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D014184:Transplantation, Homologous; D014481:United States",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "490-5",
"pmc": null,
"pmid": "19049705",
"pubdate": "2008-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "The utility of 6-month protocol renal biopsy under modern immunosuppression.",
"title_normalized": "the utility of 6 month protocol renal biopsy under modern immunosuppression"
} | [
{
"companynumb": "US-PFIZER INC-2020323651",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nGlucocorticoid treatment remains the cornerstone of therapy for immune checkpoint inhibitor (ICI) myocarditis, but data supporting the use of additional immunotherapy for steroid refractory cases remains limited. We investigate the safety and efficacy of infliximab in patients with ICI myocarditis who are refractory to corticosteroids. Additionally, we highlight the importance of a multi-disciplinary approach in the care for these complex patients.\n\n\nMETHODS\nWe retrospectively identified consecutive patients who developed ICI myocarditis at our institution between January 2017 and January 2020. Baseline characteristics, laboratory data and clinical outcomes were compared between patients who received infliximab and those who did not.\n\n\nRESULTS\nOf a total of 11 patients who developed ICI myocarditis, 4 were treated with infliximab. Aside from age, there were no significant differences in baseline patient characteristics between the two groups including total number of ICI doses received and duration from initial ICI dose to onset of symptoms. The time to troponin normalization was 58 vs. 151.5 days (p = 0.25). The duration of prednisone taper was longer in the infliximab group (90 vs. 150 days p = 0.32). All patients survived initial hospital admission. Over a median follow-up period of 287 days, two of the 4 patients died from sepsis 2 and 3 months after initial treatment of their myocarditis; one of these patients was on a steroid taper and the other patient had just completed a steroid taper.\n\n\nCONCLUSIONS\nInfliximab, despite its black box warning in patients with heart failure, may be a safe and effective treatment for ICI myocarditis.",
"affiliations": "Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Pharmacy, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Cardiothoracic Surgery, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA.;Department of Medicine, University of Pennsylvania, PA, Philadelphia, USA. rupal.o'quinn@pennmedicine.upenn.edu.",
"authors": "Zhang|Robert S|RS|;Padegimas|Allison|A|;Murphy|Kathleen M|KM|;Evans|Peter T|PT|;Peters|Carli J|CJ|;Domenico|Christopher M|CM|;Vidula|Mahesh K|MK|;Mather|Paul J|PJ|;Cevasco|Marisa|M|;Cohen|Roger B|RB|;Carver|Joseph R|JR|;O'Quinn|Rupal P|RP|http://orcid.org/0000-0002-9834-763X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40959-021-00095-x",
"fulltext": "\n==== Front\nCardiooncology\nCardiooncology\nCardio-oncology\n2057-3804\nBioMed Central London\n\n95\n10.1186/s40959-021-00095-x\nResearch\nTreatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series\nZhang Robert S. 1\nPadegimas Allison 12\nMurphy Kathleen M. 13\nEvans Peter T. 1\nPeters Carli J. 1\nDomenico Christopher M. 4\nVidula Mahesh K. 12\nMather Paul J. 12\nCevasco Marisa 5\nCohen Roger B. 16\nCarver Joseph R. 126\nhttp://orcid.org/0000-0002-9834-763X\nO’Quinn Rupal P. rupal.o'quinn@pennmedicine.upenn.edu\n\n12\n1 grid.25879.31 0000 0004 1936 8972 Department of Medicine, University of Pennsylvania, PA Philadelphia, USA\n2 grid.25879.31 0000 0004 1936 8972 Division of Cardiovascular Medicine, University of Pennsylvania, PA Philadelphia, USA\n3 grid.25879.31 0000 0004 1936 8972 Division of Infectious Disease, University of Pennsylvania, PA Philadelphia, USA\n4 grid.25879.31 0000 0004 1936 8972 Department of Pharmacy, University of Pennsylvania, PA Philadelphia, USA\n5 grid.25879.31 0000 0004 1936 8972 Department of Cardiothoracic Surgery, University of Pennsylvania, PA Philadelphia, USA\n6 grid.25879.31 0000 0004 1936 8972 Division of Hematology-Oncology, University of Pennsylvania, PA Philadelphia, USA\n30 3 2021\n30 3 2021\n2021\n7 133 10 2020\n7 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nGlucocorticoid treatment remains the cornerstone of therapy for immune checkpoint inhibitor (ICI) myocarditis, but data supporting the use of additional immunotherapy for steroid refractory cases remains limited. We investigate the safety and efficacy of infliximab in patients with ICI myocarditis who are refractory to corticosteroids. Additionally, we highlight the importance of a multi-disciplinary approach in the care for these complex patients.\n\nMethods\n\nWe retrospectively identified consecutive patients who developed ICI myocarditis at our institution between January 2017 and January 2020. Baseline characteristics, laboratory data and clinical outcomes were compared between patients who received infliximab and those who did not.\n\nResults\n\nOf a total of 11 patients who developed ICI myocarditis, 4 were treated with infliximab. Aside from age, there were no significant differences in baseline patient characteristics between the two groups including total number of ICI doses received and duration from initial ICI dose to onset of symptoms. The time to troponin normalization was 58 vs. 151.5 days (p = 0.25). The duration of prednisone taper was longer in the infliximab group (90 vs. 150 days p = 0.32). All patients survived initial hospital admission. Over a median follow-up period of 287 days, two of the 4 patients died from sepsis 2 and 3 months after initial treatment of their myocarditis; one of these patients was on a steroid taper and the other patient had just completed a steroid taper.\n\nConclusions\n\nInfliximab, despite its black box warning in patients with heart failure, may be a safe and effective treatment for ICI myocarditis.\n\nKeywords\n\nImmune checkpoint inhibitor\nMyocarditis\nInfliximab\nCardio‐oncology\nPembrolizumab\nNivolumab\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nImmune checkpoint inhibitors (ICIs) have brought about a paradigm shift in the treatment of many cancers. ICIs enhance the immune system’s detection and targeting of tumor cells and improve progression-free and overall survival in a growing number of adult cancers that are refractory to traditional chemotherapeutic agents [1, 2]. With increasing use of ICIs, immune-related adverse events (irAEs) have become more prevalent, and most commonly include endocrinopathies, pneumonitis, colitis and hepatitis [3]. Immune-related adverse events are more severe and more likely to occur with combinations of checkpoint inhibitors [4–6]. While cardiovascular toxicity is less frequent than other irAEs with a reported incidence of 1.14 %, it is associated with a high mortality rate of 25–50 % [5, 7–9]; making it unsurprising that the number of cases published discussing life-threatening cardiotoxicity continues to rise [10]. There are various proposed treatment algorithms for ICI-mediated cardiotoxicity but standardized guidelines are lacking. While glucocorticoid therapy has become a widely accepted treatment, only about 50 % of patients with fulminant myocarditis respond to glucocorticoid monotherapy [11]. Various additional immunosuppressive agents have been used in steroid-refractory cases; however, data supporting the use of these therapies are limited. In this retrospective study, we describe our single center experience with four patients who had steroid-refractory ICI myocarditis that improved with infliximab administration. We compare their clinical characteristics and outcomes with those who did not require immunosuppression beyond steroids. Finally, we provide a suggested treatment algorithm created by a multi-disciplinary team of experts in cardio-oncology, heart failure, infectious disease, medical oncology and cardiothoracic surgery.\n\nMethods\n\nStudy population and data collection\n\nWe retrospectively identified consecutive patients who developed ICI myocarditis at our institution between January 2017 and January 2020. ICI myocarditis was diagnosed in consultation with a cardio-oncology expert based on standard histological features present on endomyocardial biopsy or a guideline-recommended scoring system incorporating several factors including clinical presentation, biomarkers and imaging features [12]. Grading of ICI myocarditis was performed according to the American Society of Clinical Oncology (ASCO) practice guidelines [13]. Patients treated with infliximab were those with persistent evidence of cardiac dysfunction such as malignant arrhythmias or cardiogenic shock despite treatment with high doses of glucocorticoids [14]. Clinical data including baseline demographics, medications, laboratory values, and the results of echocardiography, cardiac MRI (cMRI) and endomyocardial biopsy were obtained from electronic medical records abstracted by a physician. This study was approved by the University of Pennsylvania Institutional Review Board.\n\nCovariates\n\nCovariates were selected based on clinical relevance and prior studies [7]. Demographic covariates included age, sex, and race. Clinical covariates included body mass index (BMI), baseline cardiovascular risk factors, baseline echocardiographic data if available, and medications. Cancer-specific covariates included type of cancer, the type and number of cycles of ICI treatments received, and any exposure to prior cardiotoxic chemotherapy and/or chest radiation. Myocarditis-specific covariates included clinical presentation, ischemic cardiac evaluation, initial and peak cardiac biomarkers (i.e., troponin), time to resolution of cardiac biomarkers, treatment regimen for myocarditis and if available, cardiac MRI and endomyocardial biopsy results. Admission troponin was defined as first serum troponin measured, and peak troponin was the highest measured troponin value. Time to troponin resolution was defined as the time (in months) from first troponin elevation to the first troponin that was undetectable.\n\nOutcomes\n\nThe outcomes of interest were major adverse cardiac events (MACE), which we defined as cardiovascular death, cardiac arrest, cardiogenic shock, hemodynamically significant heart block and hemodynamically significant arrhythmias.\n\nStatistical analysis\n\nContinuous variables are presented as mean ± standard deviation (SD) or median with interquartile range (IQR) for skewed data. Categorical data are expressed as frequencies and proportions. Continuous variables were compared using unpaired Student’s t-test for normally distributed continuous variables, the Wilcox rank-sum when normal distributions were not met, and Fisher’s exact test for categorical variables. Analyses were performed using Stata software (version 15.0; StataCorp LP, College Station, TX). All analyses were two-sided and a p value less than 0.05 was considered significant.\n\nResults\n\nOf a total of 11 patients at our institution who developed ICI myocarditis, 4 were treated with one dose of 5 mg/kg infliximab (Table 1). In all 11 cases, ICIs were subsequently discontinued permanently. The median follow-up time from the onset of ICI myocarditis was 279 days in the non-infliximab group and 287 days in the infliximab group. As expected, patients treated with infliximab had more severe disease by the ASCO classification compared to those not treated with infliximab. All four patients requiring treatment with infliximab had grade 4 myocarditis and experienced a MACE prompting infliximab initiation. Aside from age, there were no significant differences in baseline patient characteristics between patients treated with and without infliximab including the type of cancer and type of ICI therapy. Patients treated with infliximab were younger (72.7 vs. 61.8 years, p = 0.02). Notably there was no significant difference in the total number of ICI doses received (2.0 vs. 2.5, p = 0.77) or duration from initial ICI dose to onset of symptoms (53 vs. 75 days, p = 0.71) between the two groups. There was a nonsignificant trend toward higher admission and peak troponins (0.7 vs. 0.2 ng/ml p = 0.089 and 1.0 vs. 0.2 ng/mL p = 0.13, respectively) in the infliximab group. The time to troponin normalization was numerically longer in the infliximab group (151.5 vs. 58 days p = 0.25). Both groups had pre-ICI ejection fractions > 50 % and both groups had moderately reduced ejection fractions at diagnosis of ICI myocarditis (42.5 % vs. 38.8 % p = 0.73). The duration of prednisone taper was numerically longer in the infliximab group (90 vs. 150 days p = 0.32). All patients survived initial hospital admission for ICI-associated myocarditis. Table 1 Baseline characteristics comparing patients with immune checkpoint inhibitor myocarditis treated with and without infliximab\n\n\tNot Treated with Infliximab\tTreated with Infliximab\tp-value\t\n\tN = 7\tN = 4\t\t\nBaseline Patient Characteristics\t\t\t\t\nAge, mean (SD)\t72.7 (6.5)\t61.8 (4.6)\t0.016\t\nGender (male)\t6 (86 %)\t2 (50 %)\t0.20\t\nBMI, mean (SD)\t23.4 (4.8)\t27.7 (9.8)\t0.35\t\nHypertension\t2 (29 %)\t2 (50 %)\t0.48\t\nDiabetes\t1 (14 %)\t0 (0 %)\t0.43\t\nTobacco Use\t0 (0 %)\t0 (0 %)\t\t\nCoronary Artery Disease\t1 (17 %)\t0 (0 %)\t0.39\t\nHeart Failure\t2 (29 %)\t0 (0 %)\t0.24\t\nCerebral Vascular Accident\t7 (100 %)\t4 (100 %)\t\t\nObstructive Sleep Apnea\t7 (100 %)\t4 (100 %)\t\t\nChronic Kidney Disease\t2 (29 %)\t1 (25 %)\t0.90\t\nBaseline Cancer Demographics\t\t\t\t\nTotal No. of ICI doses, median (IQR)\t2.0 (1.0, 14.0)\t2.5 (1.5, 6.0)\t0.77\t\nTime from ICI dose to Onset of Symptoms, Days, (median IQR)\t53.0 (21.0, 424.0)\t74.0 (52.0, 171.5)\t0.71\t\nMalignancy\t\t\t0.23\t\nMetastatic Melanoma\t1 (14 %)\t2 (50 %)\t\t\nMetastatic RCC\t0 (0 %)\t1 (25 %)\t\t\nOvarian Adenocarcinoma\t0 (0 %)\t1 (25 %)\t\t\nNSCLC\t3 (43 %)\t0 (0 %)\t\t\nMetastatic SCC of tongue\t1 (14 %)\t0 (0 %)\t\t\nLaryngeal SCC\t1 (14 %)\t0 (0 %)\t\t\nDLBCL\t1 (14 %)\t0 (0 %)\t\t\nImmune Checkpoint Inhibitor\t\t\t0.31\t\nNivolumab\t2 (29 %)\t3 (75 %)\t\t\nPembrolizumab\t4 (57 %)\t1 (25 %)\t\t\nDarvalumab\t1 (14 %)\t0 (0 %)\t\t\nCombined ICI (anti-CTLA-4 + anti-PD1/PDL1)\t1(14 %)\t0 (0 %)\t0.77\t\nPrior Chemotherapy or Radiation\t\t\t\t\nRadiation\t6 (86 %)\t1 (25 %)\t0.044\t\nAnthracycline\t0 (0 %)\t0 (0 %)\t\t\nVEGF inhibitors\t0 (0 %)\t0 (0 %)\t\t\nMyocarditis Presentation and Management\t\t\t\t\nFollow up time, days (mean SD)\t279.0 (219.8)\t287.2 (258.2)\t0.96\t\nBNP, mean (SD)\t8562.0 (14856.4)\t11749.3 (9355.2)\t0.75\t\nAdmission Troponin, ng/ml (median IQR)\t0.2 (0.0, 0.6)\t0.7 (0.4, 4.8)\t0.089\t\nPeak Troponin ng/ml (median IQR)\t0.2 (0.1, 0.6)\t1.0 (0.5, 4.9)\t0.13\t\nTime for Troponin Normalization, days (median IQR)\t1740 (1245, 2160)\t4545 (1680, 9315)\t0.25\t\nICI Myocarditis Grade\t\t\t0.023\t\n1\t0 (0 %)\t0 (0 %)\t\t\n2\t4 (57 %)\t0 (0 %)\t\t\n3\t2 (29 %)\t0 (0 %)\t\t\n4\t1 (14 %)\t4 (100 %)\t\t\nClinical Presentation\t\t\t\t\nMACE\t1 (14 %)\t4 (100 %)\t0.006\t\nCongestive Heart Failure\t4 (57 %)\t4 (100 %)\t0.12\t\nCardiogenic Shock\t0 (0 %)\t2 (50 %)\t0.039\t\nComplete Heart Block\t1 (14 %)\t2 (50 %)\t0.20\t\nVentricular Tachycardia\t0 (0 %)\t4 (100 %)\t< 0.001\t\nCardiac Arrest\t1 (14 %)\t1 (25 %)\t0.66\t\nEchocardiogram\t\t\t\t\nPre-ICI EF, mean (SD) (n = 4)\t57.5 (15.0)\t63.3 (2.9)\t0.54\t\nNew EF, mean (SD)\t42.5 (20.2)\t38.8 (4.8)\t0.73\t\nMitral Inflow E, cm/s (mean SD) (n = 7)\t85 (27)\t75 (31)\t0.65\t\nMitral Inflow A, cm/s (mean SD) (n = 7)\t89 (13)\t50 (9)\t0.007\t\nE/A, mean (SD) (n = 7)\t0.9 (0.3)\t1.5 (0.7)\t0.16\t\nAverage Mitral E/e’, (mean SD) (n = 7)\t12.3 (3.0)\t12.3 (7.5)\t0.99\t\nCardiac MRI\t\t\t\t\nECV, % (n = 4)\t32.0\t35.5\t0.65\t\nNative T1 value (ms) (n = 5)\t1076 (102)\t1130 (27)\t0.53\t\nPredominant LGE Pattern (n = 6)\t\t\t0.63\t\nSub-endocardial/Transmural\t0\t2\t\t\nSub-epicardial\t0\t0\t\t\nMid-myocardial\t2\t2\t\t\nDiffuse\t0\t0\t\t\nTreatment\t\t\t\t\nInitial Treatment on Presentation\tPrednisone 1 mg/kg\tIV solumedrol 1 g x3 days and infliximab 5 mg/kg\t\t\nPrednisone Duration, days (median IQR)\t90 (60,150)\t150 (75, 300)\t0.32\t\nSurvival at discharge\t7 (100 %)\t4 (100 %)\t\t\nAbbreviations: BMI, body mass index; BNP, B-type natriuretic peptide; CTLA-4, cytotoxic T-lymphocyte associated protein 4; extracellular volume, ECV; DLBCL, diffuse large B-cell lymphoma; late gadolinium enhancement, LGE; EF, ejection fraction; MACE, major adverse cardiovascular ev ent; NSCLC, non-small cell lung cancer; No., number; PD-L1, programmed death-ligand 1; ICI, immune checkpoint inhibitor; RCC, renal cell carcinoma; SCC, squamous cell cancer; VEGF, vascular endothelial growth factor\n\nAll four patients who received infliximab were admitted to the cardiac intensive care unit. Patient 1 presented with refractory ventricular tachycardia (VT) despite anti-arrhythmic therapy and pulse dose steroids (Fig. 1). Patient 2 presented with severe right heart failure (RHF) with subsequent cardiogenic shock, refractory VT and complete heart block (CHB). Patient 3 initially presented with a newly reduced EF and hemodynamically unstable CHB requiring a permanent pacemaker (PPM). This patient required a prolonged steroid taper due to persistent troponin elevations and during the 8th month of this taper, he was readmitted for refractory VT. Patient 4 presented with inotrope-dependent cardiogenic shock. Two patients received infliximab (infliximab 5 mg/kg) after completing three doses of 1 g of intravenous solumedrol and two patients received infliximab after the first dose of intravenous solumedrol. All 4 patients received infliximab due to worsening clinical status despite the high-dose steroids. All 4 patients survived initial hospitalization but required prolonged steroid tapers guided by serial troponin monitoring. Over a median follow-up period of 287 days, two of the 4 patients died from septic shock 2 and 3 months after initial treatment of their myocarditis; one of these patients was on a steroid taper and the other patient had just completed a steroid taper. The other two patients have completed their steroid tapers without further evidence of myocarditis at their most recent follow-up. Fig. 1 Clinical Course of Patients that Received Infliximab. The clinical course of ICI myocarditis patients treated with infliximab over time. Abbreviations: CHB, complete heart block; CHF, congestive heart failure; Dx, Diagnosis; EF; ejection fraction, ICI, immune checkpoint inhibitory; PPM, permanent pacemaker; Rx, Treatment; RV, right ventricle; VT, ventricular tachycardia\n\nDiscussion\n\nGlucocorticoids remain the cornerstone of treatment for ICI myocarditis. Most patients experienced clinical improvement and biomarker normalization with steroid monotherapy. However, there remain several gaps in our understanding of the optimal medical therapy. There is no consensus on the initial dosing of steroids, the type of steroid, addition of alternative immunosuppressive agents when necessary, or outpatient steroid tapering protocols.\n\nMahmood et al. observed that MACE occurred less frequently in patients who received high-dose (> 2 mg/kg of prednisone or equivalent) steroids compared with those receiving low-dose steroids (< 1 mg/kg of prednisone or equivalent) [7]. In addition, Zhang et al. showed that initiating corticosteroids earlier and at higher doses was associated with lower risk of MACE [15]. The ASCO guidelines recommend 1 mg/kg of prednisone or equivalent either by mouth or intravenously [13]. Our clinical practice has been to administer 1 gram of intravenous solumedrol daily for three days, followed by a 1–2 mg/kg steroid taper of oral prednisone. The ASCO clinical practice guidelines for irAEs recommend a glucocorticoid taper over 4–6 weeks while trials for viral myocarditis have examined steroid treatment durations of at least 3 months and in some cases up to a year [12]. For ICI-mediated myocarditis, most case reports and case series track response to steroids by monitoring troponin levels. If the troponin levels increase, our practice has been to increase the steroid dose and extend the taper. This situation arose in one patient in our cohort who had a significant clinical deterioration when the troponin levels began to rise despite steroid therapy. However, we acknowledge that there is a lack of research into a standardized steroid protocol in these patients. Additionally, whether the ICI should be permanently discontinued or whether restarting ICI therapy is safe remains controversial. Our institution has not restarted anyone on ICI therapy after the development of grade 4 myocarditis. In addition to immunosuppressive therapy, patients should also receive appropriate cardiac support including inotropes, mechanical circulatory support, and management of arrhythmias including temporary pacemakers and external defibrillators when indicated. Our approach has been to treat ICI myocarditis aggressively as a potentially reversible complication of therapy even in patients with advanced incurable cancer. Decisions regarding levels of mechanical circulatory support offered to patients with active malignancy but a reversible cause of cardiac decompensation are controversial and need to be discussed with heart failure, cardiothoracic surgery and oncology. The intensity of therapy offered to individual patients should always be consistent with their stated goals of care.\n\nThere have been case reports or small case series describing the use of several immunomodulating agents for ICI-induced myocarditis with varying degrees of efficacy. These therapies include intravenous immunoglobulin, [16, 17] mycophenolate, [17] anti-thymocyte globulin, [18] plasmapheresis, [17] infliximab, [17] alemtuzumab, [19]] and abatacept [20]. In our cohort, we have demonstrated that infliximab, a chimeric IgG1 monoclonal antibody that blocks tumor necrosis factor-alpha, appears to be an effective and safe agent for steroid-refractory ICI myocarditis. Although there is a black box warning regarding the potential for infliximab to worsen heart failure based on observations by Kwon et al. of the development of heart failure in patients with rheumatoid arthritis treated with infliximab, [21] we have demonstrated in a small sample that infliximab safely improved decompensated heart failure and cardiogenic shock due to ICI myocarditis. In our limited experience, a single dose of infliximab 5 mg/kg has been effective and safe. While we have not re-dosed infliximab at our institution, there have been case series describing additional 5 mg/kg doses or a single dose of 10 mg/kg [22, 23]. There are limited data outside oncology suggesting that 5 mg/kg may be safer in treating patients with heart failure not due to ICIs [24].\n\nIn the setting of therapeutic immunosuppression with both infliximab and prolonged high dose steroids, patients are at increased risk for opportunistic infections and need to be monitored closely. Two of the four patients in our series eventually died of septic shock, so it is formally possible that these events were due to the effects of combined immune suppression with infliximab and glucocorticoids. Anti-TNF agents such as infliximab have been associated with an increased risk of mycobacterial infections, invasive fungal infections, viral infections as well as bacterial pathogens [25–27]. Prior to starting therapy, patients should be screened for HIV and Hepatitis B and C, a history of invasive fungal infections and should undergo assessment for active or latent tuberculosis. Concern for any of these infections warrants consultation with Infectious Diseases. Of note, immediate therapy for ICI myocarditis may be necessary and should not be withheld even with infectious screening tests pending, particularly if the patient is in cardiogenic shock or having sustained life-threatening arrythmias refractory to other therapies.\n\nTo prevent infections, we recommend patients receive prophylaxis for Pneumocystis jirovecii pneumonia until the steroid taper dose is below 20 mg of prednisone or equivalent, ideally with trimethoprim-sulfamethoxazole. There are insufficient data at this time to recommend prophylaxis against invasive fungal infections [27, 28]. Patients should also be up to date on all appropriate vaccinations, noting that administration may be deferred in the acute setting given significant immunosuppression and lower likelihood of vaccine response.\n\nWhile we have only used infliximab in steroid-refractory cases, further study should consider earlier initiation of infliximab or other additional immunosuppressive agents together with initial high-dose steroids in patients with grade 3 or 4 myocarditis. Early initiation of a second immunosuppressive agent such as infliximab may reduce the total duration of steroid exposure. Given the potential effect of corticosteroids on T-cell function, prolonged use in patients with advanced cancer may decrease the efficacy of ICIs and is generally avoided whenever possible [29, 30]. Additionally, initial dosing of steroids should be studied further; data from heart transplant cellular rejection, which has similarities to T-cell driven ICI myocarditis, has shown equivalent outcomes with 500 mg and 1000 mg of intravenous solumedrol [31, 32]. While many questions remain unanswered and additional prospective studies are needed to address the best ways to manage ICI-related cardiovascular adverse events, we believe it is prudent to have a multidisciplinary team to help manage these high-risk patients. The Fig. 2 is a suggested algorithm for the treatment of ICI myocarditis developed by a multi-disciplinary team involving medical oncology, heart failure, cardiothoracic surgery, cardio-oncology, and pharmacists. We recognize that this protocol will surely change as more research is done within this field, but we hope this serves as a guide until then as there is currently a paucity of data and treatment recommendations for ICI myocarditis. Fig. 2 Suggested Treatment Algorithm for Suspected Immune Checkpoint Inhibitor Myocarditis. Abbreviations: CHB, complete heart block; CI, cardiac index; CMR, cardiac MRI; EMBx, endomycardial biopsy; HSV, herpes simplex virus; ICD, internal cardiac defibrillator; IV, intravenous; PCP, pneumocystis pneumonia; RWMA, regional wall motion abnormality; TTE, transthoracic echocardiogram; VT, ventricular tachycardia, VZV; varicella zoster virus\n\nThere are several limitations to the current study. This is a single center study, which limits its generalizability. This study is also limited by its retrospective nature, which increases the possibility of comorbidity misclassification. The lack of control subjects makes it difficult for comparative evaluation to determine if the standard therapy also produced the same outcomes, although it may be difficult to power studies in this population for clinically important outcomes. Given the small sample size, our study has insufficient power to detect small changes in the effectiveness and safety associated with infliximab. A larger sample size is needed to confirm our findings.\n\nConclusions\n\nICI-related myocarditis is an uncommon entity, making it difficult to study in randomized trials. Guidance for its management is therefore based on small case series and case reports. Current treatment focuses on glucocorticoids with a possible role for more targeted immune modulators in patients with severe disease or disease that responds poorly to steroids. We have demonstrated efficacy and safety of infliximab in patients with severe presentations of ICI myocarditis. Use of infliximab did not worsen heart failure in any case despite the black box warning for infliximab in patients with heart failure. With the variable presentation of ICI myocarditis and the availability of various immunosuppressive agents and strategies, it is prudent to involve a multi-disciplinary team to optimize management of these complex patients. As the indications and use for ICI continue to expand, the incidence and recognition of ICI myocarditis will likely increase. Therefore, further additional studies are indicated to help guide treatment of this complication of cancer immunotherapy.\n\nAbbreviations\n\nASCO American Society of Clinical Oncology\n\nCHB Complete heart block\n\nMACE Major adverse cardiovascular events\n\nICI Immune checkpoint inhibitor\n\nirAE Immune-related adverse events\n\nVT Ventricular Tachycardia\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nRZ – conception and design, analysis and interpretation of data, drafting of the manuscript. AP – analysis and interpretation of data, revising manuscript critically for important intellectual content, data visualization. KM – drafting of the manuscript. PE – revising manuscript critically for important intellectual content, data visualization. CP – revising manuscript critically for important intellectual content, data curation. CD – conception and design, revising manuscript critically for important intellectual content. MV – revising manuscript critically for important intellectual content, data visualization. PM – revising manuscript critically for important intellectual content. MC – revising manuscript critically for important intellectual content. RC – revising manuscript critically for important intellectual content. JR – revising manuscript critically for important intellectual content. RO – conception and design, analysis and interpretation of data, supervision, revising manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article.\n\nEthics approval and consent to participate\n\nThis study was approved by the University of Pennsylvania Institutional Review Board.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Tsai HF Hsu PN Cancer immunotherapy by targeting immune checkpoints: mechanism of T cell dysfunction in cancer immunity and new therapeutic targets J Biomed Sci 2017 24 1 35 10.1186/s12929-017-0341-0 28545567\n2. 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Escudier M Cautela J Malissen N Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity Circulation 2017 136 21 2085 7 10.1161/CIRCULATIONAHA.117.030571 29158217\n7. Mahmood SS Fradley MG Cohen JV Myocarditis in Patients Treated With Immune Checkpoint Inhibitors J Am Coll Cardiol 2018 71 16 1755 64 10.1016/j.jacc.2018.02.037 29567210\n8. Moslehi JJ Salem JE Sosman JA Lebrun-Vignes B Johnson DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis Lancet 2018 391 10124 933 10.1016/S0140-6736(18)30533-6\n9. Salem JE Manouchehri A Moey M Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study Lancet Oncol 2018 19 12 1579 89 10.1016/S1470-2045(18)30608-9 30442497\n10. Wang DY Okoye GD Neilan TG Johnson DB Moslehi JJ Cardiovascular Toxicities Associated with Cancer Immunotherapies Curr Cardiol Rep 2017 19 3 21 10.1007/s11886-017-0835-0 28220466\n11. Agrawal N Khunger A Vachhani P Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature Case Rep Oncol 2019 12 1 260 76 10.1159/000498985 31011325\n12. Caforio AL Pankuweit S Arbustini E Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases Eur Heart J 2013 34 33 2636 48 10.1093/eurheartj/eht210 23824828\n13. Brahmer JR Lacchetti C Schneider BJ Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2018 36 17 1714 68 10.1200/JCO.2017.77.6385 29442540\n14. Palaskas N Lopez-Mattei J Durand JB Iliescu C Deswal A Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment J Am Heart Assoc 2020 9 2 e013757 10.1161/JAHA.119.013757 31960755\n15. Zhang L Zlotoff DA Awadalla M Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis Circulation 2020 141 24 2031 4 10.1161/CIRCULATIONAHA.119.044703 32539614\n16. Norwood TG Westbrook BC Johnson DB Smoldering myocarditis following immune checkpoint blockade J Immunother Cancer 2017 5 1 91 10.1186/s40425-017-0296-4 29157297\n17. Arangalage D Delyon J Lermuzeaux M Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors Ann Intern Med 2017 167 9 683 4 10.7326/L17-0396 28869988\n18. Tay RY Blackley E McLean C Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy Br J Cancer 2017 117 7 921 4 10.1038/bjc.2017.253 28797029\n19. Esfahani K Buhlaiga N Thebault P Lapointe R Johnson NA Miller WH Jr. Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy The New England journal of medicine 2019 380 24 2375 6 10.1056/NEJMc1903064 31189042\n20. Salem JE Allenbach Y Vozy A Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis New England J Med 2019 380 24 2377 9 10.1056/NEJMc1901677 31189043\n21. Kwon HJ Cote TR Cuffe MS Kramer JM Braun MM Case reports of heart failure after therapy with a tumor necrosis factor antagonist Ann Intern Med 2003 138 10 807 11 10.7326/0003-4819-138-10-200305200-00008 12755552\n22. Gallegos C Rottmann D Nguyen VQ Baldassarre LA Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic resonance with pathology correlate Eur Heart J Case Rep 2019 3 1 yty149 31020225\n23. Frigeri M Meyer P Banfi C Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists Can J Cardiol 2018 34 1 92 10.1016/j.cjca.2017.09.025\n24. Chung ES Packer M Lo KH Fasanmade AA Willerson JT Anti TNFTACHFI Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial Circulation 2003 107 25 3133 40 10.1161/01.CIR.0000077913.60364.D2 12796126\n25. Ali T Kaitha S Mahmood S Ftesi A Stone J Bronze MS Clinical use of anti-TNF therapy and increased risk of infections Drug Healthc Patient Saf 2013 5 79 99 10.2147/DHPS.S28801 23569399\n26. Koo S Marty FM Baden LR Infectious complications associated with immunomodulating biologic agents Infect Dis Clin North Am 2010 24 2 285 306 10.1016/j.idc.2010.01.006 20466271\n27. Baddley JW Cantini F Goletti D ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-alpha agents) Clin Microbiol Infect 2018 24 Suppl 2 10 20 10.1016/j.cmi.2017.12.025 28082192\n28. Arnold TM Sears CR Hage CA Invasive fungal infections in the era of biologics Clin Chest Med 2009 30 2 279 86 10.1016/j.ccm.2009.02.007 19375634\n29. Arbour KC Mezquita L Long N Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer J Clin Oncol 2018 36 28 2872 8 10.1200/JCO.2018.79.0006 30125216\n30. Scott SC Pennell NA Early Use of Systemic Corticosteroids in Patients with Advanced NSCLC Treated with Nivolumab J Thorac Oncol 2018 13 11 1771 5 10.1016/j.jtho.2018.06.004 29935305\n31. Heublein B Wahlers T Haverich A Pulsed steroids for treatment of cardiac rejection after transplantation. What dosage is necessary? Circulation 1989 80 5 Pt 2 III97 99 2680162\n32. Wahlers T Heublein B Cremer J Treatment of rejection after heart transplantation: what dosage of pulsed steroids is necessary? J Heart Transplant 1990 9 5 568 74 2231096\n\n",
"fulltext_license": "CC BY",
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"issue": "7(1)",
"journal": "Cardio-oncology (London, England)",
"keywords": "Cardio‐oncology; Immune checkpoint inhibitor; Infliximab; Myocarditis; Nivolumab; Pembrolizumab",
"medline_ta": "Cardiooncology",
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"title": "Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series.",
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"abstract": "Syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop in association with several malignancies. However, as an immunohistochemical analysis is not performed in the majority cases, its true cause is often uncertain. We herein report a case of SIADH following chemotherapy due to tumor-derived ADH production in a patient with mucosa-associated lymphoid tissue (MALT) lymphoma. A retrospective immunohistochemical analysis demonstrated ADH expression by lymphoma cells. These findings highlight the importance of using an immunohistochemical analysis to determine ADH production by tumor cells in patients with SIADH. Such analyses play an important role in elucidating the pathogenesis of SIADH and determining the most appropriate treatment.",
"affiliations": "Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Japan.;Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Japan.;Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Japan.;Division of Pathology, Toho University Sakura Medical Center, Japan.;Division of Pathology, Toho University Sakura Medical Center, Japan.;Department of Hematology, Chiba University Hospital, Japan.;Department of Hematology, Chiba University Hospital, Japan.;Department of Hematology, Chiba University Hospital, Japan.;Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Japan.",
"authors": "Shimizu|Naomi|N|;Tanaka|Sho|S|;Watanabe|Yasuhiro|Y|;Tokuyama|Wataru|W|;Hiruta|Nobuyuki|N|;Ohwada|Chikako|C|;Sakaida|Emiko|E|;Nakaseko|Chiaki|C|;Tatsuno|Ichiro|I|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2902147110.2169/internalmedicine.9048-17Case ReportSyndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Mucosa-associated Lymphoid Tissue Lymphoma Shimizu Naomi 1Tanaka Sho 1Watanabe Yasuhiro 1Tokuyama Wataru 2Hiruta Nobuyuki 2Ohwada Chikako 3Sakaida Emiko 3Nakaseko Chiaki 3Tatsuno Ichiro 1\n1 Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Japan\n2 Division of Pathology, Toho University Sakura Medical Center, Japan\n3 Department of Hematology, Chiba University Hospital, JapanCorrespondence to Dr. Naomi Shimizu, naomis-cib@umin.ac.jp\n\n11 10 2017 1 12 2017 56 23 3225 3229 14 2 2017 10 4 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop in association with several malignancies. However, as an immunohistochemical analysis is not performed in the majority cases, its true cause is often uncertain. We herein report a case of SIADH following chemotherapy due to tumor-derived ADH production in a patient with mucosa-associated lymphoid tissue (MALT) lymphoma. A retrospective immunohistochemical analysis demonstrated ADH expression by lymphoma cells. These findings highlight the importance of using an immunohistochemical analysis to determine ADH production by tumor cells in patients with SIADH. Such analyses play an important role in elucidating the pathogenesis of SIADH and determining the most appropriate treatment. \n\nsyndrome of inappropriate antidiuretic hormone secretion (SIADH)antidiuretic hormone (ADH)mucosa-associated lymphoid tissue (MALT) lymphoma\n==== Body\nIntroduction\nSyndrome of inappropriate antidiuretic hormone secretion (SIADH) is caused by the excessive release of antidiuretic hormone (ADH). It has been reported in association with a variety of medical conditions, including drug therapy, central nervous system disorders, infections, and paraneoplastic syndromes accompanying several types of malignancies (1, 2).\n\nMucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade B-cell malignancy, and patients at an advanced stage are usually treated with R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) (3). A recent retrospective analysis suggested that Asians may be at an increased risk of developing SIADH during vincristine (VCR) treatment (4). However, there have been several reports of tumor-derived SIADH in patients with malignant lymphoma (5-7), as well associated with the use of anti-cancer drugs (4, 8).\n\nWe herein report the first case of tumor-derived hyponatremia following R-CHOP treatment in a patient with MALT lymphoma who was diagnosed with SIADH. After switching from VCR to vindesine sulfate (VDS), she achieved complete remission and did not show recurrence of SIADH. A retrospective immunohistochemical analysis demonstrated ADH expression by lymphoma cells.\n\nCase Report\nA 73-year-old Japanese woman attended our hospital in February 2016 with painless bilateral parotid gland swelling. A pathological examination of a needle biopsy of the left parotid gland showed infiltration of CD20-positive lymphocytes and the destruction of the parotid gland's duct, and she was diagnosed with MALT lymphoma (Fig. 1A and B). Fluorodeoxyglucose positron emission tomography revealed bilateral accumulation in the parotid glands, with a maximum standardized uptake value of 14.6 in the neck, multiple subcutaneous tumors, and multiple small consolidations in the lung. Accordingly, she was diagnosed with MALT lymphoma at clinical stage IVA.\n\nFigure 1. A: Histologic sections of swollen left parotid gland, demonstrating mucosa-associated lymphoid tissue lymphoma. Hematoxylin and Eosin staining. B: Lymphoma cells expressing CD20. C: Lymphoma cells positive for anti-diuretic hormone. D: Negative control slide for anti-diuretic hormone. E: Positive control slide for anti-diuretic hormone in human pituitary gland.\n\nAfter admission in May 2016, she was treated with R-CHOP, a chemotherapy that includes rituximab. On the day following treatment, she developed nausea and appetite loss, and her serum sodium level declined to 128 mEq/L. She was treated with intravenous furosemide 20 mg once for excess fluid volume due to the chemotherapy. Her serum sodium level improved, but the nausea and appetite loss continued. On day 12 after treatment, her serum sodium levels had again decreased to 127 mEq/L, with a serum chloride level of 90 mEq/L, plasma osmolality of 263 mOsm/kg, and serum lactate dehydrogenase level of 152 IU/L. A urinalysis demonstrated an increased sodium level of 53 mEq/L, a chloride level of 24 mEq/L, and osmolality of 665 mOsm/kg. Her serum ADH level was 1.7 pg/mL (Table). Her thyroid and adrenal function were normal. Accordingly, she was diagnosed with SIADH and treated with 1,000 mL/day of intravenous 3% saline and fluid restriction from day 13 to day 16 after treatment. On day 20 after admission, her condition improved with normalization of the sodium level, and she was discharged (Fig. 2A).\n\nTable. Laboratory Data When Syndrome of Inappropriate Antidiuretic Hormone Secretion Developed.\n\nHematology\t\tBiochemistry\t\tEndcrinology\t\t\nWBC\t3,000/μL\tCRP\t0.02 mg/dL\tACTH\t15.5 pg/mL\t\nRBC\t537×104/μL\tTP\t6.6 g/dL\tCS\t21.5 μg/dL\t\nHb\t15.0 g/dL\tAlb\t3.7 g/dL\tPAC\t122 pg/mL\t\nHt\t41.8%\tAST\t18 IU/L\tPRA\t1.5 ng/mL/h\t\nPlt\t21.7×104/μL\tALT\t15 IU/L\tADH\t1.7 pg/mL\t\nSeg\t76.5%\tLDH\t152 IU/L\t\t\t\nLymp\t20.7%\tALP\t152 IU/L\tUrinalysis\t\t\nMono\t1.9%\tγGTP\t30 IU/L\tNa\t53 mEq/L\t\nEosino\t0.6%\tT-BIL\t0.8 mg/dL\tK\t76.9 mEq/L\t\nBaso\t0.3%\tBUN\t10.6 mg/dL\tCl\t24 mEq/L\t\n\t\tCre\t0.58 mg/dL\tUosm\t665 mOsm/kg\t\n\t\tNa\t127 mEq/L\t\t\t\n\t\tK\t4.4 mEq/L\t\t\t\n\t\tCl\t90 mEq/L\t\t\t\n\t\tBS\t161 mg/dL\t\t\t\n\t\tPosm\t263 mOsm/L\t\t\t\nFigure 2. A: Clinical course during initial R-CHOP therapy. B: Clinical course during the second round of R-CHOP therapy with vindesine sulfate.\n\nWe speculated that SIADH might have developed due to the administration of VCR, so we replaced this with VDS. The SIADH resolved during subsequent chemotherapy (Fig. 2B), and the patient achieved complete remission after the sixth chemotherapy session. A retrospective immunohistochemistry analysis of the original sample showed the lymphoma cells to be positive for ADH expression (Fig. 1C) compared with a negative control (Fig. 1D). An immunohistochemical analysis of ADH in lymphoma cells was performed using rabbit anti-vasopressin antibody (dilution at 1:2,000; EMD Millipore, Temecula, USA) with a Ventana iVIEW DAB Universal Kit (Roche Diagnostics, Tokyo, Japan). The specimen was incubated with the primary antibody for 30 minutes at 37 °C. Normal rabbit immunoglobin fraction was used for negative control with same lymph node sample (Fig. 1D). For a positive control, normal human pituitary gland was stained with rabbit anti-vasopressin antibody as described above (Fig. 1E).\n\nDiscussion\nWe herein reported the first case of SIADH following R-CHOP therapy for MALT lymphoma. After switching from VCR to VDS, the patient's SIADH resolved, and she achieved complete remission after the completion of her treatment. A retrospective immunohistochemical analysis of her lymphoma cells demonstrated ADH protein expression (Fig. 1C). SIADH appeared to have developed in the present case due to tumor lysis in response to chemotherapy.\n\nSIADH may develop due to a variety of causes. There are many previous reports of drug-induced SIADH, including in response to cytotoxic agents (VCR, VDS, cisplatin, melphalan, and cyclophosphamide) as well as several other drugs (4, 8, 9). Hammond et al. reported that Asian patients might be at an increased risk of SIADH associated with VCR (4). We initially speculated that the development of SIADH in our patient was associated with VCR. However, there has been only one previous report of successful VDS treatment in a patient with SIADH secondary to VCR (10), suggesting that it is extremely rare to be able to avoid SIADH associated with VCR through using VDS.\n\nTo date, three previous reports have described SIADH associated with tumor lysis during chemotherapy in malignant lymphoma patients, with an immunohistochemical analysis demonstrating the expression of ADH by lymphoma cells. Kobayashi et al. reported tumor-derived SIADH in a case of diffuse large B-cell lymphoma, with a plasma osmolality of 231 mOsm/kg and a serum ADH level of 4.2 pg/mL on day 28 after chemotherapy (7). Hirata et al. reported two cases of lymphoma; one was a case of anaplastic large cell lymphoma, with a plasma osmolality of 265 mOsm/kg and a serum ADH level of 7.1 pg/mL on day 10 after chemotherapy (6), and the other was a case of peripheral T-cell lymphoma, with a plasma osmolality of 251 mOsm/kg and a serum ADH level of 2.1 pg/mL on day 8 after chemotherapy (5). These three patients had normal sodium levels before chemotherapy and then developed SIADH after the initiation of chemotherapy. Until now, there have been no reports of lymphoma cell-derived SIADH in a case of MALT lymphoma. The present case had a normal sodium level of 141 mEq/L at admission and then developed SIADH after chemotherapy (Fig. 2A). Her serum ADH level on day 12 after treatment was 1.7 pg/mL (the normal range is <4.2 pg/mL).\n\nSmith et al. reported formal criteria for the diagnosis of SIADH in 2,000 (11). The level of ADH is not an essential feature of these criteria. The essential features are (i) plasma osmolality <270 mOsm/kg H2O, (ii) inappropriate urinary concentration (Uosm >100 mOsm/kg), (iii) clinically euvolemic status, (iv) elevated urinary sodium (>40 mmol/L) with normal salt and water intake, and (v) hypothyroidism and glucocorticoid deficiency excluded (11). There was therefore a possibility that the patients in the previous three reports might have developed SIADH early after chemotherapy. Indeed, the sodium level of the present case decreased to 128 mEq/L on the day following chemotherapy. Nausea subsequently persisted, and her drinking intake was less than usual. She was treated with 1,000 mL/day of intravenous 3% saline on day 12 after treatment when her sodium level again decreased to 127 mEq/L. We therefore speculated that the reduction in the serum sodium was delayed due to fluid restriction, resulting in a delay in the diagnosis of SIADH.\n\nThere have been several reports of SIADH at the time of diagnosis in patients with malignant lymphoma (12-14). However, an immunohistochemical analysis of the ADH levels in the lymphoma cells was not performed for these patients, so the involvement of tumor-derived SIADH in these cases is unclear. Another patient of ours, an 81-year-old Japanese man with diffuse large B-cell lymphoma at clinical stage IVB who had developed SIADH at the time of diagnosis, was negative for ADH expression by lymphoma cells (data not shown). In this case, his serum SIADH remained constant after chemotherapy, and treatment for SIADH continued.\n\nDuring treatment for malignant lymphoma, it is not possible to reexamine the lymph nodes due to tumor shrinkage. It is therefore difficult to evaluate definitively whether or not tumor-derived ADH alone is involved in the pathogenesis of SIADH. However, it is important to examine the tumor ADH production using immunohistochemical analyses in patients who develop SIADH after chemotherapy. Immunohistochemical analyses play an important role in understanding the pathogenesis of SIADH in such patients, in addition to informing the most appropriate treatment options. Indeed, Hirata et al. reported the successful treatment with ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) of a case of tumor-derived SIADH following chemotherapy a patient with malignant lymphoma (5). It may be appropriate for patients with SIADH in malignant lymphoma to be evaluated by endocrinologists during chemotherapy.\n\nIn conclusion, this is the first report of tumor-derived SIADH in a patient with MALT lymphoma. Immunohistochemical An immunohistochemical analysis of the ADH production by lymphoma cells has an important role in determining the most appropriate therapeutic options for such cases.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nEsposito P , Piotti G , Bianzina S , Malul Y , Dal Canton A \nThe syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options . Nephron Clin Pract \n119 : 62 -73 , 2011 .\n2. \nPillai BP , Unnikrishnan AG , Pavithran PV \nSyndrome of inappropriate antidiuretic hormone secretion: revisiting a classical endocrine disorder . Indian J Endocrinol Metab \n15 (Suppl 3 ): S208 -S215 , 2011 .22029026 \n3. \nTsukamoto A , Nakamura F , Nannya Y , et al \nMalt lymphoma of the small bowel with protein-losing enteropathy . Int J Hematol \n99 : 198 -201 , 2014 .24395281 \n4. \nHammond IW , Ferguson JA , Kwong K , Muniz E , Delisle F \nHyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of vincristine: an over-representation of asians? \nPharmacoepidemiol Drug Saf \n11 : 229 -234 , 2002 .12051122 \n5. \nHirata Y , Yokote T , Kobayashi K , et al \nSyndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumor lysis in a patient with peripheral T-cell lymphoma unspecified . Leuk Lymphoma \n50 : 1226 -1229 , 2009 .19557646 \n6. \nHirata Y , Yokote T , Nishiwaki U , Tsuji M , Hanafusa T \nSyndrome of inappropriate antidiuretic hormone secretion associated with primary cutaneous anaplastic large cell lymphoma . Br J Haematol \n157 : 412 , 2012 .22409317 \n7. \nKobayashi K , Yokote T , Akioka T , Takubo T , Tsuji M , Hanafusa T \nInappropriate antidiuretic hormone production in diffuse large B-cell lymphoma . Br J Haematol \n143 : 2 , 2008 .18513282 \n8. \nVanhees SL , Paridaens R , Vansteenkiste JF \nSyndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review . Ann Oncol \n11 : 1061 -1065 , 2000 .11038047 \n9. \nAkhtar S , Cheesman E , Jude EB \nSIADH and partial hypopituitarism in a patient with intravascular large B-cell lymphoma: a rare cause of a common presentation . BMJ Case Rep \n2013 : 1 -3 , 2013 .\n10. \nNishinarita S , Sasaki I , Hiranuma M , et al \n[Successful vindesine treatment in the patient with blastic crisis of CML complicated with syndrome of inappropriate secretion of ADH secondary to vincristine] . Rinsho Ketsueki \n27 : 1916 -1921 , 1986 (in Japanese, Abstract in English).3469429 \n11. \nSmith DM , Mckenna K , Thompson CJ \nHyponatraemia . Clin Endocrinol (Oxf) \n52 : 667 -678 , 2000 .10848869 \n12. \nBockorny B , Dasanu CA \nSyndrome of inappropriate antidiuretic hormone secretion due to marginal zone lymphoma: responding to rituximab . Clin Lymphoma Myeloma Leuk \n12 : 220 -222 , 2012 .22578816 \n13. \nOnishi C , Ikejiri F , Kawakami K , et al \nAsian variant of intravascular large B cell lymphoma causes patients to frequently develop the syndrome of inappropriate antidiuretic hormone secretion . Ann Hematol \n90 : 1293 -1297 , 2011 .21340719 \n14. \nZhu CG , Zhang QZ , Zhu M , et al \nA case report of syndrome of inappropriate antidiuretic hormone secretion with Castleman's disease and lymphoma . BMC Endocr Disord \n13 : 19 -23 , 2013 .23734852\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "56(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "antidiuretic hormone (ADH); mucosa-associated lymphoid tissue (MALT) lymphoma; syndrome of inappropriate antidiuretic hormone secretion (SIADH)",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D044466:Asians; D006801:Humans; D007177:Inappropriate ADH Syndrome; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome; D014667:Vasopressins",
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"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Mucosa-associated Lymphoid Tissue Lymphoma.",
"title_normalized": "syndrome of inappropriate antidiuretic hormone secretion in a patient with mucosa associated lymphoid tissue lymphoma"
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"abstract": "BACKGROUND\nVitamin K deficiency results in serious coagulation dysfunction, but hemorrhagic shock is rare. Herein, we describe a case of vitamin K deficiency and abnormality in the path of the intercostal artery, the combination of which led to hemorrhagic shock.\n\n\nMETHODS\nAn 83-year-old woman was hospitalized for suspected gallstones. She developed septic shock after 4 days of hospitalization. We considered cholecystitis or cholangitis and performed abdominal ultrasonography, which revealed gallbladder enlargement, biliary sludge, and hyperplasia of the bile duct wall. Antibiotic treatment with sulbactam/ampicillin (SBT/ABPC) was initiated on day four, and percutaneous transhepatic gallbladder drainage (PTGBD) was performed on day five. The treatment was successful, but the patient developed bilateral pleural effusion because of hypoalbuminemia. We performed drainage for bilateral pleural effusion on days 13 and 17. The patient developed hypotension on day 18; blood tests showed anemia and severe coagulation dysfunction but a normal platelet count. We suspected vitamin K deficiency-induced coagulation dysfunction because of previous antibiotic treatment and restricted diet, and it led to hemorrhagic shock. Massive right hemothorax was observed by computed tomography, and urgent interventional radiology was performed. We observed no injury to the intercostal artery truncus but confirmed an abnormality in the course of the intercostal artery; therefore, we inferred that the cause of hemothorax in this case was injury to a small vessel, not truncus because of the abnormality. Because of the likelihood of rebleeding, we performed coil embolization from the seventh to the ninth intercostal artery. Because we confirmed vitamin K deficiency-induced coagulation dysfunction, we referred to the concentration of protein induced by vitamin K absence/antagonist-II (PIVKA-II), and it was found to increase by 23,000.\n\n\nCONCLUSIONS\nA combination of vitamin K deficiency and abnormality in the course of the intercostal artery led to hemorrhagic shock. When using certain antibiotics and restricting diet, it is important to measure coagulation function, even if the platelet count is normal. Further, when thoracentesis is performed, abnormalities in the course of the intercostal artery should be identified. Thoracentesis with ultrasound may prevent hemothorax.",
"affiliations": "Honjoudaiichi Hospital, 110, Iwabuchishita, Yurihonnjou, Akita, 015-8567, Japan. hideya.itagaki@gmail.com.;Honjoudaiichi Hospital, 110, Iwabuchishita, Yurihonnjou, Akita, 015-8567, Japan.",
"authors": "Itagaki|Hideya|H|http://orcid.org/0000-0001-6860-9734;Hagino|Takuro|T|",
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"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 97810.1186/s12876-019-0978-0Case ReportVitamin K deficiency-induced hemorrhagic shock after thoracentesis: a case report http://orcid.org/0000-0001-6860-9734Itagaki Hideya 81184-22-0111hideya.itagaki@gmail.com Hagino Takuro haginotakuro@gmail.com Honjoudaiichi Hospital, 110, Iwabuchishita, Yurihonnjou, Akita, 015-8567 Japan 18 4 2019 18 4 2019 2019 19 5821 12 2017 5 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nVitamin K deficiency results in serious coagulation dysfunction, but hemorrhagic shock is rare. Herein, we describe a case of vitamin K deficiency and abnormality in the path of the intercostal artery, the combination of which led to hemorrhagic shock.\n\nCase presentation\nAn 83-year-old woman was hospitalized for suspected gallstones. She developed septic shock after 4 days of hospitalization. We considered cholecystitis or cholangitis and performed abdominal ultrasonography, which revealed gallbladder enlargement, biliary sludge, and hyperplasia of the bile duct wall. Antibiotic treatment with sulbactam/ampicillin (SBT/ABPC) was initiated on day four, and percutaneous transhepatic gallbladder drainage (PTGBD) was performed on day five. The treatment was successful, but the patient developed bilateral pleural effusion because of hypoalbuminemia. We performed drainage for bilateral pleural effusion on days 13 and 17. The patient developed hypotension on day 18; blood tests showed anemia and severe coagulation dysfunction but a normal platelet count. We suspected vitamin K deficiency-induced coagulation dysfunction because of previous antibiotic treatment and restricted diet, and it led to hemorrhagic shock. Massive right hemothorax was observed by computed tomography, and urgent interventional radiology was performed. We observed no injury to the intercostal artery truncus but confirmed an abnormality in the course of the intercostal artery; therefore, we inferred that the cause of hemothorax in this case was injury to a small vessel, not truncus because of the abnormality. Because of the likelihood of rebleeding, we performed coil embolization from the seventh to the ninth intercostal artery. Because we confirmed vitamin K deficiency-induced coagulation dysfunction, we referred to the concentration of protein induced by vitamin K absence/antagonist-II (PIVKA-II), and it was found to increase by 23,000.\n\nConclusions\nA combination of vitamin K deficiency and abnormality in the course of the intercostal artery led to hemorrhagic shock. When using certain antibiotics and restricting diet, it is important to measure coagulation function, even if the platelet count is normal. Further, when thoracentesis is performed, abnormalities in the course of the intercostal artery should be identified. Thoracentesis with ultrasound may prevent hemothorax.\n\nKeywords\nVitamin K deficiencyHemorrhagic shockCholecystitisIntercostal arteryThoracentesisissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nVitamin K is a fat-soluble vitamin. Fat malabsorption leads to secondary vitamin K deficiency. Causes of fat malabsorption include bile tract obstruction, intestinal mucosal dysfunction, and hepatic failure. Other causes include deficient fat intake and use of broad-spectrum antibiotics [1]. Vitamin K deficiency causes bleeding in various organs [2]. However, reports of vitamin K deficiency leading to hemorrhagic shock are rare. In the present case, when treating cholecystitis, we found that a combination of antibiotic treatment and restricted fat diet led to vitamin K deficiency and hemorrhagic shock.\n\nCase presentation\nAn 83-year-old woman with epigastric pain was hospitalized for suspected gallstones. The patient’s medical history included diabetes, hypertension, hyperlipidemia, and dementia from stroke. The symptoms of epigastric pain disappeared after admission, but she developed a fever on day 2. Blood examination on day 4 revealed an inflammatory reaction (white blood cells, 12,200/μL; C-reactive protein, 27.39 mg/dL) and increased hepatobiliary enzymes (total bilirubin, 4.4 mg/dL; aspartate transaminase, 31 U/L; alanine transaminase, 54 U/L; lactate dehydrogenase, 217 U/L; alkaline phosphatase, 494 U/L; and gamma glutamyl transferase, 53 U/L). Urinalysis showed bilirubinuria. We considered cholecystitis or cholangitis and performed abdominal ultrasonography, which revealed gallbladder enlargement, biliary sludge, and hyperplasia of the bile duct wall. However, biliary expansion was not evident. Gallstone-related cholecystitis with bile duct inflammation was diagnosed. Antibiotic treatment with SBT/ABPC was initiated on day 4, and PTGBD was performed on day 5. The patient developed hypotension on day 6, and we therefore began noradrenaline administration. The disseminated intravascular coagulation did not merge (platelet count, 10.9 × 104/μL; prothrombin time(PT), 11.4 s; activated partial thromboplastin time(APTT), 31.9 s). The treatment was successful, and the noradrenaline was discontinued on day 8. However, the patient developed bilateral pleural effusion because of hypoalbuminemia. We were unable to discontinue oxygenation. Therefore, we drained the right and left pleural cavities on days 13 and 17 (Fig. 1), respectively. The thoracentesis decided a puncture position in an echo, but we did not use the echo at the time of puncture. No signs of vascular injury that may have caused the hypotension were found. There was pleural effusion discharge of 300–400 ml from both drains, and the pleural effusion were transudative pleural effusion. On the morning of day 18, the patient had tachycardia (pulse rate, 130 beats/min) and hypotension (systolic blood pressure, 50 mmHg). We confirmed the presence of severe anemia using a blood test, and hemorrhagic shock was diagnosed. Because bloody fluid was exiting the drain in the right thoracic cavity at the time and we were unable to examine the right lung using chest X-ray, we suspected that the hemorrhagic shock was due to massive hemothorax (Fig. 2). A blood test showed extensive coagulation dysfunction (PT, 68.0; APTT, immeasurable), and we considered the presence of vitamin K deficiency because the platelet level was normal. We performed red blood cell and fresh frozen plasma transfusions, and administered vitamin K to improve the anemia and coagulation disorder as quickly as possible (PT, 11.5; APTT, 32.0). On day 19, we performed cystography–computed tomography to identify the bleeding source. Enhancement rose from the 8th to 11th intercostal space during the arterial phase, and we considered this to be the bleeding site (Fig. 3). We performed contrast-enhanced examination of the intercostal arteries during urgent interventional radiology. We were unable to clearly identify the bleeding source, but confirmed an abnormality in the path of the intercostal artery (Fig. 4). We inferred that the cause of hemothorax in this case was injury to a small vessel, and not truncus due of the abnormality. Because of the likelihood of rebleeding, we performed coil embolization from the seventh to the ninth intercostal artery. Subsequently, because we confirmed vitamin K deficiency-induced coagulation dysfunction, we measured the concentration of PIVKA-II, and it was found to increase with 23,000. The patient’s condition stabilized, and she was awaiting hospital transfer at the time of this writing.Fig. 1 Draining of the left pleural cavities on day 17\n\nFig. 2 Massive hemothorax on day 18\n\nFig. 3 Enhancement rose from the 8th to the 11th intercostal(Red circle)\n\nFig. 4 Abnormality in the path of the intercostal artery\n\n\n\nDiscussion\nVitamin K deficiency causes bleeding in various organs, mucosal bleeding, bloody bowel discharge, and hematuria [2]. The absence of vitamin K affects the composition of coagulation factors II, VII, IX, and X and prolongs PT and APTT. However, other causes of PT, and APTT prolongation must be considered, such as hepatic failure and disseminated intravascular coagulation. Our patient was not believed to have hepatic failure because hepatic failure is associated with increase in liver enzymes and symptoms of hepatic failure. Because her platelet level was normal and her coagulation dysfunction normalized immediately upon transfusion, she was also not thought to have disseminated intravascular coagulation. Because high levels of PIVKA-II, an abnormal protein, were found and vitamin K deficiency was high, vitamin K deficiency was diagnosed.\n\nFat malabsorption, deficient fat intake, and use of broad-spectrum antibiotic treatment can lead to vitamin K deficiency. Particularly, use of antibiotics with an N-methyl-tetrazole-thiol group including sulbactam/cefoperazone, cefamandole, cefmetazole, and cefotetan leads to vitamin K deficiency [1]. In the present case, the patient underwent long-term fasting because of cholecystitis; antibiotic treatment was performed with SBT/ABPC, which led to vitamin K deficiency. Coagulation disorder due to cholecystitis is rare, but one such case report has been published [3]. Because we discontinued the patient’s diet, the patient was not supplemented with vitamin K. SBT/ABPC does not have an N-methyl-tetrazole-thiol group and therefore is not expected to cause vitamin K deficiency, but one case report has described vitamin K deficiency in association with SBT/ABPC [4]. Although this is considered a rare cause of vitamin K deficiency, one study showed that patients entering the intensive care unit present with vitamin K deficiency [5].\n\nPneumothorax, hemothorax, and hypotension are the main complications associated with thoracentesis. Risk factors for these complications include a clinician with limited technical experience, the presence of emphysema, and a history of chest puncture. Hemothorax occurs in approximately 1.6% of thoracentesis procedures and is thus a rare complication [6]. In the present case, we observed no injury to the intercostal artery truncus but confirmed an abnormality in the course of the intercostal artery; therefore, we inferred that the cause of hemothorax in this case was injury to a small vessel, and not truncus due to the abnormality. In another case report similar to ours, a patient developed massive hemothorax due to an abnormality in the course of the intercostal artery [7]. The use of ultrasound guidance is considered useful to prevent injury to the intercostal artery. One study showed that the risk of bleeding associated with thoracentesis was 0.27 and 1.25% with and without ultrasound guidance, respectively [8]. Thus, it seems that the use of ultrasound will be indicated in the future.\n\nConclusions\nWe have reported a case of hemorrhagic shock caused by vitamin K deficiency and an abnormality in the path of the intercostal artery. Even if platelet count is normal, measurement of coagulation function and supplementation of vitamin K are necessary in high-risk patients. Additionally, ultrasound guidance is useful during thoracentesis.\n\nAbbreviations\nAPTTActivated partial thromboplastin time\n\nPIVKA-IIProtein induced by vitamin K absence/antagonist-II\n\nPTProthrombin time\n\nPTGBDPercutaneous transhepatic gallbladder drainage\n\nSBT/ABPCSulbactam/ampicillin\n\nAcknowledgements\nWe thank Angela Morben, DVM, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll the data regarding the findings are available within the manuscript.\n\nAuthors’ contributions\nTH collected data and treated the patient with HI. HI treated the patient, interpreted the data and was a contributor in writing the manuscript. Both authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study was approved by the Honjou Daiichi Hospital ethical committee.\n\nConsent for publication\nBecause the patient herself could not communicate, written informed consent was obtained from the patient’ family for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Sattler FR Weitekamp MR Ballard JO Potential for bleeding with the new beta-lactam antibiotics Ann Intern Med 1986 105 924 931 10.7326/0003-4819-105-6-924 3535606 \n2. Fotouhie A, Desai H, King S, Parsa NA. Gastrointestinal bleeding secondary to trimethoprim-sulfamethoxazole-induced vitamin K deficiency. BMJ Case Rep. 2016;2016.\n3. Shimamoto S Tanaka A Tsuchida K Hayashi K Sawa T Serious coagulation dysfunction in a patient with gallstone-related cholecystitis successfully treated with vitamin K Japanese J Anesthesiol 2016 65 4 407 410 \n4. Iwata S The effects of antibiotics on the intestinal bacterial flora and blood coagulation system Kansenshogaku Zasshi 1984 58 903 920 10.11150/kansenshogakuzasshi1970.58.903 6440923 \n5. Crowther MA McDonald E Johnston M Cook D Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study Blood Coagulation Fibrinolysis 2002 13 49 52 10.1097/00001721-200201000-00007 11994567 \n6. Heidecker J Huggins JT Sahn SA Doelken P Pathophysiology of pneumothorax following ultrasound-guided thoracentesis Chest 2006 130 1173 1184 10.1016/S0012-3692(15)51155-0 17035453 \n7. Spanuchart I Gallacher S Hemothorax after thoracentesis N Engl J Med 2016 375 1878 10.1056/NEJMicm1507029 27959649 \n8. Mercaldi CJ Lanes SF Ultrasound guidance decreases complications and improves the cost of care among patients undergoing thoracentesis and paracentesis Chest 2013 143 532 538 10.1378/chest.12-0447 23381318\n\n",
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"abstract": "We present a 16-year-old boy, who had presented to us with catatonic features of mutism, withdrawal, passive negativism, grimacing, gesturing, echopraxia, and excitement of 5 days duration while taking antiretroviral therapy (ART) for a period of 2 years. He had history of birth asphyxia and acquired HIV infection from his father when the same syringe and needle was used on both of them in a medical setting where the father and son had consulted for treatment of pyrexia of unknown origin. He was the eldest of a three children family in which the biologic father had acquired HIV through extramarital sexual contact with HIV-infected sex workers but was unaware of his HIV positive status till our patient, the 16-year-old was admitted and treated for pulmonary tuberculosis at 14 years of age. The boy's mother had only acquired HIV after having three children with the HIV-positive husband, thus leaving the other two children HIV negative. The catatonia completely resolved within 2 days after the ART was withheld, and risperidone 1 mg twice a day was prescribed. This case highlights the risks of ART and breach of universal precautions.",
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"fulltext": "\n==== Front\nJ Pediatr NeurosciJ Pediatr NeurosciJPNJournal of Pediatric Neurosciences1817-17451998-3948Medknow Publications & Media Pvt Ltd India JPN-9-28310.4103/1817-1745.147598Case ReportAntiretroviral treatment induced catatonia in 16-year-old boy Lingeswaran Anand Department of Psychiatry, Sri Manakula Vinayagar Medical College and Hospital, Madagadipet, Kalitheerthalkuppam, Puducherry, Tamil Nadu, IndiaAddress for correspondence: Dr. Anand Lingeswaran, Department of Psychiatry, Sri Manakula Vinayagar Medical College and Hospital, Madagadipet, Kalitheerthalkuppam, Puducherry - 605 009, Tamil Nadu, India. E-mail: anafonix@gmail.comSep-Dec 2014 9 3 283 285 Copyright: © Journal of Pediatric Neurosciences2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a 16-year-old boy, who had presented to us with catatonic features of mutism, withdrawal, passive negativism, grimacing, gesturing, echopraxia, and excitement of 5 days duration while taking antiretroviral therapy (ART) for a period of 2 years. He had history of birth asphyxia and acquired HIV infection from his father when the same syringe and needle was used on both of them in a medical setting where the father and son had consulted for treatment of pyrexia of unknown origin. He was the eldest of a three children family in which the biologic father had acquired HIV through extramarital sexual contact with HIV-infected sex workers but was unaware of his HIV positive status till our patient, the 16-year-old was admitted and treated for pulmonary tuberculosis at 14 years of age. The boy's mother had only acquired HIV after having three children with the HIV-positive husband, thus leaving the other two children HIV negative. The catatonia completely resolved within 2 days after the ART was withheld, and risperidone 1 mg twice a day was prescribed. This case highlights the risks of ART and breach of universal precautions.\n\nAntiretroviral therapycatatoniaHIVolanzapine\n==== Body\nIntroduction\nGlobally an estimated 2.5 million children are living with HIV/AIDS, 10,000 becoming infected daily and 2,60,000 deaths of children under 15 occur due to AIDS-related illnesses.[1] The government of India estimates that about 2.40 million Indians are living with HIV (1.93–3.04 million) with an adult prevalence of 0.31% (2009). Children (<15 years) account for 3.5% of all infections whereas 83% are the in age group 15–49 years. India's highly heterogeneous epidemic is largely concentrated in only a few states – in the industrialized south and west, and in the north-east. The four high prevalence states of South India (Andhra Pradesh – 500,000, Maharashtra – 420,000, Karnataka – 250,000, Tamil Nadu – 150,000) account for 55% of all HIV infections in the country.[2]\n\nAlthough efficacious, (antiretroviral therapy [ART]) highly active antiretroviral treatment (HAART) is not available to more than half with HIV in India and those who receive it develop neuropsychiatric side-effects. ART, along with comorbid medical conditions and substance abuse are associated with new-onset psychosis whose prevalence among patients with HIV infection is reported to range from 0.23% to 15.2%.[3] Side-effects have been described in patients without psychiatric antecedents, but those with a previous psychiatric history are more vulnerable and should be monitored closely.[4] These problems are very debilitating when they occur in children who acquire HIV, unfortunately, from infected mothers.\n\nAlthough World Health Organization guidelines on ART prophylaxis reduces HIV transmission from mother to fetus, the United Nations guidelines on primary prevention in health care settings on universal precautions in needle use practices are equally important and together helps to reduce childhood HIV. Safe needle practices only reduce the risk of mother-to-child HIV transmission to 2%.[5] Sadly, not surprisingly breaches in safe needle practices during childhood or adolescence might sometimes lead to new onset HIV.\n\nIn this background, we report a case where there was initially a breach of safe needle practice in a health care setting that had led a 16-year-old boy to accidently acquire HIV infection from his HIV-positive father. He subsequently presented to psychiatric services with ART induced catatonic symptoms.\n\nCase Report\nA 16-year-old boy was brought to our psychiatric outpatient setting by his parents with 5 days history of mutism, grimacing, excitement, echopraxia and withdrawal symptoms in addition to poor sleep. He was admitted into the child and adolescent inpatient psychiatric unit of our hospital for further management with the consent of the parents.\n\nDetailed history and mental state examination provided a definitive diagnosis of catatonia with Bush Francis rating scale score of 12. There was no past psychiatric history. Both his parents were illiterates, and there was no family history of any neurodegenerative disorders, mental illness, and epilepsy except for the father who had a history of alcohol abuse. Antenatal history was uneventful but perinatal period was complicated with birth asphyxia and forceps delivery in a hospital with birth weight of 2.7 kg and he was breastfed and weaned normally. Immunization history was adequate, and there was no developmental delay. He had an elder sister and younger brother who were functioning well.\n\nPhysical examination showed normal head circumference and absent Kayser–Fleischer ring. Although clinically relevant differential diagnosis such as Wilson's disease, thyroid disorders, mental retardation were considered, only IQ assessment could be done which was in the average range. Blood and biochemical parameters were all normal. HIV serology was positive and negative for hepatitis B and syphilis. A plain computed tomography scan of the brain revealed gliotic changes in the left temporal lobe, which the radiologist reported as a possible consequence of birth asphyxia.\n\nPast medical history showed that HIV seropositivity was diagnosed in 2011 when the boy was admitted for pulmonary tuberculosis (PTB) at Government General Hospital, Vizhupuram and had received intensive 6 months treatment for PTB as per Revised National PTB Programme (RNTCP). Both his parents also tested positive for HIV but the other two children showed HIV negative results. Subsequently, the boy and his parents have been taking ART which consisted of tablet zidovudine (ZDV) 250 mg 2 times a day, tablet abacavir (ABC) 300 mg one in the morning and two at night with tablet efavirenz (EFV) 300 mg at night from the Integrated Counseling and Treatment Centre (ICTC), Vizhupuram. Further, it was evident from the old hospital records that the daily dosage of ZDV, ABC and EFV were increased 2 months before the onset of catatonic symptoms. In consultation with the ICTC, all the ART medications were stopped, tablet risperidone 1 mg twice daily was started, and the boy was monitored for resolution of symptoms. Within 5 days, all the catatonic symptoms resolved completely, and he was communicating relevantly and taking his feeds and sleeping well. He was referred back to the ICTC where the dosage of ART was reduced. The patient returned for review after 3 weeks and there was no evidence of any psychiatric symptomatology. He was still asymptomatic after 6 weeks follow-up on ART.\n\nDuring the inpatient admission, repeat serology of other family members showed that our patient's elder sister and younger brother tested negative for HIV as before while both his parents tested positive. This gap in seropositivity among the children was explored further, and it was found that the father had acquired HIV through unsafe extramarital sexual contact, but after having three children with his wife and remained ignorant of it. Antenatally, the boy's mother was always seronegative in all three pregnancies. Further exploration revealed a history that our patient had acquired HIV infection in 2009, when he and his father had attended a rural health care centre, for treatment of loose stools and that is when the same needle was allegedly used on both the father and the son. This history was strongly corroborated by the boy's mother who had accompanied them.\n\nDiscussion\nOur case highlights two important factors in childhood acquired HIV infection – firstly the mandatory need for safe needle use practices always which could have prevented HIV infection in our patient and secondly the neurotoxic side-effects of ART in children.\n\nWorld Health Organization's new guidelines (2010), reports that early ART for a larger group of HIV-positive pregnant women, longer provision of ART prophylaxis for HIV-positive pregnant women with relatively strong immune systems to benefit both the health of the mother and provision of ARV prophylaxis to the mother or child can prevent HIV transmission to her child during pregnancy and breastfeeding.[5] Illiteracy, low socioeconomic status, rural population, unsafe sex practices and nonavailability of ART still remain risk factors for HIV transmission in children in developing countries like India and Sub-Saharan Africa. Inadequate precautions in rural health care settings in developing countries sometimes become a matter of medical negligence and unacceptable reason for HIV transmission in children. Safer use of the same needle in a health care setting is definitely an easily preventable primary prevention method of HIV across all ages.\n\nAlthough effective against central nervous system (CNS) infection, antiretrovirals are themselves increasingly recognized as a source of neuropsychiatric disorders and the combination of at least three antiretroviral drugs also known as HAART has created a large potential for drug interactions and subsequent toxicity. The mechanisms underlying the development of neuropsychiatric symptoms in HIV are complex. Several factors interact, including the direct effect of the virus, immune mediators and medications.[6] Among the ART's, ZDV, lamivudine, didanosine cause dose-related psychiatric disturbances. ABC does not cause prominent psychiatric side-effects, although when used in combination, it may induce psychosis and catatonia.[7] EFV notably has been reported to induce a variety of CNS side-effects in up to 50% of patients that may be severe and sudden in onset. Symptoms include twilight states, personality changes, with increased hostility, and cognitive disturbances.[6] The treatment of antiretroviral-induced psychiatric disturbance varies according to its severity. Mild symptoms should be monitored, and psychotropics may be added if required. Severe cases may require switching or discontinuing the HAART regimen, which could be reinstated (often with different medication) once the patient improves. Our patient was receiving a combination of ABC, didanosine and EFV at therapeutic dosages, and the catatonic symptoms noted possibly due to a recent dose increase and the neurological effects of HIV infection.\n\nThis case stresses the need for imparting better knowledge to the vulnerable population about unsafe sex practices, stricter adherence to universal precautions of safe needle usage and to all medical professionals about neurotoxic side-effects of ART.\n\nAcknowledgment\nI am grateful to the parents and children who agreed to participate in this report. I acknowledge the support of the Department of Microbiology for providing lab support.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 HIV/AIDS in the Context of other Global Challenges, Global 2015, Special Report for the UN High Level Meeting on AIDS 2011 \n2 HIV/AIDS in India Last accessed on 2013 Aug 30th Available from:\nhttp://www.worldbank.org/en/news/feature/2012/07/10/hiv.aids.india \n3 Nebhinani N Mattoo SK Psychotic disorders with HIV infection: A review Ger J Psychiatry 2013 16 43 8 \n4 Peyriere H Mauboussin JM Rouanet I Fabre J Reynes J Hillaire-Buys D Management of sudden psychiatric disorders related to efavirenz AIDS 2001 15 1323 4 11426084 \n5 Nakatani H Mafubelu D WHO Preventing mother-to-child transmission of HIV to reach the UNGASS and millennium development goals PMTCT Strategic Vision 2010-2015 2010 \n6 Treisman GJ Kaplin AI Neurologic and psychiatric complications of antiretroviral agents AIDS 2002 16 1201 15 12045485 \n7 Foster R Olajide D Everall IP Antiretroviral therapy-induced psychosis: Case report and brief review of the literature HIV Med 2003 4 139 44 12702135\n\n",
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"keywords": "Antiretroviral therapy; HIV; catatonia; olanzapine",
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"title": "Antiretroviral treatment induced catatonia in 16-year-old boy.",
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"abstract": "Coronary artery disease (CAD) is a known potential complication of thoracic radiation treatment that typically affects the proximal segments of the coronary arteries, requiring coronary artery bypass grafting (CABG). We present a case of acute coronary syndrome occurring in a 57-year-old man with prior thoracic radiation therapy following resection of a chest wall chondrosarcoma. Coronary angiogram demonstrated significant areas of stenosis in the left main coronary artery (LMCA) and ostial left anterior descending (LAD) coronary artery. The patient was also found to have atretic bilateral internal mammary arteries as a consequence of his radiation therapy, rendering them unsuitable as grafts. Percutaneous coronary intervention (PCI) was thus performed with a successful outcome. To our knowledge, this is the first case of radiation-induced CAD of the LMCA with atretic internal mammary arteries treated successfully with PCI.",
"affiliations": "Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA.",
"authors": "Dogra|Siddhant|S|https://orcid.org/0000-0003-2386-7849;Mahajan|Asha M|AM|;Jung|Albert|A|;Attubato|Michael|M|;Saric|Muhamed|M|;Shah|Alan|A|https://orcid.org/0000-0002-0596-391X",
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"doi": "10.1155/2020/7970305",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404 2090-6412 Hindawi \n\n10.1155/2020/7970305\nCase Report\nRadiation-Induced Left Main Coronary Artery Stenosis in a Patient with Atretic Internal Mammary Arteries\nhttps://orcid.org/0000-0003-2386-7849Dogra Siddhant Mahajan Asha M. Jung Albert Attubato Michael Saric Muhamed https://orcid.org/0000-0002-0596-391XShah Alan alan.shah@nyulangone.org Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Avenue, Skirball 9U, New York, NY10016, USA\nAcademic Editor: Assad Movahed\n\n\n2020 \n11 3 2020 \n2020 797030516 12 2019 29 2 2020 Copyright © 2020 Siddhant Dogra et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Coronary artery disease (CAD) is a known potential complication of thoracic radiation treatment that typically affects the proximal segments of the coronary arteries, requiring coronary artery bypass grafting (CABG). We present a case of acute coronary syndrome occurring in a 57-year-old man with prior thoracic radiation therapy following resection of a chest wall chondrosarcoma. Coronary angiogram demonstrated significant areas of stenosis in the left main coronary artery (LMCA) and ostial left anterior descending (LAD) coronary artery. The patient was also found to have atretic bilateral internal mammary arteries as a consequence of his radiation therapy, rendering them unsuitable as grafts. Percutaneous coronary intervention (PCI) was thus performed with a successful outcome. To our knowledge, this is the first case of radiation-induced CAD of the LMCA with atretic internal mammary arteries treated successfully with PCI.\n==== Body\n1. Introduction\nRadiation therapy can play a critical role in treatment of cancers involving the chest such as breast cancer, lung cancer, lymphoma, and other thoracic-related cancers. However, radiation therapy does pose a risk of damaging pulmonary and cardiovascular tissues. Radiation-induced cardiovascular disease can manifest as acute or constrictive pericarditis, aortic disease, valvular disease, heart failure, arrhythmias, and vasculopathy involving both microvascular and macrovascular structures, including coronary artery disease (CAD). The injury can either be acute or develop years after treatment [1]. Studies in patients receiving radiation therapy suggest a dose-response relationship between radiation exposure and incidence of cardiovascular complications [2]. Radiation-induced CAD tends to affect the left main coronary artery (LMCA) or proximal left anterior descending (LAD) artery, making a patient more favorable for coronary artery bypass grafting (CABG) [3]. However, radiation may also damage the internal mammary arteries. In this report, we describe to our knowledge the first case of a patient with radiation-induced LMCA disease with atretic left and right internal mammary arteries treated successfully with percutaneous coronary intervention (PCI).\n\n2. History of Presentation and Medical History\nA 57-year-old man presented to his outpatient cardiologist with two weeks of exertional left-sided chest pain and decrease in exercise tolerance from a baseline of 20 blocks to 1 block. The pain was described as pressure in a band-like region across his chest, brought on by exertion and relieved after 5-10 minutes of rest. His history was significant for high-grade dedifferentiated chest wall chondrosarcoma involving the left ribs that was resected three years earlier (Figures 1(a) and 1(b)). The internal mammary arteries were isolated and protected perioperatively. The patient subsequently received one cycle of adjuvant high-dose ifosfamide with mesna complicated by worsening renal function. This was followed by thoracic radiation treatment of 60 Gray total delivered in 30 fractions. He then was started on pazopanib daily complicated by hypertension and hypothyroidism.\n\n3. Investigation\nThe patient experienced chest pain walking to the exam room and was sent to the emergency department for further evaluation. His electrocardiogram showed normal sinus rhythm with new T-wave inversions in the anterior and lateral leads as well as poor R wave progression. Two successive troponins were elevated at 0.13 and 0.11 ng/mL. A transthoracic echocardiogram showed severe hypokinesis in the LAD distribution with a new mildly reduced ejection fraction of 40%.\n\nCoronary angiogram showed significant LMCA stenosis extending into the ostial segment of the LAD artery with 90% stenosis, which was further evaluated by intravascular ultrasound (IVUS) noting significant plaque (Figures 2(a) and 2(b)). There were also stenotic lesions in the first diagonal branch. The right coronary artery, left circumflex artery, and ramus intermedius artery displayed minimal luminal abnormalities. Given the patient's history of chest radiation therapy, angiography of the internal mammary arteries was performed and demonstrated diminutive, possibly occluded vessels (Figures 3(a) and 3(b)).\n\n4. Management\nPCI was performed on the mid-LMCA to ostial LAD lesion. After prestent dilatation, a 3.5 × 20 mm Promus ELITE drug-eluting stent was successfully delivered (Figures 4(a) and 4(b)). Poststent balloon dilatation was performed, and IVUS confirmed good stent apposition and expansion. The decision was made to medically manage the first diagonal branch disease. The patient was discharged on aspirin 81 mg daily, ticagrelor 90 mg twice daily, and atorvastatin 80 mg daily in addition to continuing his home medications.\n\n5. Follow-Up\nThree months postdischarge, the patient was doing well, asymptomatic, and back to his baseline exercise tolerance.\n\n6. Discussion\nCardiovascular disease and cancer together are the top two leading causes of mortality worldwide and share significant common characteristics including overlap in risk factors as well as pathophysiologic components ranging from genetic to inflammatory. Moreover, numerous cancer treatments have been demonstrated to be cardiotoxic, including chemotherapeutic agents such as doxorubicin and newer targeted immunotherapies. Combination with radiation can increase the risk of cardiac toxicities. As cancer therapies have improved, cancer survival rates have significantly increased. As the number of cancer survivors grows, practitioners must be aware of the links between cancer treatment and development of future cardiac complications [4].\n\nRadiation therapy can affect both pulmonary and cardiovascular structures and function. Patients can develop pulmonary toxicities such as radiation-induced fibrosis or pleural effusions, which can be both acute and chronic. Pulmonary hypertension can develop as a consequence of this injury. They can develop vasculopathy which can involve both macrovascular and microvascular structures. There is a risk of developing aortic calcification which can complicate surgical options. CAD and microvascular disease can lead to both angina and ischemic cardiomyopathy. Patients can develop both acute and chronic pericarditis, pericardial effusions, and constrictive pericarditis. Valvular heart disease usually presents as progressive thickening and calcification which can affect the valvular structure, the subvalvular apparatus, and the aortomitral curtain. The aortic and mitral valves are more commonly affected, and symptomatic disease can develop 10 to 20 years later [5]. Conduction defects including atrial fibrillation, atrioventricular block, and ventricular arrhythmias can also occur. Finally, radiation can cause myocardial dysfunction due to diffuse fibrosis and can lead to heart failure [6, 7].\n\nThoracic radiation treatment can lead to accelerated CAD, even in patients without typical risk factors. Patients with radiation-induced CAD tend to present at a younger age than the general population. They commonly have LMCA and/or proximal LAD lesions since these structures are more anterior and central and thus likely exposed to more radiation than distal vessel segments [1, 3]. Radiation-induced CAD is thought to be driven by increased inflammatory cytokine production and inflammatory cell recruitment leading to accelerated intimal plaque formation. Furthermore, radiation induces fibrosis of the media and adventitia in the vessel wall. Inflammatory marker concentration and risk of vessel injury increase proportionally to cumulative radiation dose [1].\n\nRadiation-induced CAD management in terms of medical therapy and revascularization remains the same as that of atherosclerotic CAD. However, revascularization decisions can become challenging as radiation can damage the internal mammary arteries that are more favorable to use especially for left main and LAD disease [1, 8]. Some concern exists about whether the internal mammary arteries should be used as grafts even if they appear undamaged due to potential radiation-induced atherosclerosis. It has been reported that the use of healthy internal mammary arteries is not associated with early graft failure up to one year [9]. However, there was a reported case of a patient with radiation-induced CAD who underwent CABG using the internal mammary arteries and decompensated immediately postoperatively. Emergent angiography showed suboccluded arterial grafts, which were explanted and replaced by saphenous vein grafts. Pathological analysis of the arterial grafts showed significant atherosclerotic plaque and fibrosis [10]. In addition, among patients with radiation-induced CAD who undergo surgery, there is higher risk of postoperative complications such as poor wound healing and higher mortality up to 10 years compared to CABG patients with no history of radiation therapy [11]. PCI is an appealing alternative as it has been shown to be noninferior to CABG for LMCA disease among patients with low-intermediate SYNTAX scores [12]. However, mortality is reportedly higher in patients who undergo PCI for radiation-induced CAD compared to those without radiation exposure at up to 12 years, and there is debate about whether restenosis rates may be higher [13].\n\nGiven our patient's significant LMCA stenosis with bifurcation involvement to the LAD and low disease burden in other vessels, it would be most appropriate to pursue CABG based on the 2017 ACC/AHA Appropriate Use Criteria [14]. However, our patient had atretic left and right internal mammary arteries due to radiation, making them unfavorable grafts. In addition, he would have had increased risk of sternal wound infection given this would have been his second sternotomy in the setting of prior radiation therapy. Ultimately, our patient underwent PCI to the lesion with an excellent angiographic result.\n\n7. Conclusion\nCAD is one possible consequence of thoracic radiation treatment. The cardiovascular team should evaluate both pulmonary and cardiovascular complications of radiation in order to determine the best revascularization strategy that will lead to a good long-term patency as well as reduce comorbidities of the revascularization procedure. While CABG is commonly used, patients may have radiation damage to the internal mammary arteries. PCI is an available option in the treatment of these patients.\n\nAbbreviations\nCAD:Coronary artery disease\n\nCABG:Coronary artery bypass grafting\n\nLMCA:Left main coronary artery\n\nPCI:Percutaneous coronary intervention\n\nLAD:Left anterior descending\n\nIVUS:Intravascular ultrasound\n\nD1:First diagonal branch\n\nLIMA:Left internal mammary artery\n\nRIMA:Right internal mammary artery\n\nBCA:Brachiocephalic artery\n\nConflicts of Interest\nThere are no financial, personal, or professional conflicts of interest to disclose.\n\nFigure 1 Chest wall chondrosarcoma on prior CT scan. CT scan of chest wall chondrosarcoma in (a) transverse and (b) sagittal planes marked by asterisks.\n\nFigure 2 Initial coronary angiogram of left coronary system. Coronary angiogram showing the stenotic lesion in the (a) left internal mammary artery (LMCA) and first diagonal branch (D1) and (b) IVUS of LMCA lesion showing significant plaque (noted by yellow asterisks).\n\nFigure 3 Coronary angiogram of internal mammary arteries. Coronary angiogram of the (a) left internal mammary artery (LIMA) and the (b) right internal mammary artery (RIMA) coming just off of the right brachiocephalic artery (BCA).\n\nFigure 4 Coronary angiogram of LMCA lesion after PCI. (a, b) Coronary angiogram of LMCA lesion after stent placement.\n==== Refs\n1 Yusuf S. W. Sami S. Daher I. N. Radiation-induced heart disease: a clinical update Cardiology Research and Practice 2011 2011 9 317659 10.4061/2011/317659 2-s2.0-79959502786 21403872 \n2 Menezes K. M. Wang H. Hada M. Saganti P. B. Radiation matters of the heart: a mini review Frontiers in Cardiovascular Medicine 2018 5, article 83 10.3389/fcvm.2018.00083 \n3 Borges N. Kapadia S. R. Radiation-induced CAD: incidence, diagnosis, and management outcomes May 2018, https://www.acc.org/latest-in-cardiology/articles/2018/05/24/01/44/radiation-induced-cad \n4 Okwuosa T. M. Anzevino S. Rao R. Cardiovascular disease in cancer survivors Postgraduate Medical Journal 2017 93 1096 82 90 10.1136/postgradmedj-2016-134417 2-s2.0-84994589679 28123076 \n5 Flores-Umanzor E. J. Hernández-Enríquez M. Caldentey G. San Antonio R. Paré C. Radiation-induced cardiac valve disease American Journal of Medicine 2017 130 3 e99 e100 10.1016/j.amjmed.2016.08.050 2-s2.0-84994031943 27687070 \n6 Desai M. Y. Windecker S. Lancellotti P. Prevention, diagnosis, and management of radiation-associated cardiac disease: JACC scientific expert panel Journal of the American College of Cardiology 2019 74 7 905 927 10.1016/j.jacc.2019.07.006 2-s2.0-85071559521 31416535 \n7 Chang H. M. Okwuosa T. M. Scarabelli T. Moudgil R. Yeh E. T. H. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 2 Journal of the American College of Cardiology 2017 70 20 2552 2565 10.1016/j.jacc.2017.09.1095 2-s2.0-85032696668 29145955 \n8 Otsuka F. Yahagi K. Sakakura K. Virmani R. Why is the mammary artery so special and what protects it from atherosclerosis? Annals of Cardiothoracic Surgery 2013 2 4 519 526 10.3978/j.issn.2225-319X.2013.07.06 23977631 \n9 Nasso G. Canosa C. de Filippo C. M. Thoracic radiation therapy and suitability of internal thoracic arteries for myocardial revascularization Chest 2005 128 3 1587 1592 10.1378/chest.128.3.1587 2-s2.0-24944506347 16162762 \n10 Amabile N. Veugeois A. Zannis K. Caussin C. Radiotherapy-induced vascular damage in mammary arterial graft: correlations between optical coherence tomography and pathology European Heart Journal 2016 37 6 p. 567 10.1093/eurheartj/ehv286 2-s2.0-84962205016 26141398 \n11 Wu W. Masri A. Popovic Z. B. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study Circulation 2013 127 14 1476 1485 10.1161/CIRCULATIONAHA.113.001435 2-s2.0-84876159855 23569119 \n12 Stone G. W. Sabik J. F. Serruys P. W. Everolimus-eluting stents or bypass surgery for left main coronary artery disease The New England Journal of Medicine 2016 375 23 2223 2235 10.1056/NEJMoa1610227 2-s2.0-85003545668 27797291 \n13 Reed G. W. Masri A. Griffin B. P. Kapadia S. R. Ellis S. G. Desai M. Y. Long-term mortality in patients with radiation-associated coronary artery disease treated with percutaneous coronary intervention Circulation Cardiovascular Interventions 2016 9 6 10.1161/CIRCINTERVENTIONS.115.003483 2-s2.0-84975764064 27313281 \n14 Patel M. R. Calhoon J. H. Dehmer G. J. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons Journal of the American College of Cardiology 2017 69 17 2212 2241 10.1016/j.jacc.2017.02.001 2-s2.0-85014824441 28291663\n\n",
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"title": "Radiation-Induced Left Main Coronary Artery Stenosis in a Patient with Atretic Internal Mammary Arteries.",
"title_normalized": "radiation induced left main coronary artery stenosis in a patient with atretic internal mammary arteries"
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"abstract": "BACKGROUND\nInfection remains the most common complication following renal transplantation (RT). Cytomegalovirus (CMV) is one of the most important pathogens in this patient population and Clostridium difficile-associated colitis (CDAC) has emerged as one of the most frequent gastrointestinal complications. Only few cases of simultaneous CMV enterocolitis and CDAC have been reported.\n\n\nMETHODS\nA 73-year-old woman who underwent RT more than 10 years earlier developed severe abdominal pain and profound bloody diarrhea. She was diagnosed with simultaneous CMV enterocolitis and CDAC and treated with ganciclovir and metronidazole. She was unable to clear the infections and underwent colonic and small bowel resection, but ultimately died from indirect complications following the two severe infections.\n\n\nCONCLUSIONS\nLate-onset CMV disease in this patient who was CMV negative prior to transplantation and received a CMV-negative graft was an unexpected event; the simultaneous occurrence of CDAC aggravated the clinical picture ultimately leading to surgery, graft failure and death. Clinicians should be aware that opportunistic infections may develop many years post transplant and may occur simultaneously.",
"affiliations": "Department of Surgery, Division of Transplantation, University of Virginia Health System, Charlottesville, VA 22908, U.S.A.",
"authors": "Dahman|Mohamed|M|;Krell|Robert|R|;Brayman|Kenneth|K|;Sawyer|Robert G|RG|;Cathro|Helen P|HP|;Hagspiel|Klaus D|KD|;Sifri|Costi D|CD|;Bonatti|Hugo J R|HJ|",
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"title": "Simultaneous Clostridium difficile-associated colitis and late-onset intestinal cytomegalovirus disease in a renal transplant recipient.",
"title_normalized": "simultaneous clostridium difficile associated colitis and late onset intestinal cytomegalovirus disease in a renal transplant recipient"
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"abstract": "BACKGROUND\nAcute non-cardiogenic pulmonary edema (ANPE) is a rare but challenging complication which occurs during the perioperative period, mainly before and after the extubation in the course of the recovery period of general anesthesia. It is characterized by increased fluid in extravascular pulmonary spaces, preventing gas exchange and further resulting in respiratory failure.\nA 12-year-old boy who had undergone island skin flap in the right upper limb and who developed a unilateral pulmonary edema after the administration of neostigmine during the recovery period of general anesthesia. The neostigmine was administered to reverse neuromuscular block.\nAcute non-cardiogenic pulmonary edema.\n\n\nMETHODS\nThe patient was transferred to intensive care unit (ICU) and treated with mechanical ventilation (controlled mode ventilation pattern, CMV) and other supportive treatment.\n\n\nRESULTS\nThe oxyhemoglobin saturation of the patient returned to the normal level with symptoms and signs of ANPE significantly alleviated. The mechanical ventilation was withdrawn by the fourth day, and no sequela of vital organs was observed.\n\n\nCONCLUSIONS\nAlthough neostigmine is widely used for recovery from neuromuscular block and exhibits satisfactory effect in most cases, there is a potential risk of ANPE in some cases, which is rare but potentially fatal and could affect the patient outcomes. Therefore, it is necessary for anesthetists to closely monitor the vital signs of patients after administration of neostigmine in the perioperative period.",
"affiliations": "Department of Anesthesia, China-Japan Union Hospital of Jilin University Department of Spine Surgery, The First Hospital of Jilin University, Changchun, P.R. China.",
"authors": "Zhang|Wenjing|W|;Ning|Cong|C|;Zhao|Guoqing|G|;Su|Zhenbo|Z|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29794728MD-D-17-0826510.1097/MD.0000000000010525105253300Research ArticleClinical Case ReportAcute noncardiogenic pulmonary edema after neostigmine administration during the recovery period of general anesthesia A case reportZhang Wenjing PhDaNing Cong MDbZhao Guoqing PhDa∗Su Zhenbo PhDa∗NA. a Department of Anesthesia, China-Japan Union Hospital of Jilin Universityb Department of Spine Surgery, The First Hospital of Jilin University, Changchun, P.R. China.∗ Correspondence: Guoqing Zhao, and Zhenbo Su, Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, 130033, P.R. China (e-mails: guoqing1965@163.com, suzb@jlu.edu.cn)5 2018 25 5 2018 97 21 e105255 1 2018 14 3 2018 14 3 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nAcute non-cardiogenic pulmonary edema (ANPE) is a rare but challenging complication which occurs during the perioperative period, mainly before and after the extubation in the course of the recovery period of general anesthesia. It is characterized by increased fluid in extravascular pulmonary spaces, preventing gas exchange and further resulting in respiratory failure.\n\nPatient concerns:\nA 12-year-old boy who had undergone island skin flap in the right upper limb and who developed a unilateral pulmonary edema after the administration of neostigmine during the recovery period of general anesthesia. The neostigmine was administered to reverse neuromuscular block.\n\nDiagnoses:\nAcute non-cardiogenic pulmonary edema.\n\nInterventions:\nThe patient was transferred to intensive care unit (ICU) and treated with mechanical ventilation (controlled mode ventilation pattern, CMV) and other supportive treatment.\n\nOutcomes:\nThe oxyhemoglobin saturation of the patient returned to the normal level with symptoms and signs of ANPE significantly alleviated. The mechanical ventilation was withdrawn by the fourth day, and no sequela of vital organs was observed.\n\nLessons:\nAlthough neostigmine is widely used for recovery from neuromuscular block and exhibits satisfactory effect in most cases, there is a potential risk of ANPE in some cases, which is rare but potentially fatal and could affect the patient outcomes. Therefore, it is necessary for anesthetists to closely monitor the vital signs of patients after administration of neostigmine in the perioperative period.\n\nKeywords\nacute noncardiogenic pulmonary edemamechanical ventilationneostigmineperioperative periodOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPulmonary edema is a rare but potentially fatal complication, which may occur during the perioperative period. It is characterized by increased fluid in pulmonary interstitial spaces and alveoli, which obstructs normal gas exchange and further leads to respiratory failure.[1] The common causes of pulmonary edema are left ventricular failure, trauma, sepsis, drug reaction or overdose, and so on.[2] Due to different etiology, the pathogenesis of drug-induced pulmonary edema is multifactorial and not completely understood, which may involve cytotoxicity of lung epithelial cells and relevant inflammatory response.[3] Here, we report a rare case of a 12-year-old boy with a dry gangrene who developed acute noncardiogenic pulmonary edema (ANPE) after administration of neostigmine for the reversal of neuromuscular block at the end of the surgery.\n\n2 Case report\nThis study was approved by the Ethics Committee and Institutional Review Board of the China-Japan Union Hospital of Jilin University, and informed consent was obtained.\n\nA 12-year-old boy, 41 kg of weight, having his right forefinger bashed 70 days ago, underwent an island skin flap in the right upper limb under general anesthesia. He was also diagnosed of the dry gangrene in the distal limb. The preoperative blood routine, coagulation routine, chest X-ray, and electrocardiogram (ECG) examination results were normal. The patient fasted for 12 hours without transfusion before the operation.\n\nWhen entering the operation room for the first time, the patient was extremely frightened and refused to receive the venipuncture, so a peripheral intravenous access was established in the ward. The patient was treated with intravenous injection of midazolam 7.0 mg and escorted into the operation room in sleep. During the process, the patient had been repeatedly beaten by his parents, which aggravated his nervousness and fright.\n\nIn the operation room, ECG, oxyhemoglobin saturation (SpO2), and blood pressure (BP) were monitored with anesthesia monitor (S5 TM, GE Healthcare TM, Milwaukee, WI). The general anesthesia was induced by intravenous administration of fentanyl 4 μg/kg, cisatracurium 0.25 mg/kg, and diprivan 1.5 mg/kg. Then a tracheal intubation followed. Brachial plexus block was performed on the right upper arm with 0.375% ropivacaine (20.0 mL). All procedures were carried out smoothly, and the breath sounds of both lungs were within normal limits. General anesthesia was maintained with sevoflurane 1% to 1.5% and no additional drugs were added. During the surgery, SpO2 was 99%, airway pressure (Paw) 13 to 15 cm H2O, tidal volume (VT) 300.0 mL, respiratory rate 11/min, heart rate (HR) 90 to 105/min, and BP was 90–110/65–80 mm Hg. The surgery lasted for 1.5 hours and was finished uneventfully. Ringer solution 500 mL was used during the surgery, and the urine volume was 150 mL with the use of catheterization.\n\nAt the end of the surgery, the anesthetic inhalation was deactivated followed by a lung lavage. A respiratory resistance was found, so a mixture of neostigmine 1 mg and atropine 0.5 mg was given intravenously, and a manual-control breathing assistance was provided. Ten minutes later, another neostigmine 1 mg and atropine 0.5 mg mixture were given for the respiratory depression, which was still existing, then the BP decreased to 90/60 temporarily, and HR was 70 bpm. BP and HR returned to normal range within 3 minutes, while no significant improvement in respiration was observed. Mechanical ventilation proceeded in controlled mode ventilation with VT 300 mL, flux 15/min, and positive end-expiratory pressure (PEEP) 7 on 100% O2. Ten minutes after the 2nd administration of neostigmine-atropine, massive pink and frothy sputum were sucked from the endotracheal tube. Bilateral auscultation displayed a large amount of moist rale at the left lung bases while a few were observed at the right lung. Arterial blood gas analysis showed that Paw rose to 15 to 20 cm H2O while SpO2 dropped away to 93% to 97%. Then, the patient was propped up, and furosemide 20.0 mg, methylprednisolone 80.0 mg, and cedi-lanid 0.2 mg were given intravenously together with papaverine 30.0 mg intramuscularly. Right chest puncture proceeded with a 7# needle and no gas out was observed, then the needle was pulled out. After that, a chest X-ray was taken, the results of which showed significant left pulmonary edema (Fig. 1A).\n\nFigure 1 Chest X-ray photograph findings of (A) postoperative acute pulmonary edema phase after administration of neostigmine. (B) Recovery phase on the next day.\n\nMassive frothy pink sputum came from the patient's mouth. Paw increased significantly to 20 to 25 cm H2O, SPO2 decreased to 85% to 93%, systolic blood pressure 140 to 160 mm Hg, HR 110 to 140 bpm, and SPO2 decreased momentarily to 65% to 75% during airway suction. After that, anisodamine 10.0 mg and furosemide 80 mg were given intravenously. Two hours later, pink frothy sputum declined significantly and breathing recovered spontaneously, but SPO2 remained 85% to 93% and obvious breathing difficulty were observed. Then, the patient was transferred to intensive care unit to continue ventilation therapy. The chest X-ray on the next day showed left pulmonary edema, right pneumothorax, and a right thoracic drainage was given (Fig. 1B). Then, the pulmonary oxygenation improved (fraction of inspiration O2, FiO2: 0.4, partial pressure of carbon dioxide, PaCO2: 203 mm Hg), and myocardial enzyme level was significantly increased, liver and kidney functions improved mildly, and thrombocytocrit became 103 μg/L.\n\nThe patient was ventilated for 4 days and extubated on the 5th day after the operation. Cardiac color ultrasound, chest radiography, and bronchoscopy showed no clinical problems in vital organs, and the patient was transferred to Department of Pediatrics for further treatment.\n\n3 Discussion\nPulmonary edema is a severe perioperative complication which usually happens before or after the tracheal extubation during the recovery period of general anesthesia. It is characterized by excess fluid accumulation in the tissue and air spaces of the lungs. Due to an increase in the pulmonary capillary hydrostatic pressure, pulmonary edema can be cardiogenic while noncardiogenic is induced by increased capillary permeability.[4] It is important to understand the potential causes of pulmonary edema during the perioperative period to determine the specific therapy and prevent the disease from aggravation.\n\nIn this case, cardiogenic pulmonary edema (CPE) was first excluded. CPE may be caused by pneumothorax tension of the right lung due to vascular reactive contraction, which induces a shift to the left of the mediastinum, an obstruction of the return flow, and a vascular distortion in the left lung. At that moment, the pulmonary capillary hydrostatic pressure increases gradually and a pulmonary edema occurs. The anesthetist also considered this factor first. However, the patient had no history of cardiovascular disease, and ECG was normal throughout the process. In addition, postoperative ultrasonic cardiogram showed no compromise of cardiac functions. Therefore, the cardiogenic possibility was evaded.\n\nExcessive infusion of liquid or rapid infusion per unit time can also lead to pulmonary edema. However, only 500 mL of lactic acid Ringer solution was infused in this case at a constant speed, thus this factor was also ruled out.\n\nNegative pressure pulmonary edema (NPPE) often occurs in patients with acute upper airway obstruction or spontaneous breathing recovery after chronic partial airway obstruction. In the present case, NPPE can be ruled out as the patient had no history of chronic partial airway obstruction and the endotracheal catheter had not been removed.\n\nWhen the endotracheal tube is inserted deeply into the right lung, it may lead to atelectasis of the left lung, resulting in reexpansion pulmonary edema. In addition, repeated stimulation to the carina with the endotracheal tube end can also induce pulmonary edema by activating the vasovagal reflex.[5] However, in the present case, these factors related to endotracheal tube localization and single-lung ventilation have been ruled out by the chest X-ray.\n\nConsidering that also the above factors have been ruled out and pulmonary edema occurred within a few minutes after the injection of neostigmine, it can be speculated that the pulmonary edema was induced by neostigmine. Neostigmine is a type of cholinesterase inhibitor that can increase the amount of acetylcholine by inhibiting the activity of cholinesterase, thereby enhancing and prolonging the cholinergic effects of acetylcholine. It is conventionally used for reversal of neuromuscular block induced by nondepolarizing neuromuscular blocking drugs at the end of surgery.[6] The use of neostigmine is known to be safe and effective for most patients. However, in recent years several cases of acute pulmonary edema due to the application of neostigmine have been reported. Raiger et al[7] reported 2 cases of ANPE after the administration of neostigmine to reverse neuromuscular block. Preeti and coworkers[8] have reported a 9-year-old boy who developed ANPE following extubation after using neostigmine. Bijapur and coworkers described a case of a 1-year-old child who developed acute pulmonary edema after the use of a neostigmine–glycopyrrolate mixture for reversal of neuromuscular block.[9] In all cases, the patients had no preexisting cardiac or respiratory diseases and underwent operation under general anesthesia. Neostigmine-induced ANPE was diagnosed based on the fact that ANPE occurred soon after the administration of neostigmine while other causes of ANPE were ruled out. Preeti et al speculated that neostigmine might induce noncardiac pulmonary edema (NCPE) by impairing the function of upper airway dilating muscle and causing upper airway to narrow which may result in NPPE. Bijapur and coworkers surmised the occurrence of NCPE might be also related to the rare anaphylaxis of neostigmine. However, in the present case, the tracheal tube had not been removed when NCPE occurred and no allergy was observed through the process. Therefore, those mechanisms were not applicable to the present case. In addition, the patients were children under 12 years old in 3 of the 4 cases, so it can be assumed that the neostigmine-induced NCPE was more likely to happen to children.\n\nIn this case, a 12-year-old boy developed NCPE following the use of neostigmine for reversal of neuromuscular block before extubation. The autonomic nervous system of the child has not developed well. Meanwhile, the child was in a state of irritation before the surgery because of the fear of the operation and the abuse of his parents. Also, the patient has a history of gangrene, and the absorption of toxins can also induce the sympathetic nervous system to an excited state. It is known that the application of neostigmine may further activate the sympathetic nervous system. In our case, neostigmine was administered twice with a total dose of 50 μg/kg, which could be considered as high dose (although not over-dose) for a child. High dose of neostigmine can inhibit the activity of cholinesterase, and lead to an accumulation of acetylcholine at cholinergic nerve terminals. The accumulated acetylcholine can then stimulate the N1 receptor, induce the excitation of autonomic ganglion, and upregulate the excitement of sympathetic nervous system. Moreover, the sympathetic nervous system was over-excited after the administration of neostigmine together with atropine. Atropine is routine use in preventing the bradyarrhythmia effects of neostigmine, because it acts by inhibiting M receptor in the parasympathetic postganglionic postsynaptic membrane. The regulation of peripheral vessels is mainly accomplished by the binding of acetylcholine to N receptor in the postsynaptic membrane of the sympathetic nervous system, while atropine does not bind to the N receptor or affect the sympathetic transmission process. In brief, atropine used in this case was clinical doses, which has been proved no effect on ventricular function and peripheral blood vessels mainly due to the lack of parasympathetic domination of the M receptors.[10] Therefore, the role of atropine in sympathetic hyperexcitability and pulmonary edema could be excluded and the over-excited state of sympathetic nervous system was mainly due to the administration of neostigmine.\n\nThe excessive excitation of sympathetic nervous system has a lot to do with the occurrence of pulmonary edema.[11,12] It has been reported that the significant activation of the sympathetic nervous system is a necessary precondition of neurogenic pulmonary edema in rats with spinal cord injury.[13] The significant increase of catecholamine including norepinephrine and adrenaline in the blood is closely related to the development of neurogenic pulmonary edema. It can be speculated that due to the over-excitation of the sympathetic nervous system, a surge of catecholamine, including epinephrine and norepinephrine, was released into the bloodstream and induced systemic vasoconstriction and rapid changes in hemodynamics, which then induced a sudden increase of arterial BP and a large amount of blood in the pulmonary circulation. On one hand, the effective filtration pressure of pulmonary capillary bed increased sharply and a large amount of fluid accumulated in the lung clearance, resulting in the formation of pulmonary edema. On the other hand, the impact of blood flow induced the injury of vascular endothelial cells and the release of vasoactive substances (such as histamine, etc.), which resulted in increased vascular permeability and extravasation of massive plasma protein and further aggravated acute pulmonary edema.\n\nIn view of the diagnosis and treatment process of ANPE in our case, several tips were summarized as follows to effectively prevent, diagnose, and treat acute pulmonary edema during the perioperative period.(1) Routine medication may also induce rare but fatal complications such as ANPE in some cases especially when patients are in an irritable or infectious state. This phenomenon may have individual differences and should draw enough attention.\n\n(2) The sympathetic nervous system of children has not well developed and is more likely to be over-excited by the external environment. When using neostigmine for children, it is necessary to appropriately regulate the dose and closely monitor the vital signs for the effective prevention and prompt diagnosis of pulmonary edema.\n\n(3) The diagnosis of drug-induced pulmonary edema is difficult due to the lack of detection methods. If pulmonary edema occurs soon after the administration of drugs with other factors ruled out, drug-induced pulmonary edema should be considered.\n\n(4) The treatment of pulmonary edema should be based on mechanical ventilation and other supportive treatment such as a cardiac stimulant, diuretics, and other symptomatic treatment should be applied when necessary.\n\n\n\n4 Conclusion\nIn conclusion, we report a case of pulmonary edema caused by neostigmine during the period of general anesthesia recovery. There was no drug induced allergy in this case report and the dose of neostigmine was relatively high but not over dose. This complication is unpredictable and challenging which could affect the prognosis of patients, and careful attention should be paid on the administration of neostigmine for the reversal of neuromuscular block, especially for young patients or those in an irritable state. Once the pulmonary edema occurs, mechanical ventilation and other appropriate supportive treatment should be provided in accordance with the severity of the conditions.\n\nAcknowledgements\nThe authors thank the Foundation of Health Committee of Jilin Province (Grant Nos. 2015Z028) and the Educational Committee of Jilin Province (Grant Nos. JJKH20170862KJ) for financial support.\n\nAuthor contributions\nConceptualization: Zhenbo Su.\n\nData curation: Wenjing Zhang.\n\nResources: Guoqing Zhao.\n\nWriting – original draft: Cong Ning.\n\nAbbreviations: ANPE = acute noncardiogenic pulmonary edema, BP = blood pressure, CPE = Cardiogenic pulmonary edema, ECG = electrocardiogram, HR = heart rate, NCPE = noncardiac pulmonary edema, NPPE = negative pressure pulmonary edema, Paw = airway pressure, SpO2 = oxyhemoglobin saturation.\n\nFunding/support: This study was financially supported by Foundation of Health Committee of Jilin Province (Grant Nos. 2015Z028) and the Educational Committee of Jilin Province (Grant Nos. JJKH20170862KJ).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Lee J-Y Kwon H-J Park S-W \nAcute pulmonary edema caused by takotsubo cardiomyopathy in a pregnant woman undergoing transvaginal cervical cerclage a case report . Medicine \n2017 ;96 : e5536 .\n[2] Kurdowska AK \nUnusual causes of acute pulmonary oedema . Clin Sci \n2003 ;104 :265–6 .12605584 \n[3] Kapoor MC \nCould postoperative pulmonary oedema be attributed to the use of neostigmine? \nIndian J Anaesth \n2010 ;54 :582.\n[4] Kushimoto S Taira Y Kitazawa Y \nThe clinical usefulness of extravascular lung water and pulmonary vascular permeability index to diagnose and characterize pulmonary edema: a prospective multicenter study on the quantitative differential diagnostic definition for acute lung injury/acute respiratory distress syndrome . Crit Care \n2012 ;16 : R232 .\n[5] Sugiyama Y Shimizu F Shimizu S \nSevere re-expansion pulmonary edema induced by one-lung ventilation . Respir Care \n2015 ;60 :E134–40 .25691768 \n[6] Green MS Venkatesh AG Venkataramani R \nManagement of residual neuromuscular blockade recovery: age-old problem with a new solution . Case Rep Anesthesiol \n2017 ;2017 : 8197035 .\n[7] Raiger L Naithani U Vijay B \nNon-cardiogenic pulmonary oedema after neostigmine given for reversal: a report of two cases . Indian J Anaesth \n2010 ;54 :338–41 .20882179 \n[8] More PG Durve SR \nAcute pulmonary oedema: a post-operative complication due to neostigmine and post obstructive pulmonary oedema in a case of tonsillectomy . J Clin Diagn Res \n2015 ;9 : UD05-06 .\n[9] Nagella AB Bijapur MB Shreyavathi S \nNeostigmine and pulmonary oedema . BMJ Case Rep \n2014 ;pii: bcr2014204992 .\n[10] McGraw-Hill Education/Medical , Butterworth J Mackey DC Wasnick J \nMorgan and Mikhail's Clinical Anaesthesiology . 2013 .\n[11] Duplain H Vollenweider L Delabays A \nAugmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema . Circulation \n1999 ;99 :1713–8 .10190881 \n[12] Sarnoff SJ Sarnoff LC \nNeurohemodynamics of pulmonary edema. II. The role of sympathetic pathways in the elevation of pulmonary and stemic vascular pressures following the intracisternal injection of fibrin . Circulation \n1952 ;6 :51–62 .14936200 \n[13] Sedy J Zicha J Nedvidkova J \nThe role of sympathetic nervous system in the development of neurogenic pulmonary edema in spinal cord-injured rats . J Appl Physiol \n2012 ;112 :1–8 .21903880\n\n",
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"mesh_terms": "D000762:Anesthesia Recovery Period; D000768:Anesthesia, General; D002648:Child; D002800:Cholinesterase Inhibitors; D006801:Humans; D008297:Male; D009388:Neostigmine; D011654:Pulmonary Edema; D012121:Respiration, Artificial",
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"title": "Acute noncardiogenic pulmonary edema after neostigmine administration during the recovery period of general anesthesia: A case report.",
"title_normalized": "acute noncardiogenic pulmonary edema after neostigmine administration during the recovery period of general anesthesia a case report"
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"abstract": "Beta-adrenergic blockade without adequate alpha blockade is an established trigger of pheochromocytoma crisis (PC). Carvedilol is a nonselective beta-adrenergic and alpha 1-adrenergic blocking agent, and its use for preoperative preparation of pheochromocytoma patients with prior cardiomyopathy secondary to PC resulting from unopposed beta-blocker therapy has never been reported.\nA 48-year-old woman was admitted to the Urology Department for evaluation of a huge right upper abdominal mass. She developed hypertensive crisis with acute pulmonary edema resulting in respiratory failure after administration of atenolol to treat hypertension and tachycardia. Transthoracic echocardiogram revealed global hypokinesia. The patient was managed with intravenous nicardipine, furosemide, and prazosin because of the clinical suspicion of pheochromocytoma that was subsequently confirmed by elevated plasma and urine catecholamine levels. Within 3 days of alpha-adrenergic blockers treatment, there was rapid amelioration of hypertension and pulmonary congestion, as well as normalization of left ventricular function by echocardiography. However, tachycardia persisted after 1 month of adequate alpha-adrenergic blockade. Given the benefit of beta-adrenergic blockers in patients with systolic dysfunction, we slowly titrated carvedilol while carefully monitoring the patient's condition in the intensive care unit. Tachycardia was controlled without inducing PC. Surgical resection was successful without perioperative complications.\nClinicians should be cautious when prescribing beta-adrenergic blocker in patients with hypertension and upper quadrant mass of unknown etiology. The mass may be pheochromocytoma. Preoperative use of carvedilol after sufficient alpha-adrenergic blockade for control of tachycardia in a patient with prior cardiomyopathy associated with atenolol-induced PC is safe and effective.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Wannachalee|Taweesak|T|;Chunharojrith|Paweena|P|",
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"doi": "10.1016/j.amsu.2020.11.014",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801 Elsevier \n\nS2049-0801(20)30441-6\n10.1016/j.amsu.2020.11.014\nCase Report\nSafety of preoperative carvedilol in a patient with recent atenolol-induced pheochromocytoma crisis and cardiomyopathy: A case report\nWannachalee Taweesak Chunharojrith Paweena paweena.chn@mahidol.ac.th∗ Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand\n∗ Corresponding author. Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Asadang Building 8th Floor, Siriraj Hospital, 2 Prannok Road, Bangkok Noi, Bangkok, 10700, Thailand. paweena.chn@mahidol.ac.th\n06 11 2020 \n12 2020 \n06 11 2020 \n60 360 364\n21 8 2020 1 11 2020 1 11 2020 © 2020 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nBeta-adrenergic blockade without adequate alpha blockade is an established trigger of pheochromocytoma crisis (PC). Carvedilol is a nonselective beta-adrenergic and alpha 1-adrenergic blocking agent, and its use for preoperative preparation of pheochromocytoma patients with prior cardiomyopathy secondary to PC resulting from unopposed beta-blocker therapy has never been reported.\n\nCase presentation\nA 48-year-old woman was admitted to the Urology Department for evaluation of a huge right upper abdominal mass. She developed hypertensive crisis with acute pulmonary edema resulting in respiratory failure after administration of atenolol to treat hypertension and tachycardia. Transthoracic echocardiogram revealed global hypokinesia. The patient was managed with intravenous nicardipine, furosemide, and prazosin because of the clinical suspicion of pheochromocytoma that was subsequently confirmed by elevated plasma and urine catecholamine levels. Within 3 days of alpha-adrenergic blockers treatment, there was rapid amelioration of hypertension and pulmonary congestion, as well as normalization of left ventricular function by echocardiography. However, tachycardia persisted after 1 month of adequate alpha-adrenergic blockade. Given the benefit of beta-adrenergic blockers in patients with systolic dysfunction, we slowly titrated carvedilol while carefully monitoring the patient's condition in the intensive care unit. Tachycardia was controlled without inducing PC. Surgical resection was successful without perioperative complications.\n\nConclusion\nClinicians should be cautious when prescribing beta-adrenergic blocker in patients with hypertension and upper quadrant mass of unknown etiology. The mass may be pheochromocytoma. Preoperative use of carvedilol after sufficient alpha-adrenergic blockade for control of tachycardia in a patient with prior cardiomyopathy associated with atenolol-induced PC is safe and effective.\n\nHighlights\n• Beta-adrenergic blocker should be used cautiously in patients with hypertension and upper quadrant mass.\n\n• The mainstay of treatment for pheochromocytoma crisis is adequate alpha-adrenergic blockade.\n\n• Preoperative use of carvedilol after alpha-adrenergic blockade in recent pheochromocytoma crisis is safe.\n\n\n\nKeywords\nPheochromocytoma crisisCardiomyopathyBeta-adrenergic blockerAlpha-adrenergic blockadeCase reportAbbreviations\nPC, Pheochromocytoma crisisHR, heart rateBP, blood pressureCT, Computed tomographyECG, Electrocardiogram\n==== Body\n1 Introduction\nThe classic symptoms of pheochromocytoma are paroxysmal headache, diaphoresis, and palpitations. However, the clinical presentations of these tumors are extremely variable, ranging from an absence of symptoms to hemodynamic instability and end-organ dysfunction to pheochromocytoma crisis (PC), which has a significant mortality rate. PC can manifest spontaneously or be triggered by certain factors, including surgical procedures, general anesthesia, and beta-adrenergic blockade without prior adequate alpha-adrenergic blockade [1].\n\nTransient cardiomyopathy secondary to hypertensive crisis after beta-blocker therapy is a rarely reported presentation of pheochromocytoma [2]. Furthermore, using carvedilol, a nonselective beta-blocker and selective alpha-1 blocker, to treat tachycardia in a patient who has previously presented with hypertensive crisis after beta-blocker therapy has never been reported. We present a pheochromocytoma patient who presented with transient left ventricular dysfunction secondary to hypertensive crisis after receiving a single dose of atenolol. After the hypertensive crisis had been successfully treated by alpha-adrenergic blockade, carvedilol was administered to control the patient's heart rate (HR) before tumor resection. The operation was successfully performed without any complications. This study has been reported in line with the SCARE 2018 criteria [3].\n\n2 Case report\nA 48-year-old Thai woman, farmer, complained of epigastric pain lasting 4 years. She was treated with proton pump inhibitors without further abdominal imaging. Her symptom progressively worsened. Her past medical history revealed she completed treatment for pulmonary tuberculosis 12 years earlier. She is non-smoker and has no other medical history. A month earlier, she had been admitted to another hospital for severe headache and forceful heartbeat. Her blood pressure (BP) was 224/190 mmHg and HR was 120 beats/min. On physical examination, she had normal cardiopulmonary and neurological systems. She was treated with amlodipine 10 mg/day and hydralazine 75 mg/day. The symptoms improved and the systolic BP decreased to 160–170 mmHg. Abdominal computed tomography (CT) scan was performed to evaluate the chronic epigastric pain. The CT scan showed a large heterogeneous enhancing mass (9.9 × 12.7 × 14.7 cm) with central necrosis in the right upper abdomen. The differential diagnosis included renal or suprarenal tumors (Fig. 1). Therefore, antihypertensive agents were continued and she was referred to the department of Urology for further management.Fig. 1 CT scan of the abdomen in the coronal and axial planes show a large right suprarenal mass 9.9 × 12.7 × 14.7 cm with central necrosis (arrow). The mass was exerting pressure on the liver, inferior vena cava, and right renal vein. There was no definite evidence of intraabdominal metastasis.\n\nFig. 1\n\nOn this admission, physical examination revealed BP of 170/100 mmHg, HR 120 beats/min, regular rhythm. She was well looking with mildly pale conjunctiva, without peripheral edema. The point of maximal impulse was at the 5th intercostal space and left midclavicular line. There was no heaving or thrill, S1 and S2 were normal. On bimanual palpation, no abdominal mass was detected. Initial blood laboratory test results indicated mild anemia and hyponatremia (Table 1). The cardiothoracic ratio on the chest radiograph was 0.55 (Fig. 2A). Electrocardiogram (ECG) showed sinus tachycardia, left ventricular hypertrophy, and normal axis.Table 1 Laboratory investigations in this patient.\n\nTable 1\tResult\tNormal value\t\nHematocrit (%)\t29.7\t36–48\t\nSodium (mmol/L)\t134\t135–145\t\nTroponin T (ng/ml)\t0.259\t0–0.1\t\nCreatinine kinase (ng/ml)\t9.49\t0–5\t\nFree plasma metanephrine (nmol/L)\t8.5\t0–0.9\t\nFree plasma normetanephrine (nmol/L)\t46\t0–0.5\t\nUrine metanephrine (μg/day)\t154.87\t52–341\t\nUrine normetanephrine (μg/day)\t548.72\t88–444\t\nUrine vanillylmandelic acid (mg/day)\t77.7\t1.5–10\t\nFig. 2 A chest radiograph 12 hours before (A) hypertensive crisis showed decreased lung volume and fibrosis in the left upper lung field corresponding with a history of pulmonary tuberculosis. And a chest radiograph 6 hours after (B) hypertensive crisis showed a rapid change in bilateral patchy alveolar infiltrates compatible with acute pulmonary edema.\n\nFig. 2\n\nTwelve hours after admission, she complained of palpitations. Her BP and HR were 160/90 mmHg and 120 beats/min, respectively. She was treated with 50 mg of atenolol. Twelve hours after receiving this single dose of atenolol, she presented with sudden dyspnea and agitation. Her BP rose to 220/120 mmHg, HR was 150 beats/min, respiratory rate was 40 breath/min, and oxygen saturation was 85% with ambient air. High jugular venous pressure was observed, and she presented with bilateral lung crepitations. An urgent chest radiograph (Fig. 2B) showed new bilateral patchy infiltrates compatible with acute pulmonary edema. Urgent ECG revealed sinus tachycardia, without definite ST-T changes. Therefore, she was diagnosed with hypertensive crisis and acute pulmonary edema. Intubation and positive pressure ventilation were initiated immediately. Moreover, she received a total dose of nicardipine 30 mg and furosemide 160 mg intravenously.\n\nA transthoracic echocardiography showed global hypokinesia of the left ventricular wall and the overall estimated left ventricular ejection fraction was 36%. There was no significant valvular disease. She had elevated cardiac markers (Table 1). Based on the onset of hypertensive crisis after a single dose of atenolol and the huge right upper quadrant mass, a diagnosis of pheochromocytoma was suspected. Therefore, an alpha adrenergic antagonist (prazosin) was administered and titrated until the BP normalized at approximately 12 hours after the onset of hypertensive crisis. Seventy-two hours later, her clinical status had improved dramatically. She was extubated and able to breathe without support. She received prazosin 6 mg/day and furosemide 40 mg/day, and her BP was 130/80 mmHg. Further, the HR was 86 beats/min. Intravenous nicardipine was tapered and eventually discontinued. A repeated echocardiography 72 hours after hypertensive crisis indicated completed resolution of the affected wall and a normal ejection fraction of 63%.\n\nThe biochemical markers of pheochromocytoma were significantly elevated except urine metanephrine (Table 1). Iodine-131 meta-iodobenzylguanidine (I-131 MIBG) scintigraphy revealed a sizable, intense, heterogeneous uptake in the right upper abdomen. Single-photon emission CT images also showed inhomogeneous tracer uptake in the right retroperitoneal mass. It was suggestive of pheochromocytoma without evidence of distant metastases. We switched from treatment with prazosin to doxazosin for greater pharmacokinetic results.\n\nOne week after doxazosin administration, the BP was well controlled at 120/80 mmHg with doxazosin 8 mg/day. The patient had neither orthostatic hypotension nor paroxysmal symptoms. However, she had sinus tachycardia (100 beats/min). Thus, carvedilol was added to control her HR. We slowly titrated the dose of carvedilol and closely monitored her symptoms in the intensive care unit. Two weeks later, the carvedilol dose reached 25 mg/day, and her HR was 60–70 beats/min. The patient had no signs or symptoms of heart failure and was ready to undergo surgery by an experienced urological surgeon.\n\nDuring open right adrenalectomy, the intraoperative BP varied between 120/80 and 160/90 mmHg controlled with nitroprusside. She had no congestive symptoms or hypoglycemia. The operative findings revealed a large right adrenal mass (Fig. 3). The left adrenal gland appeared normal. No extra-adrenal nodules were seen. The pathological report of the right adrenal gland revealed a mass weighing 819 g. Focal hemorrhage and geographic necrosis were noted without evidence of extra-adrenal extension or positive margins. Furthermore, the mass was positive to chromogranin that was compatible with pheochromocytoma.Fig. 3 Right adrenal mass measuring 13.5 × 13 × 9 cm.\n\nFig. 3\n\nThe immediate postoperative BP was 110/80 mmHg without antihypertensive agents. Seventy-two hours postoperatively, the BP rose to 150/90 mmHg without any symptoms. She received doxazosin 2 mg/day. Subsequently, the urinary vanillylmandelic acid (VMA) level returned to normal within 4 weeks after the tumor resection. Moreover, the follow-up I-131 MIBG scintigraphy revealed no I-131 avid lesions. The genetic testing for pheochromocytoma, including VHL, RET, and SDH genes were negative. She is healthy after surgery. To date, the patient has been treated with doxazosin 1 mg/day, and has not presented with any spells or congestive symptoms. She has been followed up at endocrinology clinic for three years and has normal result of urine metanephrine and normetanephrine.\n\n3 Discussion\nPheochromocytoma is a catecholamine producing tumor the adrenal medulla with an annual incidence of 2–8 per million [4]. Clinical manifestations of pheochromocytoma are highly variable, ranging from asymptomatic forms to life-threatening cardiovascular events. This tumor can mimic other disorders because of its gastrointestinal, neurological, and metabolic manifestations [2,5]. Because pheochromocytoma can lead to hypertensive crisis and is curable by surgical resection, it is important to have clinical suspicion when faced with a potential case, and to confirm the diagnosis and resect the tumor promptly. Catecholamines affect many cardiovascular and metabolic processes by activation of three types of adrenergic (α, β, and dopamine) receptors. The α1-adrenoreceptors mediate vascular and smooth muscle contraction; their activation causes vasoconstriction and increased BP. The vasodilatation in skeletal muscle from stimulation of β2-adrenoreceptors is important because it protects against catecholamine excess. If this protection is blocked, unopposed α1-adrenoreceptors stimulation may lead to a hypertensive crisis [1,6,7]. The present case illustrates the onset of hypertensive crisis and pulmonary edema after the administration of atenolol, a β1-antagonist, during a 12-h period without previous administration of α-adrenergic blocker. Furthermore, left ventricular dysfunction and elevated cardiac markers are consequences of acute catecholamine excess. Several mechanisms of acute myocardial damage associated with catecholamines have been proposed. One mechanism is that catecholamines have a direct toxic effect on the myocardium by enhanced lipid mobility, calcium overload, and free radical production [2]. Another mechanism is catecholamine-induced myocardial stunning [8] and coronary vasoconstriction that lead to focal myocardial necrosis [9]. The left ventricular dysfunction patterns associated with pheochromocytoma have been heterogeneous including reversible or irreversible dilated cardiomyopathy [2], hypertrophic cardiomyopathy, Takotsubo, and atypical (inverted) Takotsubo cardiomyopathies [2,8,10]. Fortunately, most of them are reversible after treatment with alpha adrenergic antagonists or complete excision of the tumor. Reportedly, it may take a few days to several months for complete resolution after treatment [2]. As in this patient, the global left ventricular wall hypokinesia returned to its normal function after a 72-h alpha adrenergic blockade treatment.\n\nThe diagnosis of pheochromocytoma must be confirmed by the presence of high concentrations of fractionated catecholamines (metanephrine, normetanephrine, VMA) in urine or plasma. According to a literature review, there is a positive linear correlation between the level of 24-h urine VMA and the size of tumor mass [11] because the metabolism of catecholamines is primarily intratumoral and VMA is its final metabolite. This patient had high levels of 24-h urine VMA and slightly elevated 24-h urinary normetanephrine excretion corresponding to the remarkable tumor size.\n\nSurgical removal is the gold standard of treatment of pheochromocytoma. There were approximately 140 cases of pheochromocytoma in our hospital during the past ten years. Every case was managed by multidisciplinary team and surgically operated by experienced surgeons. Before the operation, alpha adrenergic blockers should be administered to control BP and restore vascular volume. Beta blockers may be used as an alternative in patients unable to achieve the target BP with at least 3 days of treatment with alpha blockers [1,12]. Reportedly, patients with PC, triggered by the administration of beta blockers alone without alpha blockade use, can be rechallenged with beta blockers after adequate treatment with alpha adrenergic blockade for control of the increased HR. This could be caused by either the high levels of circulating catecholamines or the alpha adrenergic blockade therapy [13,14]. Further, there was no hypertensive crisis during the rechallenging with beta blockers. In general, combined alpha and beta adrenoreceptor antagonists (labetalol and carvedilol) are not recommended for the first choice of preoperative adrenergic blockade because they have a ratio of alpha to beta antagonist activity of approximately 1:5, which may cause hypertensive crisis from the surge of alpha adrenergic activity [1,12]. However, carvedilol has been proven to reduce the risk of death and hospitalization from cardiovascular causes in patients with heart failure [15]. Therefore, we prescribed the non-selective beta and selective alpha-1 blocker (carvedilol) to control HR after hypertensive crisis was controlled with the adequate dose of alpha blocker therapy. There were no complications because α1-adrenoreceptors were blocked completely before starting carvedilol. Postoperative BP is usually reduced to normal limits. However, our patient's BP remained elevated. The probable reasons are coincident essential hypertension, long-standing hypertension with structural changes of blood vessels and resetting of baroreceptors.\n\n4 Conclusion\nBeta-adrenergic blocker should be used cautiously in patients with hypertension and upper quadrant mass. The mass may be pheochromocytoma for which beta-blockers without appropriate alpha-receptor blockade are contraindicated. Preoperative use of carvedilol after sufficient alpha-adrenergic blockade for control of reflex tachycardia in a patient with prior cardiomyopathy associated with PC was safe and effective.\n\nData availability\nThe data that support the findings of this case report are available from the corresponding author on reasonable request.\n\nPatient confidentiality\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nFunding\nThis case report did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nDeclaration of competing interest\nAll authors have no financial or non-financial conflicts of interest related to this report.\n\nThis case report was presented as a poster presentation at International Symposium on pheochromocytoma and paraganglioma 2014 in Japan.\n\nProvenance and peer review\nNot commissioned, externally peer reviewed.\n\nAnnals of medicine and surgery\nThe following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.\n\nPlease state any conflicts of interest\nAll authors have no financial or non-financial conflicts of interest related to this report.\n\nThis case report was presented as a poster presentation at International Symposium on pheochromocytoma and paraganglioma 2014 in Japan.\n\nPlease state any sources of funding for your research\nNo funding.\n\nEthical approval\nThe case report is exempt from ethical approval in our institution.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nA copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nDr. Wannachalee conceptualized, drafted, reviewed and revised the manuscript. Dr. Chunharojrith contributed to the concept of the report, critical manuscript review and approval. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nRegistration of research studies\n1. Name of the registry:\n\n2. Unique Identifying number or registration ID:\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked):\n\n\n\nGuarantor\nPaweena Chunharojrith\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nWe would like to thank all division staff of the Endocrinology and Metabolism Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2020.11.014.\n==== Refs\nReferences\n1 Lenders J.W. Duh Q.Y. Eisenhofer G. Gimenez-Roqueplo A.P. Grebe S.K. Murad M.H. Naruse M. Pacak K. Young W.F. Jr. Endocrine S. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline J. Clin. Endocrinol. Metab. 99 6 2014 1915 1942 24893135 \n2 Prejbisz A. Lenders J.W. Eisenhofer G. Januszewicz A. Cardiovascular manifestations of phaeochromocytoma J. Hypertens. 29 11 2011 2049 2060 21826022 \n3 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. Group S. The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n4 Jafri M. Maher E.R. The genetics of phaeochromocytoma: using clinical features to guide genetic testing Eur. J. Endocrinol. 166 2 2012 151 158 21896620 \n5 Tolis G. Kuchel O. The multiple faces of the pheochromocytoma Can. Med. Assoc. J. 116 4 1977 337 338 844008 \n6 Sheaves R. Chew S.L. Grossman A.B. The dangers of unopposed beta-adrenergic blockade in phaeochromocytoma Postgrad. Med. 71 831 1995 58 59 \n7 Young W.F. Jr. Endocrine Hypertension Melmed Shlomo Auchus Richard J. Goldfine Allison B. Koenig Ronald J. Rosen C.J. Williams Textbook of Endocrinology 2020 Elsevier Philadelphia 542 572 \n8 Kim S. Yu A. Filippone L.A. Kolansky D.M. Raina A. Inverted-Takotsubo pattern cardiomyopathy secondary to pheochromocytoma: a clinical case and literature review Clin. Cardiol. 33 4 2010 200 205 20394039 \n9 Sardesai S.H. Mourant A.J. Sivathandon Y. Farrow R. Gibbons D.O. Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure Br. Heart J. 63 4 1990 234 237 2337495 \n10 Kimura S. Mitsuma W. Ito M. Suzuki H. Hosaka Y. Hirayama S. Hanyu O. Hirono S. Kodama M. Aizawa Y. Inverted Takotsubo contractile pattern caused by pheochromocytoma with tall upright T-waves, but not typical deep T-wave inversion Int. J. Cardiol. 139 2 2010 e15 e17 18722026 \n11 Stenstrom G. Waldenstrom J. Positive correlation between urinary excretion of catecholamine metabolites and tumour mass in pheochromocytoma. Results in patients with sustained and paroxysmal hypertension and multiple endocrine neoplasia Acta Med. Scand. 217 1 1985 73 77 3976435 \n12 Pacak K. Preoperative management of the pheochromocytoma patient J. Clin. Endocrinol. Metab. 92 11 2007 4069 4079 17989126 \n13 Sloand E.M. Thompson B.T. Propranolol-induced pulmonary edema and shock in a patient with pheochromocytoma Arch. Intern. Med. 144 1 1984 173 174 6691755 \n14 Sibal L. Jovanovic A. Agarwal S.C. Peaston R.T. James R.A. Lennard T.W. Bliss R. Batchelor A. Perros P. Phaeochromocytomas presenting as acute crises after beta blockade therapy Clin. Endocrinol. 65 2 2006 186 190 \n15 Packer M. Bristow M.R. Cohn J.N. Colucci W.S. Fowler M.B. Gilbert E.M. Shusterman N.H. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group N. Engl. J. Med. 334 21 1996 1349 1355 8614419\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Annals of medicine and surgery (2012)",
"keywords": "Alpha-adrenergic blockade; BP, blood pressure; Beta-adrenergic blocker; CT, Computed tomography; Cardiomyopathy; Case report; ECG, Electrocardiogram; HR, heart rate; PC, Pheochromocytoma crisis; Pheochromocytoma crisis",
"medline_ta": "Ann Med Surg (Lond)",
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"pages": "360-364",
"pmc": null,
"pmid": "33224491",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
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"title": "Safety of preoperative carvedilol in a patient with recent atenolol-induced pheochromocytoma crisis and cardiomyopathy: A case report.",
"title_normalized": "safety of preoperative carvedilol in a patient with recent atenolol induced pheochromocytoma crisis and cardiomyopathy a case report"
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"abstract": "BACKGROUND\nDrug-induced acute pancreatitis (AP) is rare, but as there are no systematic data on it, the true incidence is not known.\n\n\nMETHODS\nThis case report is a first description of two episodes of AP occurring after administration and subsequent re-administration of mefenamic acid to a young woman without comorbidities. Other common causes of AP could be ruled out. With both episodes, the latency of AP was less than 24 h after drug intake.\n\n\nCONCLUSIONS\nMefenamic acid should be considered as a possible cause of drug-induced AP.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria. Electronic address: walter.spindelboeck@medunigraz.at.",
"authors": "Wurm|S|S|;Schreiber|F|F|;Spindelboeck|W|W|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D008528:Mefenamic Acid",
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"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Acute pancreatitis; Classification of drug-induced AP; Drug-induced acute-pancreatitis; Idiosyncratic drug reaction; Mefenamic acid; NSAIDs",
"medline_ta": "Pancreatology",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D016861:Cyclooxygenase Inhibitors; D005260:Female; D006801:Humans; D008528:Mefenamic Acid; D010195:Pancreatitis",
"nlm_unique_id": "100966936",
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"title": "Mefenamic acid: A possible cause of drug-induced acute pancreatitis.",
"title_normalized": "mefenamic acid a possible cause of drug induced acute pancreatitis"
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"abstract": "Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.",
"affiliations": "Renal Division, Massachusetts General Hospital, Boston, Massachusetts, USA.;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA.;Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Department of Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Advanced Kidney Care of Hudson Valley, Poughkeepsie, New York, USA.;Department of Pathology, Columbia University Medical Center, New York, New York, USA.;Division of Nephrology, Kaiser Permanente, Portland, Oregon, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Divison of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address: DELEAF@partners.org.",
"authors": "Cortazar|Frank B|FB|;Marrone|Kristen A|KA|;Troxell|Megan L|ML|;Ralto|Kenneth M|KM|;Hoenig|Melanie P|MP|;Brahmer|Julie R|JR|;Le|Dung T|DT|;Lipson|Evan J|EJ|;Glezerman|Ilya G|IG|;Wolchok|Jedd|J|;Cornell|Lynn D|LD|;Feldman|Paul|P|;Stokes|Michael B|MB|;Zapata|Sarah A|SA|;Hodi|F Stephen|FS|;Ott|Patrick A|PA|;Yamashita|Michifumi|M|;Leaf|David E|DE|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D007155:Immunologic Factors; D003404:Creatinine",
"country": "United States",
"delete": false,
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"issn_linking": "0085-2538",
"issue": "90(3)",
"journal": "Kidney international",
"keywords": "acute kidney injury; ipilimumab; nivolumab; pembrolizumab",
"medline_ta": "Kidney Int",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001706:Biopsy; D003404:Creatinine; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D007167:Immunotherapy; D007668:Kidney; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009395:Nephritis, Interstitial; D006435:Renal Dialysis; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "638-47",
"pmc": null,
"pmid": "27282937",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24067875;19587352;15752251;26873574;15588223;26282644;25891304;19414839;22547592;24610577;25482239;16943303;26406148;20525992;18185501;7584144;24927897;10485649;26342047;8676074;15340098;26115796;24687600;22010388;26028407;26874776;23060594;23341990;19679669;25605845",
"title": "Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.",
"title_normalized": "clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors"
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"abstract": "The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined.\n\n\n\nWe performed a retrospective analysis of the safety and outcomes of adult patients with newly diagnosed acute myeloid leukemia (AML) treated with GO with intensified versus standard anthracycline doses (daunorubicin dose 90 mg/m2 vs 60 mg/m2) ± FLT3 inhibitors. The χ2 test and Mann-Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan-Meier method and survival comparisons made using log-rank test.\n\n\n\nWe report a 97% overall response rate in 34 patients with newly diagnosed AML with a median age of 54 years (19-75 years) treated with GO and standard induction. The 11 patients (100%) receiving GO plus daunorubicin dose 90 mg/m2 as part of 7 + 3 induction achieved complete response versus 91% (20/22) complete response in the standard daunorubicin dose group (P = NS). No increased toxicity was noted with the higher daunorubicin dose or when GO and 7 + 3 were combined with FLT3 inhibitors in 3 younger patients (<60 years). Two older patients treated with GO+7 + 3 and FLT3i experienced grade 3 or higher cardiotoxicity. We observed a longer estimated event-free survival for patients with newly diagnosed AML in our cohort (median, 24 months; 95% confidence interval, 17.2 to not reached) compared with historical data.\n\n\n\nWe demonstrate that anthracycline dose intensification with GO may offer higher response rates without increased toxicity in younger patients presenting with de novo AML across European Leukemia Net risk categories.",
"affiliations": "Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA). Electronic address: sthota3@uthsc.edu.;Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System, FL, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Pharmacy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).;Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States (USA).;Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System, FL, United States (USA).;Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System, FL, United States (USA).;Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).",
"authors": "Singh|Abhay|A|;Thota|Swapna|S|;Bradley|Terrence|T|;Griffiths|Elizabeth A|EA|;Faber|Mark G|MG|;Sadek|Sarah|S|;Przespolewski|Amanda|A|;Thompson|James E|JE|;Baron|Jeffrey|J|;Cronin|Tara|T|;Attwood|Kristopher|K|;Madarang|Ellen Cvejanovich|EC|;Watts|Justin|J|;Wang|Eunice S|ES|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2021.04.007",
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"issue": "21(9)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": null,
"medline_ta": "Clin Lymphoma Myeloma Leuk",
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"nlm_unique_id": "101525386",
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"pubdate": "2021-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcomes of Adult Acute Myeloid Leukemia Treated With Gemtuzumab-Ozogamicin: Cue To Optimized Chemotherapy Backbone.",
"title_normalized": "outcomes of adult acute myeloid leukemia treated with gemtuzumab ozogamicin cue to optimized chemotherapy backbone"
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"activesubstancename": "GEMTUZUMAB OZOGAMICIN"
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"abstract": "We examined an immediate, but short-lived, response to crizotinib, a drug with a new indication for ROS1 rearranged non-small cell lung cancer (NSCLC) in a middle-aged non-smoker. The patient presented with metastatic NSCLC and extensive disease in multiple organs. He was treated with crizotinib 250 mg twice a day. Within 2-3 days, his condition rapidly improved, which was evident in a CT scan 2 months later. However, after 3 months of treatment, his condition deteriorated dramatically. The patient did not respond to ceritinib, a second-line drug that targets anaplastic lymphoma kinase, and died shortly after. This case demonstrated an impressive but brief response to crizotinib.",
"affiliations": "Quality Medical Oncology, Flushing, New York, USA.;Quality Medical Oncology, Flushing, New York, USA.",
"authors": "Zhong|Eric|E|;Huang|Hua|H|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human",
"country": "England",
"delete": false,
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"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D017809:Fatal Outcome; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27797842",
"pubdate": "2016-10-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24629636;24279718;22989574;27328934;25264305;25667280;25688157;25651787;22919003",
"title": "Crizotinib in ROS1 rearranged non-small cell lung cancer (NSCLC), from response to resistance.",
"title_normalized": "crizotinib in ros1 rearranged non small cell lung cancer nsclc from response to resistance"
} | [
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"druga... |
{
"abstract": "Serotonin syndrome (SS) is an iatrogenic, drug-induced syndrome caused by serotoninergic agent. Various serotonergic drugs are used in different headache disorders. Therefore, a possibility of developing SS exists in patients with headache. Herein, we are reporting two patients with headache disorders who developed SS.Case 1: a 49-year-old man had a 6-year history of episodic cluster headache (CH). However, he had never been diagnosed with CH before reporting to us. He had been receiving amitriptyline, tramadol/acetaminophen combination and flunarizine. Lithium was started for CH. He developed features consistent with SS. The patient responded to cyprohepatdine.Case 2: a 36-year-old chronic migraineur was on amitriptyline. Addition of sodium valproate led to the development of new features that fulfilled the criteria of SS. The patient responded to cyprohepatdine.As SS may be fatal, there is a need to increase awareness about SS in physicians treating patients with headache.",
"affiliations": "Department of Neurology, Smt. B.K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India.;Department of Medicine, Smt. B.K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India.;Department of Neurology, Smt. B.K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India.",
"authors": "Prakash|Sanjay|S|http://orcid.org/0000-0001-7322-904X;Adroja|Banshi|B|;Parekh|Haresh|H|",
"chemical_list": "D000700:Analgesics; D018490:Serotonin Agents; D000639:Amitriptyline; D000082:Acetaminophen; D014147:Tramadol; D014635:Valproic Acid; D008094:Lithium; D005444:Flunarizine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drug interactions; headache (including migraines); neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000639:Amitriptyline; D000700:Analgesics; D003027:Cluster Headache; D004359:Drug Therapy, Combination; D005444:Flunarizine; D006801:Humans; D008094:Lithium; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D018490:Serotonin Agents; D020230:Serotonin Syndrome; D014147:Tramadol; D014635:Valproic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28784913",
"pubdate": "2017-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12925718;1524068;15784664;16389357;16460699;26019424;5570457;7249508;8736630;9031998;9211572;9755356",
"title": "Serotonin syndrome in patients with headache disorders.",
"title_normalized": "serotonin syndrome in patients with headache disorders"
} | [
{
"companynumb": "IN-UNICHEM LABORATORIES LIMITED-UCM201708-000220",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
... |
{
"abstract": "The selective serotonin reuptake inhibitor (SSRI) sertraline is widely used as an antidepressant agent during pregnancy and lactation because of its low placental transfer and low level of excretion into breastmilk. Symptoms such as neonatal abstinence syndrome and serotonergic overstimulation have been reported after in utero exposure to SSRIs. These symptoms are self-limiting and usually peak within the first 48 hours after birth. In our case, a preterm infant was exposed to sertraline and its main metabolite desmethylsertraline in utero and via breastmilk. Beyond the first 48 hours after birth, the infant developed increasing clinical signs of serotonergic overstimulation associated with substance intake via breastmilk, until breastfeeding was discontinued on postnatal Day 9. In spite of a low calculated daily substance intake via breastmilk, the serum substance levels of the preterm infant were within the therapeutic range of adults. The serotonergic overstimulation may be explained by the limited metabolic capacity of the infant and the immaturity of the blood-brain barrier.",
"affiliations": "Department of Paediatric Cardiology and Intensive Care Medicine, Georg-August-University Goettingen , Goettingen, Germany. matthias.mueller@med.uni-goettingen.de",
"authors": "Müller|Matthias J|MJ|;Preuß|Christoph|C|;Paul|Thomas|T|;Streit|Frank|F|;Brandhorst|Gunnar|G|;Seeliger|Stephan|S|",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1089/bfm.2012.0084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-8253",
"issue": "8(3)",
"journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine",
"keywords": null,
"medline_ta": "Breastfeed Med",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D001812:Blood-Brain Barrier; D003866:Depressive Disorder; D005260:Female; D006801:Humans; D041943:Infant Formula; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008895:Milk, Human; D009035:Mothers; D011247:Pregnancy; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D014202:Tremor",
"nlm_unique_id": "101260777",
"other_id": null,
"pages": "327-9",
"pmc": null,
"pmid": "23249132",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonergic overstimulation in a preterm infant after sertraline intake via breastmilk.",
"title_normalized": "serotonergic overstimulation in a preterm infant after sertraline intake via breastmilk"
} | [
{
"companynumb": "DE-CIPLA LTD.-2014DE00069",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).",
"affiliations": "Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.;Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.;Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.;Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.;UJF Grenoble I, University Hospital Albert Michallon, Department of Pharmacy, Grenoble, France.;Institut Daniel Hollard, Department of Medical Oncology, Grenoble, France.;University Hospital Albert Michallon, Medical Intensive Care Unit, UJF Grenoble I, Grenoble, France.;Centre Oscar Lambret, Department of Medical Oncology, Lille, France.;Institut Paoli Calmettes, Department of Medical Oncology, Marseille, France.;EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.;Institut Claudius Regaud, IUCT-O, Laboratory of Oncogenetics, Toulouse, France.;Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.",
"authors": "Thomas|F|F|;Hennebelle|I|I|;Delmas|C|C|;Lochon|I|I|;Dhelens|C|C|;Garnier Tixidre|C|C|;Bonadona|A|A|;Penel|N|N|;Goncalves|A|A|;Delord|J P|JP|;Toulas|C|C|;Chatelut|E|E|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D004247:DNA; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1002/cpt.210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "99(2)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D001711:Biotransformation; D004247:DNA; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP); D005190:Family; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil; D020440:Gene Duplication; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D014498:Uracil",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "235-42",
"pmc": null,
"pmid": "26265035",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio.",
"title_normalized": "genotyping of a family with a novel deleterious dpyd mutation supports the pretherapeutic screening of dpd deficiency with dihydrouracil uracil ratio"
} | [
{
"companynumb": "FR-ACCORD-029963",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Alternate donor HSCT for thalassemia major from a matched unrelated donor or haploidentical family donor is a feasible therapeutic option in children with no matched family donor. Aggressive pretransplant immunosuppression, reduced toxicity conditioning, and PTCY result in excellent thalassemia-free survival. We describe here our experience in this cohort. We performed a retrospective analysis of the data on children who underwent a haploidentical HSCT for thalassemia major with PTCY at our center from August 2017 to August 2019. All children received pretransplant immune suppression for 6 weeks with fludarabine and dexamethasone, hypertransfusion and chelation with intravenous desferrioxamine. Conditioning included thiotepa, fludarabine, rabbit ATG, and cyclophosphamide, and GvHD prophylaxis included PTCY with tacrolimus. Twenty children were included and nineteen children engrafted. Acute hypertension occurred in five children, bacterial infection in eight children and viral respiratory infection in three children. Three children suffered from graft rejection. Reactivation of viruses namely CMV, adenovirus, and BK virus was seen in 60% of children. Grades 1-2 acute GvHD of the skin in four children (20%) and limited chronic GvHD of the skin in four children (20%). Immune cytopenia was documented in three children (15%). Haploidentical HSCT offers a therapeutic option for children with thalassemia major with no suitably matched family or unrelated donors. Our reduced toxicity regimen with PTCY offers a DFS of 75% and OS of 95% with low transplant-related mortality of 5%.",
"affiliations": "Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Biostatistics, Apollo Cancer Institutes, Chennai, India.;Department of Pediatric Intensive Care, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.;Department of Paediatric Hematology, Oncology and Blood and Marrow Transplantation, Apollo Cancer Institutes, Chennai, India.",
"authors": "Vellaichamy Swaminathan|Venkateswaran|V|0000-0001-5965-1930;Ravichandran|Nikila|N|;Ramanan|Kesavan Melarcode|KM|;Meena|Satish Kumar|SK|;Varla|Harika|H|;Ramakrishnan|Balasubramaniam|B|;Jayakumar|Indra|I|;Uppuluri|Ramya|R|0000-0001-5771-8214;Raj|Revathi|R|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13893",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(2)",
"journal": "Pediatric transplantation",
"keywords": "GvHD; PTCY; thalassemia major",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13893",
"pmc": null,
"pmid": "33111490",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Augmented immunosuppression and PTCY-based haploidentical hematopoietic stem cell transplantation for thalassemia major.",
"title_normalized": "augmented immunosuppression and ptcy based haploidentical hematopoietic stem cell transplantation for thalassemia major"
} | [
{
"companynumb": "IN-SA-2020SA320753",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the safety of midazolam and diazepam for adolescents during third molar extraction and whether any differences in perioperative complications exist when using the 2 benzodiazepines alone or in combination.\n\n\nMETHODS\nA prospective study was performed in adolescents (<21 yr old) who underwent at least 1 third molar extraction by an oral and maxillofacial surgeon in the ambulatory setting from January 2001 through December 2010 using the Oral and Maxillofacial Surgery Outcomes System. The primary predictor variable was type of benzodiazepine used, divided into the total number of patients who received diazepam with or without midazolam. The outcome of interest was adverse complications resulting from anesthesia. Multivariable logistic regression was applied to measure the association between benzodiazepine type and adverse complications.\n\n\nRESULTS\nPatients in the diazepam group (n = 4,213) and in the combination group (n = 426) had a complication rate of 1.4%, whereas those in the midazolam group (n = 13,451) had a complication rate of 1.0% (P = .027). Multiple logistic regression analysis showed a 50% increased odds of adverse complications in patients receiving diazepam (adjusted odds ratio = 1.50; 95% confidence interval, 1.05 to 2.16; P = .027).\n\n\nCONCLUSIONS\nAdolescent patients who received intravenous diazepam during third molar procedures had an increased odds of anesthesia-related complications compared with those given midazolam.",
"affiliations": "Postgraduate Year 1 Resident, Department of Oral and Maxillofacial Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA. Electronic address: gino.inverso@uphs.upenn.edu.;Attending Oral and Maxillofacial Surgeon, Department of Plastic and Oral Surgery, Boston Children's Hospital, Boston, MA.;Senior Research Associate, American Association of Oral and Maxillofacial Surgeons, Rosemont, IL.;Associate Professor, Harvard School of Dental Medicine; Director, Center for Applied Clinical Investigation, Massachusetts General Hospital, Boston, MA.",
"authors": "Inverso|Gino|G|;Resnick|Cory M|CM|;Gonzalez|Martin L|ML|;Chuang|Sung-Kiang|SK|",
"chemical_list": "D018686:Anesthetics, Intravenous; D003975:Diazepam; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "74(6)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000293:Adolescent; D000766:Anesthesia, Dental; D018686:Anesthetics, Intravenous; D003975:Diazepam; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam; D008964:Molar, Third; D011446:Prospective Studies; D014081:Tooth Extraction",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "1140-4",
"pmc": null,
"pmid": "26968802",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anesthesia Complications of Diazepam Use for Adolescents Receiving Extraction of Third Molars.",
"title_normalized": "anesthesia complications of diazepam use for adolescents receiving extraction of third molars"
} | [
{
"companynumb": "US-ROCHE-1727244",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NALBUPHINE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "We describe a 65-year-old Caucasian female with well-controlled Hailey-Hailey disease (HHD) who developed acute generalized exanthematous pustulosis (AGEP) with severe systemic symptoms. Despite sparing of the patient's intertriginous skin, histopathologic evidence of HHD was observed in all biopsies, suggestive of a unique koebernization phenomenon of HHD to areas of cutaneous drug eruption. While internal organ involvement is less commonly reported in AGEP, there are an increasing number of patients with signs and symptoms suggestive of an AGEP/drug reaction with eosinophilia and systemic symptoms (DRESS) spectrum of cutaneous drug disorders. Early diagnosis of patients with AGEP and systemic symptoms is critical so that these patients may receive prompt and aggressive systemic therapy to decrease the risk of end organ damage and improve overall morbidity and mortality.",
"affiliations": "Department of Dermatology, Yale School of Medicine, New Haven, CT, 06520-8059, USA. mariam.totonchy@yale.edu.;Department of Dermatology, Yale School of Medicine, New Haven, CT, 06520-8059, USA.;Department of Dermatology, Yale School of Medicine, New Haven, CT, 06520-8059, USA. Christopher.bunick@yale.edu.",
"authors": "Totonchy|Mariam B|MB|;McNiff|Jennifer M|JM|;Bunick|Christopher G|CG|",
"chemical_list": "D014221:Triamcinolone; D008776:Methylprednisolone Hemisuccinate; D014640:Vancomycin; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.12771",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "43(11)",
"journal": "Journal of cutaneous pathology",
"keywords": "Hailey-Hailey disease; acute generalized exanthematous pustulosis; drug hypersensitivity; koebnerization; systemic drug reaction",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D063926:Drug Hypersensitivity Syndrome; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008776:Methylprednisolone Hemisuccinate; D016506:Pemphigus, Benign Familial; D011239:Prednisolone; D016896:Treatment Outcome; D014221:Triamcinolone; D014640:Vancomycin",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "1031-1035",
"pmc": null,
"pmid": "27433827",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Koebnerization of Hailey-Hailey disease into a cutaneous drug eruption of acute generalized exanthematous pustulosis associated with systemic symptoms.",
"title_normalized": "koebnerization of hailey hailey disease into a cutaneous drug eruption of acute generalized exanthematous pustulosis associated with systemic symptoms"
} | [
{
"companynumb": "PHHY2017US122935",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Although current quetiapine labeling recommends that its dosage should be lowered 6-fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions' Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor-quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6-fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors.",
"affiliations": "Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Review, Food and Drug Administration, Silver Spring, MD, USA.;Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Review, Food and Drug Administration, Silver Spring, MD, USA.;Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.;Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Review, Food and Drug Administration, Silver Spring, MD, USA.",
"authors": "Sampson|Mario R|MR|;Cao|Kelly Y|KY|;Gish|Paula L|PL|;Hyon|Kyong|K|;Mishra|Poonam|P|;Tauber|William|W|;Zhao|Ping|P|;Zhou|Esther H|EH|;Younis|Islam R|IR|",
"chemical_list": "D014150:Antipsychotic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D000069348:Quetiapine Fumarate",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1345",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "59(4)",
"journal": "Journal of clinical pharmacology",
"keywords": "HIV protease inhibitors; US Food and Drug Administration; coma; drug interactions; pharmacoepidemiology; quetiapine",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D014150:Antipsychotic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004348:Drug Labeling; D017320:HIV Protease Inhibitors; D006801:Humans; D008954:Models, Biological; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "500-509",
"pmc": null,
"pmid": "30452774",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors.",
"title_normalized": "dosing recommendations for quetiapine when coadministered with hiv protease inhibitors"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-11014",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "OBJECTIVE\nData concerning rates of gastrointestinal (GI) events in non-steroidal anti-inflammatory drug (NSAID) users derive mainly from clinical trials. The EVIDENCE study quantified the incidence of symptomatic uncomplicated and/or complicated GI events in at-risk European patients treated with NSAIDs in real-life practice.\n\n\nMETHODS\nThis non-interventional study assessed 4144 adults with at least one GI risk factor who recently initiated NSAID therapy for osteoarthritis (85%), rheumatoid arthritis (11%), ankylosing spondylitis (3%) or a combination (1%). Patient characteristics and medical history were collected from medical records. GI events (upper and lower) were recorded at in-clinic visits during 6 months' follow-up.\n\n\nRESULTS\nMean time on index NSAID at enrolment was 33 days. The incidence (per 100 person-years) was 18.5 per 100 person-years for uncomplicated GI events and 0.7 per 100 person-years for complicated GI events. Upper GI events were far more common (12%) than lower GI events (1%) during study follow-up (median 182 days (range 61-320)). Other reported rates for cardiovascular, anaemia or non-GI events were much less frequent. A minority (28%) of patients had ongoing proton pump inhibitor use at enrolment, with strong variation by practice and country.\n\n\nCONCLUSIONS\nEVIDENCE is the largest prospective study of the real-life management of European patients treated with NSAIDs for rheumatic diseases and at increased GI risk. It shows that GI events from the upper GI tract are far more common than those from the lower GI tract. It also shows adherence to guidelines for gastroprotection is generally low.\nNCT01176682.",
"affiliations": "Servicio de Aparato Digestivo, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University Clinic Hospital, University of Zaragoza, Zaragoza, Spain.;Departments of Epidemiology and Biostatistics and Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.;Observational Research Centre, Global Medicines Development, AstraZeneca, Madrid, Spain.",
"authors": "Lanas|Angel|A|;Boers|Maarten|M|;Nuevo|Javier|J|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2013-204155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "74(4)",
"journal": "Annals of the rheumatic diseases",
"keywords": "Inflammation; NSAIDs; Treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001172:Arthritis, Rheumatoid; D003967:Diarrhea; D004415:Dyspepsia; D004941:Esophagitis; D005060:Europe; D005260:Female; D005756:Gastritis; D005767:Gastrointestinal Diseases; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis; D010437:Peptic Ulcer; D011446:Prospective Studies; D012307:Risk Factors; D013167:Spondylitis, Ankylosing",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "675-81",
"pmc": null,
"pmid": "24351518",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice.",
"title_normalized": "gastrointestinal events in at risk patients starting non steroidal anti inflammatory drugs nsaids for rheumatic diseases the evidence study of european routine practice"
} | [
{
"companynumb": "ES-ROCHE-1625392",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NAPROXEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "We present the 16th reported case of Acute Lymphoblastic Leukemia (ALL) with involvement in the bladder. Our patient was a 22 year-old man with T-cell ALL with a mediastinal mass. He received hyperfractionated cyclophos-phamide, vincristine, doxorubicin, dexamethasone (HyperCVAD) with mediastinal radiation. Prior to starting maintenance, he relapsed in the bladder and marrow. He received a nelarabine-based induction regimen and achieved remission. This was followed by an unrelated 11/12 HLA-matched myeloablative allogeneic stem cell transplant. He is in complete remission for the past 409 days.",
"affiliations": "Department of Medicine and.",
"authors": "Pham|Alexander|A|;Steinberg|Amir|A|;Kwok|Brian|B|;Lopez|Angela|A|;Lim|Stephen|S|;Lill|Michael|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2011.e18",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2038-8322",
"issue": "3(2)",
"journal": "Hematology reports",
"keywords": "allogeneic stem cell transplantation.; bladder involvement; precursor t-cell acute lymphoblastic leukemia/lymphoma",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "e18",
"pmc": null,
"pmid": "22184539",
"pubdate": "2011-08-31",
"publication_types": "D002363:Case Reports",
"references": "16295033;14335085;20385996;2056971;15908649;12972811;2039854;18605011;15178574;17158775;20814137;17344466;9045306;265682",
"title": "Precursor T-Cell acute lymphoblastic leukemia/lymphoma with rare presentation in the urinary bladder.",
"title_normalized": "precursor t cell acute lymphoblastic leukemia lymphoma with rare presentation in the urinary bladder"
} | [
{
"companynumb": "US-JNJFOC-20150109669",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects.\n\n\n\nTwo open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed.\n\n\n\nEsaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively.\n\n\n\nItraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.",
"affiliations": "Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;SOUSEIKAI Hakata Clinic, 6-18, Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;SOUSEIKAI Hakata Clinic, 6-18, Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan.;SOUSEIKAI Hakata Clinic, 6-18, Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.;Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.",
"authors": "Kirigaya|Yoshiaki|Y|0000-0002-8581-0381;Shiramoto|Masanari|M|;Ishizuka|Tomoko|T|;Uchimaru|Hinako|H|;Irie|Shin|S|;Kato|Manabu|M|;Shimizu|Takako|T|;Nakatsu|Takafumi|T|;Nishikawa|Yasuhiro|Y|;Ishizuka|Hitoshi|H|",
"chemical_list": "D011758:Pyrroles; D018161:Receptors, Mineralocorticoid; D013450:Sulfones; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A; C000607547:esaxerenone; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14302",
"fulltext": "\n==== Front\nBr J Clin Pharmacol\nBr J Clin Pharmacol\n10.1111/(ISSN)1365-2125\nBCP\nBritish Journal of Clinical Pharmacology\n0306-5251 1365-2125 John Wiley and Sons Inc. Hoboken \n\n10.1111/bcp.14302\nBCP14302\nMP-00900-19.R1\nOriginal Article\nOriginal Articles\nEffects of itraconazole and rifampicin on the single‐dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects\nKirigaya et al.Kirigaya Yoshiaki https://orcid.org/0000-0002-8581-0381\n1\nkirigaya.yoshiaki.c8@daiichisankyo.co.jp Shiramoto Masanari \n2\n Ishizuka Tomoko \n1\n Uchimaru Hinako \n2\n Irie Shin \n2\n Kato Manabu \n1\n Shimizu Takako \n1\n Nakatsu Takafumi \n1\n Nishikawa Yasuhiro \n1\n Ishizuka Hitoshi \n1\n \n1 \nDaiichi Sankyo Co., Ltd.\n1‐2‐58 Hiromachi, Shinagawa‐ku\nTokyo\n140‐8710\nJapan\n\n\n2 \nSOUSEIKAI Hakata Clinic\n6‐18, Tenyamachi, Hakata‐ku\nFukuoka\n812‐0025\nJapan\n\n* Correspondence\n\nYoshiaki Kirigaya, Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., 1‐2‐58 Hiromachi, Shinagawa‐ku, Tokyo 140‐8710, Japan.\n\nEmail: kirigaya.yoshiaki.c8@daiichisankyo.co.jp\n\n13 5 2020 \n10 2020 \n13 5 2020 \n86 10 10.1111/bcp.v86.10Themed Section: Medicines in Older People. Guest Editors: Sven Stegemann, Diana van Riet‐Nales and Anthonius de Boer2070 2079\n21 11 2019 10 3 2020 19 3 2020 © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological SocietyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Aims\nTo investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single‐dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects.\n\nMethods\nTwo open‐label, single‐sequence, crossover studies were conducted in healthy Japanese males aged 20–45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9–16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8–16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed.\n\nResults\nEsaxerenone exposure increased when coadministered with itraconazole. Geometric least‐square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax), area under the plasma concentration–time curve (AUC) from zero until the last measurable concentration (AUClast) and AUC from zero until infinity (AUCinf) were 1.13 (1.05, 1.20) ng mL−1, 1.47 (1.40, 1.54) ng h mL−1 and 1.53 (1.45, 1.62) ng h mL−1, respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least‐squares mean ratios (90% confidence interval) of esaxerenone Cmax, AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively.\n\nConclusion\nItraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.\n\nCYP3Adrug–drug interactionsitraconazolepharmacokineticsrifampicinDaiichi Sankyo Co., Ltd. source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:17.09.2020\n\n\nKirigaya \nY \n, \nShiramoto \nM \n, \nIshizuka \nT \n, et al. Effects of itraconazole and rifampicin on the single‐dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects\n. Br J Clin Pharmacol . 2020 ;86 :2070 –2079\n. 10.1111/bcp.14302 \n\n\n\nThe authors confirm that the Principal Investigator for this paper is Masanari Shiramoto and that he had direct clinical responsibility for subjects.\n==== Body\n1 What is already known about this subject\n\nEsaxerenone, a nonsteroidal mineralocorticoid receptor blocker, has demonstrated clinical efficacy and safety in the treatment of hypertension.\n\nEsaxerenone is eliminated via multiple pathways, including oxidation, glucuronidation and hydrolysis.\n\nThe contribution of CYP3A‐mediated oxidation to esaxerenone clearance is approximately 30%, as indicated by the excretion ratio of oxidised metabolites into urine and faeces.\n\n\n\n\nWhat this study adds\n\nItraconazole, a strong CYP3A inhibitor, increased esaxerenone AUCinf by approximately 1.5‐fold, compared with administration of esaxerenone alone, which was caused by inhibition of oxidative metabolism of esaxerenone.\n\nRifampicin, a strong CYP3A inducer, reduced esaxerenone AUCinf by approximately 0.3‐fold, compared with administration of esaxerenone alone, which was caused by induction of oxidative metabolism and glucuronidation of esaxerenone.\n\nThese results suggest that caution is recommended when esaxerenone is coadministered with a strong inhibitor or inducer of CYP3A in patients with hypertension.\n\n\n\n\n1 INTRODUCTION\n\nEsaxerenone (CS‐3150) is a nonsteroidal mineralocorticoid receptor (MR) blocker approved for the treatment of hypertension and in development for the treatment of diabetic nephropathy in Japan. Results from an in vitro study showed that esaxerenone possesses a favourable pharmacological profile relative to other MR blockers such as spironolactone and eplerenone.\n1\n The MR affinity of esaxerenone is 4‐ and 76‐fold greater than that of eplerenone and spironolactone, respectively.\n1\n The half‐maximal inhibitory concentration of esaxerenone for the transcriptional activity of human MR is 3.7 nM, and its potency was superior to that of spironolactone and eplerenone, whose half‐maximal inhibitory concentrations were 66 and 970 nM, respectively.\n1\n The clinical efficacy of esaxerenone for essential hypertension was demonstrated in a recent double‐blind phase 3 study,\n2\n in which esaxerenone 2.5 mg d−1 was shown to be noninferior to eplerenone 50 mg d−1; furthermore, the esaxerenone 5 mg d−1 dosage was superior to the 2.5 mg d−1 dosage.\n2\n Both dosages of esaxerenone demonstrated efficacy in lowering blood pressure (BP) and were well tolerated.\n2\n\n\n\nWe have already characterised the pharmacokinetics (PK) of esaxerenone in several studies.\n3\n, \n4\n Esaxerenone has shown dose‐proportionality after administration of single and multiple doses (5–200 mg in the single‐dose study and 10–100 mg d−1 in the multiple‐dose study) to healthy Japanese adult males with its time to reach maximum plasma concentration and terminal elimination half‐life remaining relatively unchanged across the dose ranges of 2.5 to 3.5 hours and 18.7 to 22.9 hours, respectively.\n3\n Esaxerenone has a high absolute bioavailability of approximately 90%.\n4\n\n\n\nBased on a mass balance study in healthy volunteers, most of the radioactivity of 14C‐labelled esaxerenone was excreted as metabolites in faeces and urine, with proportions of unchanged drug of 18.7 and 1.6%, respectively.\n5\n Thus, the main elimination route of esaxerenone is via metabolism, and it has been suggested that oxidation, glucuronic acid conjugation and hydrolysis are involved.\n5\n Esaxerenone metabolites include oxidised metabolite (M1), O‐glucuronide conjugate (M4) and acyl‐glucuronide (M11), which are formed by cytochrome P450 3A (CYP3A), 5′‐diphospho‐glucuronosyltransferase (UGT) and hydrolysis followed by glucuronidation, respectively.\n\n\nIn vitro metabolism studies using human liver microsomes and a human CYP expression system showed that CYP3A4 and CYP3A5 are involved in the oxidative metabolism of esaxerenone and no metabolites are produced by other major P450 isoforms.\n5\n Based on metabolite profiles in faeces and urine, it was estimated that the overall excretion rate of oxidised metabolites, the production of which is catalysed by CYP3A, was about 30% of the total dose.\n5\n Additionally, esaxerenone is a substrate of P‐glycoprotein (P‐gp) and breast cancer resistance protein in vitro,\n5\n but given an absolute bioavailability of approximately 90%,\n4\n these transporters do not appear to play an important role in esaxerenone absorption. Consequently, the effect of concomitant administration of P‐gp modulators on esaxerenone PK is likely to be limited. However, there is potential for esaxerenone exposure to vary when coadministered with inhibitors/inducers of CYP3A, as about 1/3 of the clearance of esaxerenone appears to be through oxidative metabolism by CYP3A.\n\nThe MR blocker eplerenone is mainly metabolised via the CYP3A4 pathway, and it has been reported that inhibitors of CYP3A4, such as ketoconazole, erythromycin, saquinavir, verapamil and fluconazole, can cause 2‐ to 5‐fold increases in eplerenone drug exposure.\n6\n Concomitant use of eplerenone with strong CYP3A inhibitors, such as itraconazole, is therefore contraindicated, and dose adjustment is necessary when moderate CYP3A inhibitors are coadministered with eplerenone.\n6\n, \n7\n, \n8\n\n\n\nThus, it is important to evaluate the effects of CYP3A inhibitors and inducers on the PK of the novel MR blocker esaxerenone. Itraconazole, a strong inhibitor of CYP3A, and rifampicin, a strong inducer of CYP3A, are agents often used in drug–drug interaction (DDI) studies. Thus, expanding on our previously published PK studies,\n3\n, \n4\n this paper reports the results of 2 esaxerenone DDI studies conducted in healthy Japanese subjects: Study 1 investigated the effect of multiple doses of itraconazole on esaxerenone PK following a single dose; and Study 2 investigated the effect of multiple doses of rifampicin on esaxerenone PK following a single dose. Given that rifampicin has the ability to induce not only CYP3A, but also UGT, the plasma concentrations of esaxerenone metabolites—M1, M4 and M11—were also evaluated in Study 2.\n\n2 METHODS\n2.1 Study design and treatments\nStudies 1 and 2 were both single‐centre, open‐label, single‐sequence, crossover studies. Both studies received institutional review board approval (Hakata Clinic Institutional Review Board: Study 1: 1464P1CP‐2, Study 2: 1464P3CP‐5), and all individuals provided written informed consent to participate. All procedures were carried out in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice.\n\n2.1.1 Study 1\nPeriod 1 (Days 1–7) comprised the esaxerenone alone, single‐dose administration phase of the study. A single esaxerenone 2.5 mg tablet (Daiichi Sankyo Co., Ltd., Tokyo, Japan) was administered orally on Day 1 (start of Period 1), in the fasting state (fasting for ≥10 h before and 4 h after administration; Figure 1), after which subjects rested in a sitting position for 4 hours. The esaxerenone tablet was administered with 200 mL water; no other beverage consumption was permitted for 1 hour before or 2 hours after study drug administration. Caffeinated drinks were prohibited during the hospitalisation period, and the only food permitted was prepared by the study centre and provided at predetermined times.\n\nFIGURE 1 Study designs: a2.5 mg esaxerenone was administered in a fasting state concomitantly with itraconazole; b5 mg esaxerenone was administered in a fasting state 2 hours after rifampicin administration\n\nPeriod 2 (Days 8–17) comprised the coadministration phase of the study, commencing 7 days after the first dose of esaxerenone. On Day 8, 200‐mg oral itraconazole tablets (ITRIZOLE Capsules 50; Janssen Pharmaceutical KK, Tokyo, Japan) were administered twice daily with 200 mL of water: 1 dose 30 minutes after breakfast and another 30 minutes after dinner. Breakfast and dinner consisted of 500–600 kcal of total energy, of which fat accounted for 20–30%, and each meal was consumed within 20 minutes. On Days 9–16, a 200–mg itraconazole tablet was administered once daily 30 minutes after breakfast. On Day 13, a single 2.5‐mg dose of esaxerenone was administered with a 200‐mg itraconazole tablet in the fasting state as previously described (Figure 1). A final follow‐up visit occurred on Days 29–31.\n\n2.1.2 Study 2\nA similar 2‐period study design was implemented for Study 2, with an esaxerenone single dose administered at the beginning of Period 1 (Days 1–7) and esaxerenone plus rifampicin coadministered during Period 2 (Days 8–17). In Period 1, esaxerenone 5 mg was administered orally on Day 1 (Figure 1), following the same food and beverage conditions as described for Study 1. During Period 2 (starting on Day 8), 600 mg rifampicin (RIFADIN Capsules; Daiichi Sankyo Co., Ltd., Tokyo, Japan) was administered orally with 200 mL of water once daily before breakfast for 9 days. On Day 13, a single oral dose of 5 mg esaxerenone was administered in a fasted state 2 hours after administration of 600 mg rifampicin (Figure 1). A final follow‐up visit occurred on Days 29–31.\n\n2.2 Study population\nInclusion criteria for the 2 studies were identical: healthy Japanese males aged 20–45 years; body mass index (BMI) ≥18.5 kg m−2 and <25.0 kg m−2; BP <140/90 mmHg; and heart rate ≤99 beats min−1.\n\nKey exclusion criteria for both studies were: a history of serious conditions, including central nervous system, cardiovascular, respiratory, blood, gastrointestinal, hepatic/renal, thyroid, pituitary gland or adrenal diseases; any drug hypersensitivity; drug or alcohol dependence; and a positive hepatitis B surface antigen, hepatitis C virus antibody, syphilis or HIV antibody test result. Subjects were also excluded if they had undergone whole blood collection of ≥1200 mL within 1 year, ≥400 mL within 84 days or ≥200 mL within 28 days before screening, or plasmapheresis or platelet apheresis within 14 days before screening. Exclusion criteria also comprised any symptom considered clinically significant by the investigator or subinvestigator, or any abnormal electrocardiograph finding at screening, or a deviation in laboratory data from the reference range of the study centre at screening. Drugs, food or supplements containing St John's Wort, concomitant therapies, the consumption of grapefruit (juice or pulp) within 7 days before admission, and any medical treatment from another physician since the screening examination, were prohibited.\n\n2.3 PK assessments\n2.3.1 Blood sampling for PK assays\nIn Study 1, blood samples (3 mL) were collected to measure the plasma concentrations of esaxerenone on Day 1 (Period 1) and Day 13 (Period 2). Samples were collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 60, 72 and 96 hours after esaxerenone administration.\n\nIn Study 2, blood samples (8 mL) were collected to measure plasma concentrations of esaxerenone and its metabolites on Day 1 (Period 1) and Day 13 (Period 2). As in Study 1, samples were collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours after esaxerenone administration.\n\nPlasma for assays of esaxerenone and its metabolites was obtained by centrifugation (1700 g for 10 minutes at 4°C) and was frozen (−20°C or lower) until the assays were performed.\n\n2.3.2 Plasma assay\nPlasma samples were treated by solid phase extraction (Oasis HLB μElution Plate; Waters Corporation, Milford, MA, USA), and drug concentrations were measured by liquid chromatography–tandem mass spectrometry.\n\n2.3.3 Esaxerenone and its oxidised metabolite (M1)\nThe methodology for chromatographic separation and determination for esaxerenone has been reported previously.\n3\n, \n4\n Multiple‐reaction monitoring of the esaxerenone metabolite M1 (m/z 421 to 224) and its internal standard (d3‐M1, m/z 424 to 24) were conducted. For M1 test samples of 0.3, 4.0 and 80.0 ng mL−1, intrastudy assay precisions were 2.2, 3.2 and 2.6%, respectively; the assay accuracy ranged from −2.8 to 6.3% (lower limit of quantification [LLOQ] 0.1 ng mL−1).\n\n2.3.4 Esaxerenone metabolites: M4 and M11\nChromatographic separation was performed using a CAPCELL PAK C18 MGII column (Shiseido Co., Ltd.; Tokyo, Japan) with an internal diameter of 2.0 mm, length of 150 mm and pore size of 3 μm. Detection was performed using an API 5000 tandem mass spectrometer with TurboIonSpray source by electrospray ionisation in the negative ion mode; multiple‐reaction monitoring of M4 (m/z 641 to 447), M11 (m/z 488 to 312) and their internal standard (d7‐esaxerenone, m/z 472 to 370) was conducted. For M4 test samples of 0.1, 0.3, 4.0 and 80.0 ng mL−1, intrastudy assay precisions were 2.9–6.3, 4.8–7.1, 1.0–6.5 and 2.5–6.6%, respectively; the assay accuracy ranged from −3.9 to 8.0% (LLOQ 0.1 ng mL−1). For M11 test samples of 0.1, 0.3, 4.0 and 80.0 ng mL−1, intrastudy assay precisions were 3.8–6.7, 2.4–4.6, 1.6–4.1 and 2.3–7.6%, respectively; the assay accuracy ranged from −13.5 to 5.0% (LLOQ 0.1 ng mL−1).\n\n2.3.5 PK analysis\nPK parameters were calculated using noncompartmental analysis, using Phoenix WinNonlin (version 6.3; Certara, Princeton, NJ, USA). For Studies 1 and 2, the primary endpoints were maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUC) to the last quantifiable time (AUClast) and AUC from time zero to infinity (AUCinf) for esaxerenone. Secondary endpoints in both studies included time to maximum esaxerenone concentration (tmax), esaxerenone half‐life (t1/2) and apparent total body clearance (CL/F). Study 2 also assessed Cmax, AUClast and AUCinf for esaxerenone metabolites, and ratios of plasma metabolites to parent (esaxerenone; M/P) for Cmax, AUClast and AUCinf, which were adjusted to accommodate differences in molecular weight between esaxerenone and its metabolites.\n\n2.4 Safety and tolerability\nSafety was evaluated through the assessment of adverse events (AEs), laboratory tests, vital signs (BP, pulse rate and body temperature) and 12‐lead electrocardiogram. AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA/J versions 19.0 and 19.1) System Organ Class and Preferred Terms.\n\n2.5 Sample size\nThe sample sizes for both studies were calculated assuming within‐subject variations in Cmax and AUC of 20 and 10%, respectively, based on a previous study.\n4\n\n\n\nFor Study 1, assuming that geometric least‐squares mean (GLSM) ratios of Cmax and AUC were ≤1.05, when ratios were estimated after a single oral dose of esaxerenone and concomitant itraconazole administration, a sample size of 18 subjects would provide ≥80% statistical power with 2‐sided 90% confidence intervals (CIs) for GLSM ratios of Cmax and AUC to detect the CIs within 0.80–1.25. To allow for unexpected circumstances, such as subject withdrawals, the number of subjects was specified as 20.\n\nFor Study 2, it was estimated that 12 subjects would be required. Two‐sided 90% CIs of GLSM ratios of Cmax and AUC, when ratios were estimated after a single oral dose of esaxerenone and concomitant rifampicin administration, were assumed to be 0.2–1.0 based on a case series of 12 subjects (unpublished data on file, Daiichi Sankyo Co., Ltd.). The estimation accuracy for GLSM ratios was within about 10% in all cases, indicating sufficient accuracy for assessing DDIs.\n\n2.6 Statistical analyses\nIn all studies, the PK analysis sets included subjects who received esaxerenone, and for whom data were available for at least 1 primary endpoint in Periods 1 and 2. The safety analysis sets included all subjects who agreed to participate in the study and who received at least 1 dose of esaxerenone, itraconazole or rifampicin. Differences between the results when esaxerenone was administered alone or with itraconazole or rifampicin, were calculated using GLSM ratios and their 90% CIs. If the GLSM ratio was contained within the bounds (0.80–1.25) of the 90% CIs, it was inferred that there was no DDI. For all statistical analyses, SAS software (version 9.2; SAS Institute, Cary, NC, USA) was used.\n\n2.7 Nomenclature of targets and ligands\nKey protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY.\n\n3 RESULTS\n3.1 Baseline characteristics\nA total of 20 subjects were enrolled in, and completed, Study 1. The mean (standard deviation [SD]) age was 29.9 (6.91) years, height was 172 (5.99) cm and BMI was 21.4 (1.69) kg m−2 (Table 1).\n\nTABLE 1 Demographic characteristics of subjects at baseline (pharmacokinetic analysis set)\n\nCharacteristics\tStudy 1 (n = 20)\tStudy 2 (n = 11\na\n)\t\nAge, y\t29.9 (6.91)\t31.9 (8.12)\t\nHeight, cm\t172 (5.99)\t169 (6.48)\t\nWeight, kg\t63.0 (5.88)\t64.1 (6.87)\t\nBody mass index, kg m−2\n\t21.4 (1.69)\t22.3 (1.31)\t\nValues are mean (standard deviation).\n\na One subject was withdrawn due to an adverse event and not included in this analysis.\n\nA total of 12 subjects were enrolled in Study 2; 1 subject was withdrawn because of an AE (rash) and was not included in the analysis. The mean (SD) age was 31.9 (8.12) years, height was 169 (6.48) cm and BMI was 22.3 (1.31) kg m−2 (Table 1).\n\n3.2 Effects of itraconazole on esaxerenone PK (Study 1)\nThe plasma concentration–time profile for esaxerenone is shown in Figure 2a. A slight increase in Cmax was observed when esaxerenone was coadministered with itraconazole (mean [SD], 41.7 [8.46] ng mL−1) compared with esaxerenone alone (36.7 [5.36] ng mL−1). However, mean values for AUClast and AUCinf were approximately 50% greater with coadministration vs esaxerenone alone (AUClast 920 [186] vs 625 [113] ng h mL−1; AUCinf 996 [219] vs 648 [121] ng h mL−1). The median (range) tmax of esaxerenone when coadministered with itraconazole and when administered alone were 2.00 (1.00–4.00) hours and 2.25 (1.50–4.00) hours, respectively. The mean t1/2 for esaxerenone was slightly prolonged after coadministration with itraconazole (25.9 [4.21] h) compared with esaxerenone alone (20.7 [3.96] h; Table 2).\n\nFIGURE 2 Plasma concentration–time profiles for esaxerenone, administered alone and in combination with (A) itraconazole or (B) rifampicin (semi‐log plots; insets show linear plots). LLOQ, lower limit of quantification; SD, standard deviation\n\nTABLE 2 Pharmacokinetic parameters for esaxerenone alone and in combination with itraconazole\n\n\tEsaxerenone 2.5 mg\tRatio\na\n (90% CI)\t\nAlone (n = 20)\t+ Itraconazole (n = 20)\t\t\n\nArithmetic mean values\n\nb\n\n\t\nCmax, ng mL−1\n\t36.7 (5.36)\t41.7 (8.46)\t–\t\nAUClast, ng h mL−1\n\t625 (113)\t920 (186)\t–\t\nAUCinf, ng h mL−1\n\t648 (121)\t996 (219)\t–\t\ntmax, h\t2.25 (1.50–4.00)\t2.00 (1.00–4.00)\t–\t\nt1/2, h\t20.7 (3.96)\t25.9 (4.21)\t–\t\nCL/F, L h−1\n\t3.98 (0.696)\t2.61 (0.477)\t–\t\n\nGLSM values\n\t\nCmax, ng mL−1\n\t36.4\t41.0\t1.13 (1.05, 1.20)\t\nAUClast, ng h mL−1\n\t616\t904\t1.47 (1.40, 1.54)\t\nAUCinf, ng h mL−1\n\t637\t976\t1.53 (1.45, 1.62)\t\na (Esaxerenone + itraconazole)/(esaxerenone alone).\n\nb Values are mean (standard deviation) or median (range) for tmax.\n\nAUCinf, area under the plasma concentration–time curve up to infinity; AUClast, area under the concentration–time curve up to the last quantifiable time; CI, confidence interval; CL/F, apparent total body clearance; Cmax, maximum plasma concentration; GLSM, geometric least‐squares mean; t1/2, terminal elimination half‐life; tmax, time to reach Cmax.\n\nThe GLSM ratio (90% CI) of the Cmax with and without coadministration of itraconazole was 1.13 (1.05, 1.20), which was within the no‐DDI range of 0.80 to 1.25. However, GLSM ratios (90% CI) of AUClast and AUCinf were 1.47 (1.40–1.54) and 1.53 (1.45–1.62), respectively, and were, therefore, above the no‐DDI range (Table 2).\n\n3.3 Effects of rifampicin on esaxerenone PK (Study 2)\nExposure to esaxerenone decreased in the presence of rifampicin (Figure 2b; Table 3). The mean Cmax decreased by 34.1% when esaxerenone was coadministered with rifampicin (47.6 [6.22] ng mL−1) rather than administered alone (72.4 [10.1] ng mL−1), and the AUClast and AUCinf were approximately 70% lower with coadministration vs esaxerenone alone (AUClast 347 [24.5] vs 1110 [149] ng h mL−1; AUCinf 351 [24.8] vs 1130 [150] ng h mL−1). The median (range) tmax of esaxerenone when coadministered with rifampicin or administered alone were 2.50 (1.00–4.00) hours and 2.50 (1.50–3.50) hours, respectively. The mean t1/2 for esaxerenone was markedly shortened after coadministration with rifampicin (8.63 [1.67] h) compared with esaxerenone alone (16.6 [2.38] h; Table 3).\n\nTABLE 3 Pharmacokinetic parameters for esaxerenone alone and in combination with rifampicin\n\n\tEsaxerenone 5 mg\tRatio\na\n (90% CI)\t\nAlone (n = 11)\t+ rifampicin (n = 11)\t\n\nArithmetic mean values\n\nb\n\n\t\nCmax, ng mL−1\n\t72.4 (10.1)\t47.6 (6.22)\t–\t\nAUClast, ng h mL−1\n\t1110 (149)\t347 (24.5)\t–\t\nAUCinf, ng h mL−1\n\t1130 (150)\t351 (24.8)\t–\t\ntmax, h\t2.50 (1.50–3.50)\t2.50 (1.00–4.00)\t–\t\nt1/2, h\t16.6 (2.38)\t8.63 (1.67)\t–\t\nCL/F, L h−1\n\t4.50 (0.634)\t14.3 (1.01)\t–\t\n\nGLSM values\n\t\nCmax, ng mL−1\n\t71.7\t47.2\t0.659 (0.599, 0.724)\t\nAUClast, ng h mL−1\n\t1098\t346\t0.315 (0.300, 0.332)\t\nAUCinf, ng h mL−1\n\t1121\t350\t0.312 (0.297, 0.328)\t\na (Esaxerenone + rifampicin)/(esaxerenone alone).\n\nb Values are mean (standard deviation) or median (range) for tmax.\n\nAUCinf, area under the plasma concentration–time curve up to infinity; AUClast, area under the concentration–time curve up to the last quantifiable time; CI, confidence interval; CL/F, apparent total body clearance; Cmax, maximum plasma concentration; GLSM, geometric least‐squares mean; t1/2, terminal elimination half‐life; tmax, time to reach Cmax.\n\nEsaxerenone Cmax, AUClast and AUCinf GLSM ratios (90% CI) when coadministered with rifampicin, compared with esaxerenone alone, were 0.659 (0.599–0.724), 0.315 (0.300–0.332) and 0.312 (0.297–0.328), respectively, and were below the no‐DDI range of 0.80–1.25 (Table 3).\n\n3.4 Effects of rifampicin on esaxerenone metabolites (Study 2)\nExposure to esaxerenone metabolites in the presence of rifampicin is shown in Figures 3a–c, and the PK parameters are listed in Table 4. For M1, Cmax and AUClast were increased (more than doubled) by coadministration of rifampicin (Table 4). The M/P ratios for Cmax and AUClast for M1 were increased after coadministration of esaxerenone and rifampicin compared with esaxerenone alone (Table 4). The t1/2 and AUCinf of M1 could not be estimated because of the lack of an apparent terminal phase owing to a long t1/2 for M1.\n\nFIGURE 3 Plasma concentration–time profiles for: (A) M1, esaxerenone oxidised metabolite (semi‐log plot; inset shows linear plot); (B) M4, O‐glucuronide (semi‐log plot; inset shows linear plot); and (C) M11, acyl‐glucuronide of amide‐bond hydrolysate (semi‐log plot; inset shows linear plot), when esaxerenone was administered alone or in combination with rifampicin. LLOQ, lower limit of quantification; SD, standard deviation\n\nTABLE 4 Pharmacokinetic parameters for esaxerenone metabolites following administration of a single dose of esaxerenone and in combination with rifampicin\n\nParameter\na\n\n\tEsaxerenone 5 mg\tMetabolite/parent ratio\t\nAlone (n = 11)\t+ rifampicin (n = 11)\tAlone (n = 11)\t+ rifampicin (n = 11)\t\n\nM1 (oxidised metabolite)\n\t\nCmax, ng mL−1\n\t0.281 (0.065)\t0.652 (0.123)\t0.004 (0.001)\t0.015 (0.003)\t\nAUClast, ng h mL−1\n\t21.5 (5.24)\t51.4 (8.05)\t0.021 (0.003)\t0.163 (0.021)\t\nAUCinf, ng h mL−1\n\tNA\tNA\tNA\tNA\t\ntmax, h\t48.0 (48.0–72.0)\t23.9 (3.50–47.8)\t–\t–\t\nt1/2, h\tNA\tNA\t–\t–\t\n\nM4 (O‐glucuronide)\n\t\nCmax, ng mL−1\n\t50.7 (12.5)\t49.4 (8.54)\t0.510 (0.101)\t0.760 (0.131)\t\nAUClast, ng h mL−1\n\t1080 (326)\t453 (94.5)\t0.710 (0.199)\t0.947 (0.185)\t\nAUCinf, ng h mL−1\n\t1100 (332)\t455 (94.8)\t0.713 (0.200)\t0.943 (0.183)\t\ntmax, h\t4.00 (3.00–4.00)\t4.00 (2.50–4.00)\t–\t–\t\nt1/2, h\t17.3 (2.34)\t7.72 (3.12)\t–\t–\t\n\nM11 (acyl‐glucuronide of amide‐bond hydrolysate)\n\t\nCmax, ng mL−1\n\t10.7 (1.95)\t5.25 (0.802)\t0.141 (0.013)\t0.106 (0.016)\t\nAUClast, ng h mL−1\n\t278 (49.3)\t63.5 (11.8)\t0.241 (0.038)\t0.174 (0.029)\t\nAUCinf, ng h mL−1\n\t286 (50.9)\t66.3 (11.9)\t0.242 (0.038)\t0.180 (0.028)\t\ntmax, h\t4.00 (3.00–6.00)\t3.50 (3.00–4.00)\t–\t–\t\nt1/2, h\t17.4 (2.53)\t7.14 (0.783)\t–\t–\t\na Values are arithmetic mean (standard deviation) or median (range) for tmax.\n\nAUCinf, area under the plasma concentration–time curve up to infinity; AUClast, area under the concentration–time curve up to the last quantifiable time; CL/F, apparent total body clearance; Cmax, maximum plasma concentration; NA, not assessable because the elimination rate constant (Kel) is not appropriately estimated; t1/2, terminal elimination half‐life; tmax, time to reach Cmax.\n\nThe Cmax for M4 did not differ markedly after administration of esaxerenone plus rifampicin, compared with esaxerenone alone, whereas AUClast and AUCinf decreased by approximately 40% when esaxerenone was coadministered with rifampicin. The t1/2 for M4 decreased from 17.3 (2.34) to 7.72 (3.12) hours in the presence of rifampicin. M/P ratios for Cmax, AUClast and AUCinf for M4 were increased by coadministration of rifampicin compared with esaxerenone alone (Table 4).\n\nThe Cmax of M11 decreased by approximately 50%, and AUClast and AUCinf were reduced by approximately 20% when esaxerenone was coadministered with rifampicin; t1/2 decreased from 17.4 (2.53) to 7.14 (0.783) hours. M/P ratios for Cmax, AUClast and AUCinf for M11 were decreased for esaxerenone coadministered with rifampicin vs esaxerenone alone (Table 4).\n\n3.5 Safety\nNo serious AEs occurred in either study. Treatment‐emergent AEs (TEAEs) were reported by 1 subject in Study 1 and 2 subjects in Study 2 (Table 5). In Study 1, the only TEAE was increased blood creatine phosphokinase level, which occurred after the first dose of esaxerenone (mild severity; resolved without treatment) and was not considered by the investigator to be causally related to treatment. In Study 2, TEAEs considered by the investigator to be related to treatment were rash with esaxerenone alone (moderate severity; resolved with treatment) and increased eosinophil level (mild severity; resolved without treatment). Early withdrawal due to a TEAE occurred in 1 subject who experienced rash in Study 2. No clinically meaningful abnormalities in vital signs, electrocardiogram parameters or other laboratory values were observed in either study.\n\nTABLE 5 Treatment‐emergent adverse events (safety analysis set)\n\nAdverse events\tStudy 1\tStudy 2\t\nEsaxerenone 2.5 mg\tEsaxerenone 5 mg\t\n\tAlone (n = 20)\t+ Itraconazole (n = 20)\tAlone (n = 12)\t+ Rifampicin (n = 11\na\n)\t\nRash\t0\t0\t1 (8.3)\t0\t\nEosinophil count increased\t0\t0\t0\t1 (9.1)\t\nBlood creatine phosphokinase increased\t1 (5.0)\t0\t0\t0\t\nValue is the number of subjects, and percentages were calculated using the number of subjects in the column heading as the denominator.\n\na One subject was withdrawn due to an adverse event and not included in this analysis.\n\n4 DISCUSSION\nThese 2 studies clinically evaluated the effects of a strong CYP3A inhibitor, itraconazole, and a strong CYP3A inducer, rifampicin, on esaxerenone PK.\n\nIn Study 1, coadministration of itraconazole increased mean esaxerenone Cmax, AUClast and AUCinf by 12.6, 46.8 and 53.1%, respectively, and slightly prolonged the mean t1/2 for esaxerenone. The slight increase in esaxerenone Cmax observed after coadministration with itraconazole is likely due to increased esaxerenone bioavailability, which, in turn, may be secondary to increased absorption of esaxerenone caused by the inhibition of intestinal P‐gp and inhibition of the CYP3A involved in first‐pass metabolism in the small intestine and liver. The contribution of CYP3A to esaxerenone clearance was considered to be about 1/3 in the previously published mass‐balance study,\n5\n and there was sufficient plasma exposure of itraconazole to esaxerenone during the esaxerenone PK assessment period in the current study. Hence, our observed 1.5‐fold increase in esaxerenone AUCs during coadministration with itraconazole was considered a reasonable change, given that the 1/3 of esaxerenone clearance due to CYP3A was almost completely inhibited by itraconazole, reducing overall esaxerenone clearance to the remaining 2/3. Thus, the increase in esaxerenone exposure with itraconazole coadministration in the current study appears to be because of reduced esaxerenone clearance. However, the slightly increased esaxerenone AUC we observed was less pronounced than a corresponding 5‐fold increase in eplerenone exposure in the presence of ketoconazole.\n6\n Although the 1.5‐fold increase in esaxerenone AUC caused by itraconazole is unlikely to be of major clinical significance, this clinical interaction should not be overlooked in future therapeutic settings. Because it is generally known that serum K+ elevation is a side effect of MR antagonists, clinicians should exercise caution when treating patients with concurrent strong CYP3A inhibitors and esaxerenone.\n\nIn Study 2, exposure to esaxerenone decreased in the presence of rifampicin. That is, coadministration with rifampicin decreased mean esaxerenone Cmax, AUClast and AUCinf by 34.1, 68.5 and 68.8%, respectively, compared with administration of esaxerenone alone. Esaxerenone CL/F increased and its t1/2 was shortened when coadministered with rifampicin. Regarding the CYP3A induction effect of rifampicin, the dosing regimen of rifampicin in this study (600 mg once daily) was specifically selected to achieve a maximum induction effect of CYP3A, as previously described.\n9\n\n\n\nIt has been suggested that esaxerenone has multiple metabolic pathways: oxidation, glucuronidation and hydrolysis.\n5\n Therefore, we evaluated the effects of rifampicin coadministration on the disposition of esaxerenone metabolites M1, M4 and M11, which were formed by CYP3A, UGT or hydrolysis followed by glucuronidation, respectively. Because of the long t1/2 for M1, we cannot rule out the possibility that there may have been some carry‐over effect from Period 1 on the plasma concentration of M1 in Period 2. However, the data suggest that the increased plasma concentration of M1 in Period 2 was probably caused by CYP3A induction by rifampicin (Figure 3A).\n\nM4 is formed by several UGT isoforms (1A1, 1A3, 1A9, 2B7 and 2B15),\n5\n and the M/P ratio for M4 based on Cmax, AUClast and AUCinf was increased when esaxerenone was coadministered with rifampicin, suggesting increased clearance of esaxerenone derived from induction of UGTs by rifampicin.\n\nThe M/P ratio for M11, based on Cmax, AUClast and AUCinf, was reduced when esaxerenone was coadministered with rifampicin. Induction of both CYP3A and UGTs by rifampicin may have reduced the contribution of hydrolysis to total metabolism, resulting in an M/P ratio decrease for M11.\n\nOverall, the observed changes in exposure of esaxerenone and its metabolites in the presence of rifampicin suggest that rifampicin induction of both CYP3A and UGTs explains the overall decrease in exposure to unchanged esaxerenone. The decreased esaxerenone Cmax was probably because of decreased bioavailability resulting from increased intestinal and hepatic first‐pass metabolism, secondary to induction of CYP3A and UGTs by rifampicin. Additionally, reduced esaxerenone bioavailability may also be attributed to the induction of intestinal P‐gp by rifampicin, leading to reduced esaxerenone absorption. Therefore, esaxerenone efficacy may be reduced when the drug is administered concomitantly with rifampicin.\n\nIn both studies, esaxerenone was safe and well tolerated when administered concomitantly with either itraconazole or rifampicin. However, as previously noted, it may be clinically prudent to monitor serum K+ levels when esaxerenone is coadministered with strong CYP3A inhibitors.\n\nEthnic differences in the frequency of polymorphisms of CYP3A have been reported; however, they have rarely been linked to differences in PK between ethnic groups.\n10\n In a study assessing PK differences of esaxerenone in Japanese and Caucasian subjects, mean esaxerenone plasma concentrations after the administration of esaxerenone 20 mg were similar for both ethnicities (unpublished data on file, Daiichi Sankyo Co., Ltd.). Based on these results, it is unlikely that differences in CYP3A expression between Japanese and Caucasian populations influence esaxerenone metabolism.\n\nLimitations of our study included intersubject heterogeneity in CYP3A activity and the potential for CYP3A modulation by concomitant medications. In addition, the long elimination half‐life of M1 may have confounded the interpretation of the M/P results. In patients in a relevant clinical setting, the wider context of overall efficacy and safety should be considered when determining the clinical relevance of the observed DDIs. In particular, the influence of strong CYP3A inhibitor‐induced changes in esaxerenone exposure on overall esaxerenone safety warrant further evaluation.\n\nIn conclusion, itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. Therefore, caution is advised when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.\n\nCLINICAL TRIAL REGISTRATION\nStudy 1 with itraconazole: JapicCTI‐163286; Study 2 with rifampicin: JapicCTI‐163443.\n\nCOMPETING INTERESTS\nY.K., T.I., M.K., T.S., T.N., Y.N. and H.I. are employees of Daiichi Sankyo Co., Ltd. M.S., H.U. and S.I. have no potential conflicts of interest to disclose.\n\nCONTRIBUTORS\nT.N. and T.I. performed all statistical analyses and Y.K. drafted the manuscript. M.S., H.U. and S.I. conducted the study and collected the data. All authors contributed to the design and implementation of the research and provided critical feedback on the manuscript. All authors approved the final manuscript before submission.\n\nACKNOWLEDGEMENTS\nThis study was funded by Daiichi Sankyo Co., Ltd.\n\nThe authors would like to thank Nicola Ryan and David Murdoch of Edanz Medical Writing for providing medical writing services, which were funded by Daiichi Sankyo Co., Ltd.\n\nDATA AVAILABILITY STATEMENT\nAll de‐identified patient data relevant to this study are included in this article. Additional data and supporting documents pertaining to this study, such as the study protocol and statistical analysis plan, are provided upon reasonable request made via this web address (https://vivli.org/ourmember/daiichi-sankyo/) in accordance with the data sharing policy of Daiichi Sankyo Co., Ltd.\n==== Refs\nREFERENCES\n1 \n\nArai \nK \n, \nHomma \nT \n, \nMorikawa \nY \n, et al. Pharmacological profile of CS‐3150, a novel, highly potent and selective non‐steroidal mineralocorticoid receptor antagonist\n. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0306-5251",
"issue": "86(10)",
"journal": "British journal of clinical pharmacology",
"keywords": "CYP3A; drug-drug interactions; itraconazole; pharmacokinetics; rifampicin",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D017964:Itraconazole; D007564:Japan; D008297:Male; D011758:Pyrroles; D018161:Receptors, Mineralocorticoid; D012293:Rifampin; D013450:Sulfones",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2070-2079",
"pmc": null,
"pmid": "32250463",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26073023;24530864;21950349;29688582;15204695;16200104;30541878;31786983;31119692;32250463",
"title": "Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects.",
"title_normalized": "effects of itraconazole and rifampicin on the single dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy japanese subjects"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-01490",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"dru... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) are teratogenic. Chronic myeloid leukemia (CML) is increasingly identified in younger patients who wish to conceive, the management of CML during pregnancy is challenging. We reviewed 51 pregnancies involving 37 patients (30 women, 10 with >1 pregnancy and 7 men) who were either diagnosed with CML during pregnancy or receiving TKI at the time of conception. Ten women were involved in >1 pregnancies. Fifteen women were diagnosed with CML during pregnancy: 10 were treated with hydroxyurea (n = 5), interferon-alfa (n = 3), leukapheresis (n = 1), or nilotinib (n = 1). There were 14 (82%) healthy babies born on term including 2 sets of twins, 2 spontaneous miscarriages (12%), and 1 elective abortion (6%). Within 1 month of delivery or abortion, all women started TKI and achieved MR4.5 (n = 6) and MMR (n = 8) within 3-48 months. One patient, treated with interferon during pregnancy, died of blast phase within 2 months. Four of the 14 remaining women later conceived 5 other pregnancies while on TKI (3 unplanned, 2 planned). Twenty-six patients (7 men; 19 women) conceived while on TKI, with a total of 36 pregnancies. Fifteen women had 20 unplanned pregnancies while receiving TKI and discontinued immediately upon recognition of pregnancy. The median time of TKI exposure was 3 weeks (range, 2-11). Five pregnancies ended in miscarriages and 3 in elective abortion. All 7 men fathered 7 full-term healthy babies. Of 20 babies born to men and women (including one set of twins), 1 had minor abnormality. Seven women lost their responses during pregnancy but at the end of pregnancy all but 2 resumed TKI and regained responses. Seven women involved in 9 planned pregnancies discontinued TKI prior to conception for a median of 4 months (range, 1-20); 3 lost responses during pregnancy. Only 5 patients resumed therapy after delivery. Outcomes were 6 full-term healthy babies, one premature, and two miscarriages. Conception among CML patients while on TKI could be uncomplicated. While patients may lose response following treatment interruption, nearly all regain response upon resuming therapy. Therapy during pregnancy is rarely needed.",
"affiliations": "Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.;Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.",
"authors": "Assi|Rita|R|;Kantarjian|Hagop|H|;Keating|Michael|M|;Pemmaraju|Naveen|N|;Verstovsek|Srdan|S|0000-0002-6912-8569;Garcia-Manero|Guillermo|G|;Ravandi|Farhad|F|;Borthakur|Gautam|G|0000-0001-7679-6453;Dahl|Jenny|J|;Jabbour|Elias|E|;Cortes|Jorge E|JE|0000-0002-8636-1071",
"chemical_list": "D047428:Protein Kinase Inhibitors; D006918:Hydroxyurea",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1849672",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(4)",
"journal": "Leukemia & lymphoma",
"keywords": "CML; TKI; malformation; pregnancy; spontaneous abortion",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D001752:Blast Crisis; D005260:Female; D006801:Humans; D006918:Hydroxyurea; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D011247:Pregnancy; D011256:Pregnancy Outcome; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "909-917",
"pmc": null,
"pmid": "33283580",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Management of chronic myeloid leukemia during pregnancy among patients treated with a tyrosine kinase inhibitor: a single-Center experience.",
"title_normalized": "management of chronic myeloid leukemia during pregnancy among patients treated with a tyrosine kinase inhibitor a single center experience"
} | [
{
"companynumb": "US-TEVA-2021-US-1917573",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHyper-responsiveness to clopidogrel abnormally inhibits platelet aggregation and increases hemorrhagic complications. The present study investigated clinical factors related to clopidogrel hyper-responsiveness in neuro-interventional procedures.\n\n\nMETHODS\nTwo hundred twenty-four patients receiving clopidogrel for coil embolization to treat unruptured cerebral aneurysm or carotid artery stenting to treat carotid artery stenosis at the internal carotid artery origin were retrospectively reviewed for their P2Y12 reactivity unit (PRU) values and clinical characteristics. Hyper-responsiveness to clopidogrel was defined as a PRU of <95.\n\n\nRESULTS\nThe mean PRU was 218.2 ± 77.8. Hyper-responsiveness to clopidogrel was observed in 12 patients (5.4%). Hyper-responsiveness was observed in younger patients, patients with a lower concentration of hemoglobin A1c, and patients with a higher low-density lipoprotein cholesterol (LDL-C) concentration compared with non-hyper-responsive patients (P = 0.01, P < 0.01, P < 0.01, respectively). On analysis of concomitant drugs, the patients in the hyper-responsive group were less frequently administered calcium channel blockers (CCBs) compared with the non-hyper-responsive group (P = 0.01). No significant differences in the usage of proton pump inhibitors or statins were observed. A LDL-C concentration of >120 mg/dL and no usage of CCBs were significant independent predictors of hyper-responsiveness to clopidogrel with a multivariate analysis (OR; 6.16, 95% CI, 1.57-26.64, P = 0.01, OR; 0.09, 95% CI, 0.01-0.82, P = 0.03, respectively).\n\n\nCONCLUSIONS\nThe present study shows that a higher LDL-C concentration and no usage of CCBs are independent predictors of clopidogrel hyper-responsiveness. These results are useful to predict perioperative hemorrhagic complications. Considering dose reduction of clopidogrel or alternative drugs in high risk cases is necessary to prevent perioperative hemorrhagic complications.",
"affiliations": "Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya City, Saitama 343-8555, Japan. Electronic address: ryo096943@gmail.com.;Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan.;Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan.;Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan. Electronic address: takigawa@dokkyomed.ac.jp.;Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan. Electronic address: hyodo@dokkyomed.ac.jp.;Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Japan. Electronic address: kensukes@dokkyomed.ac.jp.",
"authors": "Suzuki|Ryotaro|R|;Nagaishi|Masaya|M|;Takano|Issei|I|;Takigawa|Tomoji|T|;Hyodo|Akio|A|;Suzuki|Kensuke|K|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2020.105420",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "30(1)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Antiplatelet therapy; Calcium channel blockers; Clopidogrel hyper-responsiveness; Low-density lipoprotein cholesterol; Neuro-interventional procedure",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D016893:Carotid Stenosis; D000077144:Clopidogrel; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006470:Hemorrhage; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "105420",
"pmc": null,
"pmid": "33161351",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predictors of Clopidogrel Hyper-Responsiveness in Neuro-Interventional Procedures.",
"title_normalized": "predictors of clopidogrel hyper responsiveness in neuro interventional procedures"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1885441",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3"... |
{
"abstract": "Hydrophilic polymer coatings are now widely applied to catheters and other intravascular devices used in neurovascular, cardiovascular, and peripheral vascular procedures. Emboli consisting of these materials have been previously identified in biopsies and autopsies following pulmonary infarction, stroke, gangrene, or death. We report a case involving a nonhealing foot ulcer that appeared following cardiac catheterization, stenting, and automatic implanted cardiac defibrillator (AICD) implantation in a patient without other evidence of significant peripheral artery disease. An 85-year-old woman with chronic atrial fibrillation, aortic valve stenosis, and coronary artery disease underwent coronary stenting and AICD implantation for ventricular tachycardia and syncope. She developed a toe ulcer shortly thereafter, which did not respond to standard treatment. A histological examination following amputation of the toe found amorphous basophilic material in capillaries adjacent to the edge of the ulcer, which was similar to material associated with hydrophilic polymer coatings. Ischemia and infarcts following endovascular procedures should not be presumed to result from thrombus or vascular disease, even if intravascular devices appear intact or properly placed after the procedure. To help establish the incidence of ischemia caused by hydrophilic polymer device coatings, if excision of ischemic or infarcted tissue after endovascular procedures using coated devices becomes necessary, the tissue should be evaluated microscopically. Surgeons should also consider the tolerance of distal organs to infarct or ischemia when selecting coated intravascular devices.",
"affiliations": "1 General Surgery Residency, Swedish Medical Center, Seattle, WA, USA.;1 General Surgery Residency, Swedish Medical Center, Seattle, WA, USA.;1 General Surgery Residency, Swedish Medical Center, Seattle, WA, USA.;1 General Surgery Residency, Swedish Medical Center, Seattle, WA, USA.",
"authors": "French|Bryce|B|https://orcid.org/0000-0002-7739-5974;Ranguelov|Rostislav|R|;Johansen|Kaj|K|;Tan|Swee Lian|SL|",
"chemical_list": "D020099:Coated Materials, Biocompatible; D011108:Polymers",
"country": "United States",
"delete": false,
"doi": "10.1177/1538574419861771",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-5744",
"issue": "53(7)",
"journal": "Vascular and endovascular surgery",
"keywords": "hydrophilic polymer embolism; peripheral ischemia; toe ulceration",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D000369:Aged, 80 and over; D000671:Amputation; D000792:Angiography; D001706:Biopsy; D020099:Coated Materials, Biocompatible; D004617:Embolism; D005260:Female; D016523:Foot Ulcer; D005548:Foreign-Body Migration; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007511:Ischemia; D011108:Polymers; D012039:Regional Blood Flow; D014034:Toes; D016896:Treatment Outcome",
"nlm_unique_id": "101136421",
"other_id": null,
"pages": "606-608",
"pmc": null,
"pmid": "31272303",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ischemic Toe Ulceration Due to Foreign Body Embolus From Hydrophilic Polymer-Coated Intravascular Device.",
"title_normalized": "ischemic toe ulceration due to foreign body embolus from hydrophilic polymer coated intravascular device"
} | [
{
"companynumb": "US-BAYER-2019-183735",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nStatus Epilepticus (SE) is a common medical emergency carrying a high morbidity and mortality. Levetiracetam (LEV) is a novel anticonvulsant effective against varied seizures. Few prospective studies have addressed its use in SE. We aimed to examine the efficacy of intravenous LEV in controlling SE and cluster attacks of seizures (CS), in comparison with IV phenytoin (DPH), using a prospective, randomized study design.\n\n\nMETHODS\nAdult patients with SE or CS, following an initial dose of IV benzodiazepine to control ongoing seizure, were randomized to receive either medication. Rates of seizure control over 24h, adverse effects and outcomes were compared. A logistic regression model was used to identify outcome predictors.\n\n\nRESULTS\n52 patients with SE and 63 with CS received either LEV or DPH. In the SE group, LEV was effective in18/22(82%) and DPH in 22/30(73.3%) patients in controlling seizures. Among patients with CS, LEV was effective in 31/38(81.6%) and DPH in 20/25(80%). With the use of LEV, DPH or both, SE and CS were controlled among 92% and 96% of patients respectively. Adverse events included hypotension (in 2 on DPH) and transient agitation (2 on LEV).\n\n\nCONCLUSIONS\nIV Levetiracetam controls status epilepticus or cluster seizures with an efficacy comparable to that of phenytoin. Use of these two agents consecutively may control >90% of all such conditions without resort to anaesthetic agents. Further studies should explore its efficacy in larger cohorts of epileptic emergencies.",
"affiliations": "Departments of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman. Electronic address: grarunoday@hotmail.com.;Departments of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Departments of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Departments of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Emergency Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Family Medicine and Public Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Departments of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.",
"authors": "Gujjar|Arunodaya R|AR|;Nandhagopal|Ramachandiran|R|;Jacob|Poovathoor C|PC|;Al-Hashim|Abdulhakeem|A|;Al-Amrani|Khalfan|K|;Ganguly|Shyam S|SS|;Al-Asmi|Abdullah|A|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2017.05.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "49()",
"journal": "Seizure",
"keywords": "Anticonvulsant treatment; Cluster Seizures; Levetiracetam; Phenytoin; Status Epilepticus",
"medline_ta": "Seizure",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077287:Levetiracetam; D008297:Male; D010672:Phenytoin; D010889:Piracetam; D011446:Prospective Studies; D012640:Seizures; D013226:Status Epilepticus",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "8-12",
"pmc": null,
"pmid": "28528211",
"pubdate": "2017-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.",
"title_normalized": "intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures a prospective randomized study"
} | [
{
"companynumb": "OM-VISTAPHARM, INC.-VER201706-000152",
"fulfillexpeditecriteria": "1",
"occurcountry": "OM",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nTriple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.\n\n\nMETHODS\nWe performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5-21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.\n\n\nRESULTS\nEleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59-0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11-0.69) of patients.\n\n\nCONCLUSIONS\nCombination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.",
"affiliations": "Division of Medical Oncology, Stefanie Spielman Comprehensive Breast Center, The Ohio State University Comprehensive Cancer Center, B411 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA. rachel.layman@osumc.edu",
"authors": "Layman|Rachel M|RM|;Ruppert|Amy S|AS|;Lynn|Melinda|M|;Mrozek|Ewa|E|;Ramaswamy|Bhuvaneswari|B|;Lustberg|Maryam B|MB|;Wesolowski|Robert|R|;Ottman|Susan|S|;Carothers|Sarah|S|;Bingman|Anissa|A|;Reinbolt|Raquel|R|;Kraut|Eric H|EH|;Shapiro|Charles L|CL|",
"chemical_list": "D009588:Nitrogen Mustard Compounds; D011799:Quinazolines; D000069461:Bendamustine Hydrochloride; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-013-2112-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "71(5)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D001943:Breast Neoplasms; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008231:Lymphopenia; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009588:Nitrogen Mustard Compounds; D011799:Quinazolines; D012720:Severity of Illness Index",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1183-90",
"pmc": null,
"pmid": "23430121",
"pubdate": "2013-05",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16014882;11862482;18171422;18249110;15756024;15328174;17116942;16043829;18172283;17872900;19890959;18316557;17146782;16842242;10942063;12756557;19097774;16280056;9860292;17442998;17329194;19652068;18186959;11206271;16096436",
"title": "Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer.",
"title_normalized": "severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer"
} | [
{
"companynumb": "US-MYLANLABS-2017M1007760",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Cystic Fibrosis (CF) is a lethal autosomal recessive condition due to a defect at the level of the transmembrane conductance regulator gene which plays a role in cell homeostasis. Numerous mutations have been identified as the cause of this gene defect, with delF508 being one of the most common mutations in Tunisia. This is a case report describing, up to our knowledge, the second case of a patient with CF carrying a rare mutation: W19X. W19X is a nonsense mutation that has been previously identified in only one other Tunisian patient with CF. Since both incidence of this mutation have been described in Tunisia, it seems as if W19X is specific to Tunisian CF patient with significant morbidities. The information provided by this study contributes to defining the molecular spectrum of CF in Tunisia, in the aim of improving genetic testing and prenatal diagnosis.",
"affiliations": null,
"authors": "Lamouchi|Mohamed Taher|MT|",
"chemical_list": "C505032:CFTR protein, human; D018389:Codon, Nonsense; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014364:Tryptophan",
"country": "Tunisia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4131",
"issue": "98(5)",
"journal": "La Tunisie medicale",
"keywords": null,
"medline_ta": "Tunis Med",
"mesh_terms": "D000015:Abnormalities, Multiple; D018389:Codon, Nonsense; D003550:Cystic Fibrosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D014364:Tryptophan; D014416:Tunisia",
"nlm_unique_id": "0413766",
"other_id": null,
"pages": "420-422",
"pmc": null,
"pmid": "32548846",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cystic Fibrosis mutation W19X in Tunisia: Second case identified.",
"title_normalized": "cystic fibrosis mutation w19x in tunisia second case identified"
} | [
{
"companynumb": "TN-MYLANLABS-2020M1065333",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "A 74-year-old man presented to the Andrology Clinic for management of potential complications of androgen deprivation therapy for prostate cancer. He had a rising prostate-specific antigen with a concurrent rise in alkaline phosphatase and bone remodeling markers. This was despite treatment with a radical prostatectomy, androgen deprivation, and anti-resorptive therapy. A follow-up dual-energy X-ray absorptiometry scan revealed a marked increase in his bone mineral density at both the lumbar spine and femoral neck. This increase, especially in the context of rising bone remodeling markers, was unlikely due to the effect of anti-resorptive therapy alone. Subsequent whole-body bone scintigraphy demonstrated a \"superscan\" phenomenon which is characterized by uniform and avid tracer retention throughout the skeleton, in this case due to widespread skeletal metastasis, so that the usual physiological uptake in the kidneys is no longer observed and can be misinterpreted as a \"normal\" scan if the absence of the kidneys is not recognized. This case highlights the importance of considering diffuse metastatic disease when there is a rapid increase in bone mineral density, even in individuals treated with anti-resorptive therapy.",
"affiliations": "Department of Endocrinology, Austin Health, Melbourne, Australia. yeeming.cheung1611@gmail.com.;Department of Endocrinology, Austin Health, Melbourne, Australia.;Department of Endocrinology, Austin Health, Melbourne, Australia.",
"authors": "Cheung|Y-M|YM|;Ramchand|S K|SK|;Grossmann|M|M|",
"chemical_list": "D000726:Androgen Antagonists; D050071:Bone Density Conservation Agents",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-018-4481-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "29(7)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Androgen deprivation therapy; Anti-resorptive therapy; Bone mineral density; Prostate cancer; Superscan",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D015502:Absorptiometry, Photon; D000368:Aged; D000726:Androgen Antagonists; D015519:Bone Density; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D005272:Femur Neck; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D010024:Osteoporosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D011877:Radionuclide Imaging",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "1665-1670",
"pmc": null,
"pmid": "29666893",
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"title": "Pitfalls in bone density monitoring in prostate cancer during anti-resorptive treatment.",
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"abstract": "A 56-year-old man diagnosed with sigmoid colon cancer underwent sigmoid colectomy. Nine months later, his serum carcinoembryonic antigen (CEA) level had increased, and the diagnosis of recurrent peritoneal dissemination was made based on positron emission tomography/computed tomography (PET/CT) findings. Although systemic chemotherapy comprising S-1 and oxaliplatin (SOX) plus bevacizumab was initiated, severe diarrhea occurred on day 4 of the second cycle despite reduction in S-1 dose. By changing the daily oral intake schedule for S-1 to an alternate-day intake from the third cycle (modified SOX plus bevacizumab), the patient was able to continue undergoing chemotherapy without any adverse gastrointestinal effects. All tumors disappeared after four cycles, and the patients received eight cycles of modified SOX plus bevacizumab followed by maintenance chemotherapy comprising alternate-day S-1 plus bevacizumab. Maintenance chemotherapy was discontinued after 17 cycles owing to adverse events, including thrombocytopenia, corneal and lacrimal duct disorders, and hyperbilirubinemia. The patient has been radiographically confirmed to be in remission for 5 years without any recurrence, and his serum CEA level has been within normal range for >3 years. To conclude, compared with the conventional consecutive treatment, alternate-day SOX plus bevacizumab treatment may reduce the adverse effects of these chemotherapeutic drugs.",
"affiliations": "Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.;Center of Digestive Diseases, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan.",
"authors": "Nitori|Nobuhiro|N|;Kato|Ayu|A|;Deguchi|Tomoaki|T|;Nakadai|Jumpei|J|;Tada|Ayako|A|;Takahashi|Makoto|M|;Umeda|Rumiko|R|;Miyata|Naoteru|N|;Kataoka|Mikinori|M|;Kadomura|Tomohisa|T|;Higuchi|Hajime|H|;Ebinuma|Hirotoshi|H|;Kato|Atsushi|A|;Hatori|Takashi|T|;Ikeda|Yoshifumi|Y|;Miyazaki|Masaru|M|",
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"journal": "Molecular and clinical oncology",
"keywords": "S-1; alternate-day pattern; chemotherapy; complete remission; oxaliplatin; peritoneal dissemination; peritoneal metastases; recurrent colon cancer",
"medline_ta": "Mol Clin Oncol",
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"title": "Complete remission of peritoneal dissemination of colon cancer by alternate-day S-1 and oxaliplatin plus bevacizumab treatment and maintenance chemotherapy comprising alternate-day S-1 plus bevacizumab: A case report.",
"title_normalized": "complete remission of peritoneal dissemination of colon cancer by alternate day s 1 and oxaliplatin plus bevacizumab treatment and maintenance chemotherapy comprising alternate day s 1 plus bevacizumab a case report"
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"abstract": "Severe neonatal autosomal-dominant polycystic kidney disease (ADPKD) is rare and easily confused with recessive PKD. Managing such infants is difficult and often unsuccessful.\n\n\n\nA female infant with massive renal enlargement, respiratory compromise and hyponatraemia was treated with the arginine vasopressin receptor 2 antagonist tolvaptan. This resolved hyponatraemia, and there was no further increase in renal size.\n\n\n\nTolvaptan may be a useful treatment for severe neonatal PKD.",
"affiliations": "Regional Paediatric Nephro-Urology Unit, Southampton Children's Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK. Rodney.Gilbert@uhs.nhs.uk.;Respiratory Unit, Southampton Children's Hospital, Southampton, UK.;Pharmacy, Southampton University Hospital, Southampton, UK.;Regional Paediatric Nephro-Urology Unit, Southampton Children's Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK.;Regional Paediatric Nephro-Urology Unit, Southampton Children's Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK.;Radiology Department, Southampton Children's Hospital, Southampton, UK.",
"authors": "Gilbert|Rodney D|RD|;Evans|Hazel|H|;Olalekan|Kazeem|K|;Nagra|Arvind|A|;Haq|Mushfequr R|MR|;Griffiths|Mark|M|",
"chemical_list": "C585768:AVPR2 protein, human; D001552:Benzazepines; D017483:Receptors, Vasopressin; D050396:TRPP Cation Channels; C087882:polycystic kidney disease 1 protein; D000077602:Tolvaptan",
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"fulltext": "\n==== Front\nPediatr NephrolPediatr. NephrolPediatric Nephrology (Berlin, Germany)0931-041X1432-198XSpringer Berlin Heidelberg Berlin/Heidelberg 358410.1007/s00467-017-3584-9Brief ReportTolvaptan treatment for severe neonatal autosomal-dominant polycystic kidney disease Gilbert Rodney D. Rodney.Gilbert@uhs.nhs.uk 12Evans Hazel 3Olalekan Kazeem 4Nagra Arvind 1Haq Mushfequr R. 1Griffiths Mark 51 grid.461841.eRegional Paediatric Nephro-Urology Unit, Southampton Children’s Hospital, Tremona Road, Southampton, SO16 6YD Hampshire UK 2 0000 0004 1936 9297grid.5491.9Faculty of Medicine, University of Southampton, Southampton, UK 3 grid.461841.eRespiratory Unit, Southampton Children’s Hospital, Southampton, UK 4 0000000103590315grid.123047.3Pharmacy, Southampton University Hospital, Southampton, UK 5 grid.461841.eRadiology Department, Southampton Children’s Hospital, Southampton, UK 13 2 2017 13 2 2017 2017 32 5 893 896 30 11 2016 21 12 2016 21 12 2016 © The Author(s) 2017\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nSevere neonatal autosomal-dominant polycystic kidney disease (ADPKD) is rare and easily confused with recessive PKD. Managing such infants is difficult and often unsuccessful.\n\nCase diagnosis/treatment\nA female infant with massive renal enlargement, respiratory compromise and hyponatraemia was treated with the arginine vasopressin receptor 2 antagonist tolvaptan. This resolved hyponatraemia, and there was no further increase in renal size.\n\nConclusion\nTolvaptan may be a useful treatment for severe neonatal PKD.\n\nKeywords\nAutosomal dominant polycystic kidney diseaseInfantTolvaptanUniversity of Southamptonissue-copyright-statement© IPNA 2017\n==== Body\nIntroduction\nPatients with severe neonatal polycystic kidney disease (PKD), whether dominant or recessive, have on occasion been treated with nephrectomy and early dialysis. This approach has a high mortality rate due in part to refractory hypotension pos-operatively due to loss of renin secretion [1] and the difficulties involved in managing completely anuric young infants. We present a patient with severe neonatal autosomal-dominant PKD (ADPKD) due to biallelic inheritance of PKD1 mutations. She was successfully treated with tolvaptan, a selective, competitive inhibitor of the vasopressin V2 receptor.\n\nCase report\nA 22-year-old woman with a well-established diagnosis and family history of ADPKD was referred for antenatal counselling after a scan at 17 weeks showed abnormal kidneys in the fetus. Serial antenatal ultrasound scans confirmed large, echogenic kidneys with no resolvable cysts. Urine was seen within the bladder, but the amniotic fluid index was consistently at the lower end of the normal range. The female infant was delivered by elective caesarean section at 37 weeks’ gestation weighing 3.370 kg. She was initially pink with good tone, but as soon as the cord was clamped, she became cyanosed and floppy, showing no respiratory effort and heart rate that dropped to 60/min. Inflation breaths administered via a face mask produced no visible chest movement and she was intubated. Ventilation pressures of 35/5 cm water and an inspired oxygen concentration of 50% were required to keep arterial oxygen saturation >90%. Further examination revealed a relatively small chest (Fig. 1a) and a distended abdomen, with massively enlarged kidneys (Fig. 1b). There was a left inguinal hernia; female genitalia and the rest of the examination were normal.Fig. 1 \na Chest radiograph showing distended abdomen and small chest. b Abdominal radiograph showing distended abdomen with bilateral soft tissue masses and central bowel gas, also seen within a right inguinal hernia. c Abdominal ultrasound scan showing extremely enlarged and echobright kidneys with reduced corticomedullary differentiation compressing the inferior vena cava. The right kidney measured 10.2 cm long and the left 10.7 cm. The depth of both kidneys was 5.6 cm and transverse dimension 7.5 cm. At term, mean sonographic renal length was 4.48 ± 0.31 cm. d High-resolution view showing multiple small cysts, three of which are indicated by arrows\n\n\n\n\n\n\nPKD1 sequencing showed a heterozygous c.7483 T > C; p.(Cys2495Arg), highly likely pathogenic [2], missense mutation in exon 18 and the hypomorphic variant [3] c.9829C > T; p.(Cys 2495Arg) in exon 29. The former was shown to be inherited from her mother and the latter from her father. Urine output in the first 24 h was 0.2 ml/kg/h. Plasma creatinine rose to a maximum of 189 μmol/L on day 4 and gradually reduced thereafter. Plasma sodium fell to a minimum of 126 mmol/L on day 3 despite fluid restriction to 20 ml/kg per day, which was mostly given IV. Sodium administration was 1.5 mmol/kg per day, with feeds of maternal breast milk 2 ml every 2 h. Systolic blood pressure was in the mid-80s. She was successfully extubated and managed with face-mask continuous positive airway pressure (CPAP) on day 3.\n\nAt 7 days of age, she was started on parenteral nutrition due to intolerance of enteral feeds of adequate volume. By day 8, she was weaned off oxygen and by day 9 was tolerating sufficient enteral feed to stop parenteral nutrition. She had oedema of the legs and labia. On day 14 she became hypertensive, with systolic blood pressures ranging from 98 to 106 mmHg. Treatment with captopril was started. She developed respiratory acidosis and required high-flow humidified oxygen. A sleep study on day 16 confirmed frequent arterial oxygen desaturations and hypercapnoea, with a mean pCO2 of 8.03 kPa. She was given supplementary oxygen when sleeping.\n\nFacial and leg oedema became increasingly problematic and was associated with hyponatraemia. The patient had continued respiratory distress with flaring of the alae nasi, grunting, and opisthotonic posturing. An abdominal ultrasound showed that the enlarged echogenic kidneys with multiple small cysts were compressing the inferior vena cava, and oedema was attributed to obstructed venous return (Fig. 1c, d). Hyponatraemia was attributed to nonosmotic stimulation of vasopressin release due to activation of the thoracic baroreceptors caused by impaired cardiac filling, exacerbated by reduced free water clearance due to impaired renal function. The oedema was initially managed with furosemide, but this aggravated hyponatraemia and caused hypokalaemia. Approval for treatment with tolvaptan was therefore sought to combat hyponatraemia and prevent further complications by minimising renal growth. While waiting for approval, hyponatraemia was managed with sodium chloride supplements, which caused her systolic blood pressure to rise to >110 mmHg.\n\nConsent for treatment for an unlicensed and unexplored indication was given by the parents. Tolvaptan was started in at 0.15 mg/kg per day on day 31 of postnatal life, and the sodium supplements were stopped at the same time. Urine output increased from 1.75 ml/kg per hour before tolvaptan to 2.4 ml/kg per the day of the first dose. Plasma sodium initially remained constant at 136 mmol/L, but 3 days later, the patient became mildly hyponatraemic (plasma sodium 131, falling to nadir of 129 on day 5 of tolvaptan therapy). This was attributed to variable dosing. There is no licensed liquid formulation of tolvaptan, so initially, the dose was administered by crushing a tablet and suspending it in water. However, because tolvaptan is insoluble in water (0.00005 w/v% at 25 °C) [4] and there were concerns about accuracy of the administered dose, a suspension was made by the pharmacy as follows: tolvaptan tablets (Samsca®) 4 × 15 mg tablets, Oral-Plus® 30 ml, Oral-Sweet® to 60 ml, giving a final strength of 1 mg/ml. The expiry date was set at 7 days. Thereafter, plasma sodium concentration was consistently within the normal range.\n\nBecause of concerns of hypernatraemia, the tolvaptan dose was slowly increased while increasing the feed volume. By 3 months of age, she was administered 0.5 mg/kg per day as a single dose. At 6 months, the dose was increased to 0.7 mg/kg per in two divided doses, with two thirds given in the morning and one third late afternoon. At 9 months of age, the dose was increased to 1 mg/kg per day. On this dose, her urine osmolality has been consistently <300 mOsm/kg.\n\nOn the day of the first tolvaptan dose, plasma creatinine concentration was 103 μmol/L. After 1 month of tolvaptan therapy, it had fallen to 77 μmol/L and at 12 months 43 μmol/L, giving an estimated glomerular filtration rate (eGFR) of 55 ml/min/1.73 m2. This remained similar at 18 months of age, when plasma creatinine was 41 μmol/l and eGFR 60 ml/min/1.73 m2. Kidney size (assessed by ultrasound) has not changed since starting tolvaptan. While there is no evidence of a reduction in renal size, a 3% volume change would be within the limits of accuracy of the technique. Breathing is normal, and oxygen administration was stopped following a normal sleep study at 12 months of age. Development is normal.\n\nDiscussion\nADPKD is the most common monogenic disease causing end-stage renal failure, occurring in 1:400 to 1:1000 individuals worldwide [5]. Although ADPKD is dominant, with almost 100% penetrance at the individual level, it appears to be recessive at the cellular level. Only a relatively small proportion of nephrons develop cysts. Several investigators demonstrated deletion or other inactivating somatic mutations in the remaining normal PKD1 or PKD2 gene in epithelial cells lining individual cysts [6]. In further support of a gene–dosage effect, several authors reported unusually early and severe disease, often mimicking renal manifestations of recessive PKD, in patients with either biallelic abnormalities of PKD1 or PKD2, such as our patient [1, 7, 8], or a pathogenic mutation of PKD1 or PKD2 in association with a mutation in another gene associated with renal cystic disease, such as PKHD1 or HNF1β [9].\n\nReduced expression of polycystin 1 or 2 results in accumulation of cyclic adenosine monophosphate (cAMP) within the cytoplasm of renal tubular cells [10]. Although under normal circumstances cAMP inhibits cell proliferation, in ADPKD it increases both cell proliferation and fluid secretion [11]. Arginine vasopressin (AVP) is the main agonist of adenyl cyclase in collecting ducts, and patients and experimental animals with PKD have increased levels of circulating AVP and upregulation of AVP- and cAMP-dependent genes, such as the V2 receptor and aquaporin-2. In adult patients with ADPKD, tolvaptan slowed the increase in kidney size and the rate of glomerular filtration rate (GFR) decline [12], with an average reduction in kidney volume (assessed by MRI) of 3.1% after 1 week of treatment [13]. Tolvaptan has now been licensed for treating adults with ADPKD in a number of jurisdictions.\n\nThe rationale for treating this patient was to treat the hyponatraemia and presumed excessive AVP secretion (plasma copeptin was not measured) and secondly to prevent or reduce renal growth as much as possible. Kidney volume tends to increase at a greater rate in children than in adults [14], and those with higher AVP secretion have greater disease severity [15]. Our patient was therefore considered to be at high risk of a rapid increase in renal size. On tolvaptan therapy, she has grown well and maintained a normal plasma sodium concentration, while her kidneys have not grown and she is now completely untroubled by renal size. Estimated GFR also improved. While it is impossible to know whether it would have improved to the same extent had the patient survived without tolvaptan therapy, renal function may even have deteriorated. Polyuria has not been a significant problem, and there have been no incidents of hypernatraemia or hepatotoxicity. Although we cannot know what renal growth without tolvaptan would have been, we suggest that this treatment was beneficial in our patient. Further study is necessary to determine the role of tolvaptan in managing infants with severe dominant or recessive PKD.\n\nCompliance with ethical standards\nDeclaration\nRDG is a member of the data monitoring committee for paediatric trials of tolvaptan.\n==== Refs\nReferences\n1. Gilbert RD Sukhtankar P Lachlan K Fowler DJ Bilineal inheritance of PKD1 abnormalities mimicking autosomal recessive polycystic kidney disease Pediatr Nephrol 2013 28 2217 2220 10.1007/s00467-013-2484-x 23624871 \n2. Autosomal Dominant Polycystic Kidney Disease: Muation Database. http://pkdb.mayo.edu/index.html\n3. Cornec-Le Gall E Audrézet M-P Chen J-M Hourmant M Morin M-P Perrichot R Charasse C Whebe B Renaudineau E Jousset P Guillodo M-P Grall-Jezequel A SaliouP FC Le Meur Y Type of PKD1 mutation influences renal outcome in ADPKD J Am Soc Nephrol 2013 24 1006 1013 10.1681/ASN.2012070650 23431072 \n4. EMEA. CHMP Assessment Report for Samsca (Tolvaptan) Ref: EMEA/502935/2009 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000980/WC500048715.pdf [Accessed 01/04/2015]\n5. Dalgaard OZ Nørby S Autosomal dominant polycycstic kidney disease in the 1980s Clin Genet 1989 36 320 325 10.1111/j.1399-0004.1989.tb03204.x 2689002 \n6. Brasier JL Henske EP Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis J Clin Invest 1997 99 194 199 10.1172/JCI119147 9005987 \n7. Vujic M Heyer CM Ars E Hopp K Markoff A Örndal C Rudenhed B Nasr SH Torres VE Torra R Bogdanova N Harris PC Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD J Am Soc Nephrol 2010 21 1097 1102 10.1681/ASN.2009101070 20558538 \n8. Losekoot M Ruivenkamp CA Tholens AP Grimbergen JE Vijfhuizen L Vermeer S Dijkman HB Cornelissen EA Bongers EM Peters DJ Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy J Med Genet 2012 49 37 40 10.1136/jmedgenet-2011-100452 22114106 \n9. Bergmann C von Bothmer J Ortiz Brüchle N Venghaus A Frank V Fehrenbach H Hampel T Pape L Buske A Jonsson J Sarioglu N Santos A Ferreira JC Becker JU Cremer R Hoefele J Benz MR Weber LT Buettner R Zerres K Mutations in multiple PKD genes may explain early and severe polycystic kidney disease J Am Soc Nephrol 2011 22 2047 2056 10.1681/ASN.2010101080 22034641 \n10. Choi H-Y Suzuki A Hajarnis S Ma Z Chapin HC Caplan MJ Pontoglio M Somlo S Igarashi P Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases PNAS 2011 108 10679 10684 10.1073/pnas.1016214108 21670265 \n11. Hanaoka K Guggino W cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells J Am Soc Nephrol 2000 11 1179 1187 10864573 \n12. Torres VE Chapman AB Devuyst O Gansevoort RT Grantham JJ Higashihara E Perrone RD Krasa HB Ouyang J Czerwiec FS TEMPO 3.4 Trial Investigators Tolvaptan in patients with autosomal dominant polycystic kidney disease N Engl J Med 2012 367 2407 2418 10.1056/NEJMoa1205511 23121377 \n13. Irazabal MV Torres VE Hogan MC Glockner J King BF Ofstie TO Krasa HB Ouyang J Czerwiec FS Short-term effects on renal function and volume in patients with autosomal dominant polycystic kidney disease Kidney Int 2011 80 295 301 10.1038/ki.2011.119 21544064 \n14. Cadnapaphornchai MA Masoumi A Strain JD McFann K Schrier RW Magnetic resonance imaging of kidneys and cyst volume in children with ADPKD Clin J Am Soc Nephrol 2011 6 369 376 10.2215/CJN.03780410 21115621 \n15. Meijer E Bakker SJ van der Jagt EJ Navis G de Jong PE Struck J Gansevoort RT Copeptin, a surrogate marker for vasopressin, is associated with disease severity in autosomal dominat polycystic kidney disease Clin J Am Soc Nephrol 2011 6 361 368 10.2215/CJN.04560510 20930090\n\n",
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"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Autosomal dominant polycystic kidney disease; Infant; Tolvaptan",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D001552:Benzazepines; D004487:Edema; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007231:Infant, Newborn; D007677:Kidney Function Tests; D010288:Parenteral Nutrition; D016891:Polycystic Kidney, Autosomal Dominant; D011247:Pregnancy; D017483:Receptors, Vasopressin; D050396:TRPP Cation Channels; D000077602:Tolvaptan; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Tolvaptan treatment for severe neonatal autosomal-dominant polycystic kidney disease.",
"title_normalized": "tolvaptan treatment for severe neonatal autosomal dominant polycystic kidney disease"
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"abstract": "OBJECTIVE\nTo compare different treatment regimens on pregnancy rate and outcome in patients with anovulatory infertility.\n\n\nMETHODS\nA prospective observational study was conducted on patients with infertility due to anovulation. Patients treated with clomiphene citrate (CC) 50/100 mg/day from 2nd to 6th day of menstrual cycle (MC) (n = 38), short gonadotropin-releasing hormone (GnRH) agonist regimen (leuprolide [0.5 mg subcutaneous] + recombinant follicle-stimulating hormone [rFSH] [225 IU intramuscular [IM] from 2nd to 10th day of MC [n = 32]), long GnRH agonist regimen (leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of MC [n = 19]), and antagonist regimen (human menopausal gonadotropin [hMG] [150 IU IM] from 2nd day followed by hMG + cetrorelix from 7th to 10th day of MC) (n = 6) were recruited and followed up for follicular size, endometrial thickness, and pregnancy test. Data were analyzed using appropriate statistical test andP < 0.05 was considered statistically significant.\n\n\nRESULTS\nA significant increase in follicular diameter and endometrial thickness was observed in patients treated with gonadotropin regimens as compared to CC alone (P < 0.0001). The highest number of positive pregnancy test with ultrasonographic evidence of gestational sac was observed with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) and CC (1/38, 2.63%). All regimens were well tolerated.\n\n\nCONCLUSIONS\nTreatment outcome was better with long agonist regimen.",
"affiliations": "Department of Pharmacology, B.J. Medical College, Ahmedabad, Gujarat, India.;Department of Pharmacology, B.J. Medical College, Ahmedabad, Gujarat, India.;Department of Pharmacology, B.J. Medical College, Ahmedabad, Gujarat, India.;Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Civil Hospital, Ahmedabad, Gujarat, India.;Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Civil Hospital, Ahmedabad, Gujarat, India.;Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Civil Hospital, Ahmedabad, Gujarat, India.",
"authors": "Prajapati|Kinjal|K|;Desai|Mira|M|;Shah|Samidh|S|;Choudhary|Sumesh|S|;Aggarwal|Rohina|R|;Mishra|Vineet|V|",
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"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-8-11610.4103/jpp.JPP_43_17Research PaperTreatment Outcome of Ovulation-inducing Agents in Patients with Anovulatory Infertility: A Prospective, Observational Study Prajapati Kinjal Desai Mira Shah Samidh Choudhary Sumesh 1Aggarwal Rohina 1Mishra Vineet 1Department of Pharmacology, B.J. Medical College, Ahmedabad, Gujarat, India1 Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Civil Hospital, Ahmedabad, Gujarat, IndiaAddress for correspondence: Kinjal Prajapati, Department of Pharmacology, B.J. Medical College, Ahmedabad - 380 016, Gujarat, India. E-mail: drkinjal.7290@gmail.comJul-Sep 2017 8 3 116 121 20 3 2017 17 6 2017 24 7 2017 Copyright: © 2017 Journal of Pharmacology and Pharmacotherapeutics2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Objective:\nTo compare different treatment regimens on pregnancy rate and outcome in patients with anovulatory infertility.\n\nPatients and Methods:\nA prospective observational study was conducted on patients with infertility due to anovulation. Patients treated with clomiphene citrate (CC) 50/100 mg/day from 2nd to 6th day of menstrual cycle (MC) (n = 38), short gonadotropin-releasing hormone (GnRH) agonist regimen (leuprolide [0.5 mg subcutaneous] + recombinant follicle-stimulating hormone [rFSH] [225 IU intramuscular [IM] from 2nd to 10th day of MC [n = 32]), long GnRH agonist regimen (leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of MC [n = 19]), and antagonist regimen (human menopausal gonadotropin [hMG] [150 IU IM] from 2nd day followed by hMG + cetrorelix from 7th to 10th day of MC) (n = 6) were recruited and followed up for follicular size, endometrial thickness, and pregnancy test. Data were analyzed using appropriate statistical test andP < 0.05 was considered statistically significant.\n\nResults:\nA significant increase in follicular diameter and endometrial thickness was observed in patients treated with gonadotropin regimens as compared to CC alone (P < 0.0001). The highest number of positive pregnancy test with ultrasonographic evidence of gestational sac was observed with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) and CC (1/38, 2.63%). All regimens were well tolerated.\n\nConclusion:\nTreatment outcome was better with long agonist regimen.\n\nKeywords\nAnovulatory infertilityclomiphene citrategonadotropinspregnancy outcome\n==== Body\nINTRODUCTION\nInfertility is defined as the “failure to achieve a clinical pregnancy after 12 months or more of regular, unprotected sexual intercourse.”[1] Female infertility is a complex problem and requires effective interventions and solutions.[2] Ovulatory disorders account for 30%–40% of female infertility.[3]\n\nPolycystic ovarian disease (PCOD) is one of the common causes for anovulation. It is a common reproductive and endocrinologic disorder found in 6%–10% of the female population, characterized by hyperandrogenism, polycystic ovaries, and anovulation.[4] Medicines commonly used to treat infertility and induce ovulation include antiestrogens, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and dopamine agonists. The second-line ovulation-inducing agents include gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), available as recombinant gonadotropins (recombinant FSH [rFSH], rLH). These are used along with GnRH agonists/antagonist in different doses, duration, and combination are prescribed as short, long, or antagonist protocol. In recent years, rFSH has increasingly been used in ovulation induction and in vitro fertilization (IVF) treatments although meta-analysis of compromising true randomized-controlled trials showed an equivalent clinical efficacy of rFSH and human menopausal gonadotropin (hMG).[5] However, a systematic review of randomized trials showed a significant difference in the pregnancy outcome in different gonadotropin preparation.[6] In context with, which regimen is best in terms of pregnancy rate and outcome in anovulatory infertility needs to be investigated. The present study was undertaken to investigate pregnancy rate and outcome as well as safety of these drugs in patients with anovulatory infertility.\n\nPATIENTS AND METHODS\nThis prospective, observational study was conducted at the Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Civil Hospital, Ahmedabad, to evaluate the effects of drugs on ovulation and pregnancy outcome in patients with anovulatory infertility. The study was carried out over a period of 18 months from March 2015 to September 2016 after Ethics Committee approval (Reference number-EC/Approval/42/15). Patients of 21–37 years of age with PCOD with other causes of ovulatory dysfunction, i.e., thyroid abnormalities and hyperprolactinemia were included while those with infertility due to other causes were excluded from the study. For induction of ovulation, patients prescribed either clomiphene citrate (CC) (50 mg or 100 mg/day from 2nd to 6th day of menstrual cycle [MC]) or gonadotropins as short or long or antagonist regimen by consultant obstetrician. The different gonadotropins regimens were as follows:\n\n\nShort regimen = leuprolide (0.5 mg subcutaneous [SC]) + rFSH (225 IU intramuscular [IM]) from 2nd to 10th day of MC (8 days)\n\nLong regimen = leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of the next MC (maximum 18 days)\n\nAntagonist regimen = hMG (150 IU IM) from 2nd day followed by hMG + cetrorelix (250 mcg SC) from 7th to 10th day of MC (8 days).\n\n\n\n\nTreatment flowchart is depicted [Figure 1]. The patients were followed up at every MC for follicular development and endometrial thickness by transvaginal ultrasonography. If patient conceived, pregnancy was confirmed by urine pregnancy test and subsequently by ultrasonography and followed up for pregnancy outcome till end. In addition, safety monitoring was done and suspected adverse drug reactions (ADRs) were recorded and assessed for causality, severity, and preventability. Data were analyzed using ANOVA; P < 0.05 was considered statistically significant. Multiple regression analysis was done to find correlation of pregnancy outcome with variables such as patients' age, body mass index (BMI), type of infertility, follicular size, endometrial thickness, and regimen prescribed.\n\nFigure 1 Treatment details of the patients with anovulatory infertility\n\nRESULTS\nOf 65 patients with anovulation due to PCOD, 38 were prescribed CC, while 57 patients (including those not responded to CC) were prescribed short/long/antagonist gonadotropin regimens as per discretion of consulting obstetricians. A total seven patients were lost to follow-up [Figure 1].\n\nBaseline characteristics of patients included in the study\nPatients' characteristics such as age, BMI, duration of infertility, associated presenting complaints, and comorbidities of all four groups were comparable. However, statistically significant higher mean age was observed in antagonist group when compared to CC-treated patients [Table 1]. Oligomenorrhea, obesity, and hirsuitism were the common complaints of patients with PCOD. In addition, few patients also had hypothyroidism and hyperprolactinemia [Table 1].\n\nTable 1 Baseline characteristics of patients with anovulatory infertility (n=65)\n\nPrimary outcome\nPatients treated with clomiphene citrate\nA total 38 patients were administered CC initially in a dose of 50 or 100 mg for 5 days for a maximum of 4 cycles with total 76 treatment cycles. Majority of the patients (19) received two treatment cycles with CC followed by one cycle (11 patients), three cycles (5 patients), and four cycles (3 patients). The treatment cycle was considered successful when follicular size reached ≥18 mm. Maximum number of cycles were cancelled in CC cycle 1 and 2.\n\nEffect of clomiphene citrate on follicular size and endometrial thickness\nThe mean follicular size and endometrial thickness in CC treatment cycles are shown in Figure 2.\n\nFigure 2 Effect of clomiphene citrate on follicular size and endometrial thickness in patients with anovulatory infertility (n=38) (values are mean±SEM)\n\nPatients treated with gonadotropins\nA total of 57 patients were prescribed gonadotropins along with GnRH agonist/GnRH antagonist in three regimens, considering the age of the patients as well as antral follicle counts (by transvaginal sonography) on 2nd day of MC.\n\nEffect of gonadotropin regimens on follicular size and endometrial thickness\n\nNo difference on follicular size was observed among different regimens. However, endometrial thickness was significantly increased in patients treated with short regimen as compared to antagonist regimen (P < 0.05) [Table 2].\n\nTable 2 Comparison of gonadotropin regimens on follicular size and endometrial thickness (mean±SEM) in patients with anovulatory infertility\n\nComparison of clomiphene citrate and gonadotropin regimens on follicular size and endometrial thickness\n\nA significant increase in follicular diameter was observed in patients treated with short and long gonadotropin regimens (P < 0.001) and antagonist regimen (P < 0.01) as compared to CC alone [Table 3]. Second, a significant increase in the endometrial thickness was observed in patients treated with short regimen as compared to CC (P < 0.001) and antagonist regimen group (P < 0.05) [Table 3].\n\nTable 3 Effect of clomiphene citrate and gonadotropin regimens on follicular size and endometrial thickness (mean±SEM)\n\nSecondary outcome\nPregnancy rate\nPatients treated with clomiphene citrate\n\nOf 38 patients treated with CC, one patient conceived (with intra uterine insemination) after 3 treatment cycles.\n\nPatients treated with gonadotropins\n\nThe overall pregnancy rate (positive pregnancy test with ultrasonographic evidence of gestational sac) observed with gonadotropin regimen was 43.5% (25/57). However, among different regimens, it was highest with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) as shown in Table 4.\n\nTable 4 Comparison of effect of clomiphene citrate and various gonadotropin regimens on pregnancy outcome (n=65)\n\nOf 57 patients treated with gonadotropins, 25 patients conceived, 8 delivered successfully, 5 had abortion, 2 had intrauterine death, while 10 patients had ongoing pregnancy [Table 4].\n\nMoreover, an attempt made to do multiple regression analysis to find correlation of pregnancy outcome with variables such as patients' age, BMI, type of infertility, follicular size, endometrial thickness, and regimen prescribed showed no statistically significant difference (P > 0.05).\n\nSafety of the drug regimens\nAll the drugs were well tolerated. Total seven patients developed ADRs such as ovarian hyperstimulation (mild), headache, and abdominal pain. Patients treated with CC (n = 1) developed ovarian hyperstimulation, with short regimen (n = 4) developed ovarian hyperstimulation, headache, and abdominal pain while in long regimen (n = 2) headache developed. However, none of them required stoppage of the ongoing drug treatment or hospitalization. Majority of the ADRs were of moderate severity, not preventable and categorized as possible in nature as per the WHO-UMC and Naranjo's algorithm.\n\nDISCUSSION\nIn recent years, multiple products with variety of regimens have been employed to stimulate ovaries to obtain an adequate number of good quality follicles to treat anovulatory infertility patients undergoing IVF. Several studies comparing different gonadotropin preparations in different doses have been designed to explore the quantitative response (number of oocytes retrieved).[7] However, from patient and clinician perspective, more important is pregnancy rate and live birth following pharmacological interventions. The present study represents evaluation of ovarian response, pregnancy rate, and outcome in patients undergoing assisted reproduction with CC and three different gonadotropin regimes at a tertiary care infertility center.\n\nComparison of different gonadotropin regimens revealed no statistical significant difference (P > 0.05) on the follicular size, but endometrial thickness was significantly higher in short regimen as compared to antagonist regimen. A significant increase in follicular size and endometrial thickness was observed with gonadotropin regimens as compared to CC. In addition, overall pregnancy rate was superior with gonadotropin regimens (43.9%) as compared to CC. Further, among all three gonadotropin regimens, it was highest with long regimen (52.6%).\n\nIt has been reported that obesity is associated with abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis that contributes to development of PCOD along with altered hormonal profile, clinically represents as hirsuitism (hyperandrogenism) and oligomenorrhea.[8910] Majority of the patients in the study presented with these features along with obesity and BMI ≥25 kg/m2 higher than normal Asian women (18.6–22.9).[11] A study by Dasari and Pranahita supports our observation.[12] Interestingly, fertility problems such as anovulation and pregnancy loss are linked with obesity.[13] This indicates that patients enrolled in our study displayed typical features of altered HPO axis.\n\nCC being a first-line drug for ovulation induction is generally offered for maximum six ovulatory cycles. While in the present study, patients were treated with CC for a maximum of four cycles with an average of two cycles. The US Food and Drug Administration approved initial dosage is 50 mg daily for 5 days per cycle; which can be increased to 150 mg daily if patients do not respond. Surprisingly, no benefit in ovarian response and pregnancy rate was observed by increasing the CC dose and treatment cycle subsequently. Similar observation has been reported by Moy and Ekpo.[14] In addition, the cycle cancellation rate was high (11 out of 27, 40.7%) during the second cycle. The cycle was considered as cancelled if mean follicular size in patients treated with CC could not reach the cutoff value of 18 mm.[15] The response was much less as compared to observation by Shalom-Paz et al.[16] Poor response can be attributed to clomiphene resistance. Moreover, most of these patients were treated at private clinic for infertility and it is possible that this may not be the actual number of treatment cycles with CC.\n\nIn short regimen, GnRH agonist stimulates release of a large amount of FSH (and LH) that leads to flare-up of the follicles so that more mature follicles for IVF can be obtained.[17] However, in the long regimen, GnRH agonist is started (in previous MC) to “switch off” ovarian function (desensitization) followed by ovarian stimulation with FSH from day 2 of next MC.[17] Therefore, the total duration of treatment is more (maximum 18 days) in long regimen as compared to short regimen. Thus, the rationale of using short and long regimen is to strongly stimulate ovaries. The preference of prescribing short or long regimen depends on ovarian substance, i.e., the existing antral follicle counts in ovaries. The use of GnRH antagonist has given new hope for the management of poor responders to short and long regimens. Antagonist regimen is safer in the patients with previous experience of hyperstimulation with FSH. The administration of GnRH antagonists avoids the premature LH surge and utilize maximum ovarian oocyte cohort by minimizing the suppressing effects of the GnRH on the ovarian receptors.\n\nOur study showed that short regimen was commonly prescribed and administered to patients with 25–32 years age group, while antagonist regimen was prescribed to higher age group having low ovarian reserve. All three regimens had equal efficacy in terms of ovarian response except for endometrial thickness which was significantly higher in short regimen as compared to antagonist regimen. Moreover, no cycle cancellation was observed with all the three gonadotropin regimens which were seen with CC. Further, the successful pregnancy rate (live birth) was higher in long regimen (21.1%), followed by antagonist regimen (16.7%) and short regimen (9.4%) in our study. Furthermore, the ongoing pregnancy rate was higher in both agonist long regimen 21.1% and short regimen (18.8%). A study done by Al-Inany et al. 2007 showed significantly higher ongoing pregnancy/live birth rate in the agonist group.[18] Thus, successful pregnancy rate was superior with long agonist regimen while ongoing pregnancy was almost similar in long and short regimen. This mixed picture clearly restricts us to identify the best regimen for successful treatment outcome. Multiple regression analysis showed no association between different variables including drug regimen, ovarian response, and successful treatment outcome. Moreover, we also observed that short regimen had a trend toward higher endometrial thickness and probably implantation. However, it failed to reflect on pregnancy rate. This suggests that good ovarian response does not predict pregnancy rate and successful treatment. It will be of great relevance to identify other factors that will enable prescriber to achieve desired outcome and minimize chance of treatment failure. The use of CC and all three gonadotropin regimens were very well tolerated. Although the use of gonadotropins often cause multiple pregnancies, our study reported a single case of twin pregnancy and two cases of mild ovarian hyperstimulation syndrome.[1920]\n\nThe present study too has a few limitations. The small sample size, particularly in antagonist regimen, is a concern. Being a tertiary care referral center, most of these patients were treated at private clinic for infertility and did not respond to conventional ovulation-inducing agents, i.e., CC and required gonadotropins. Further, they were not able to quantify antral follicles on day 2 and number of oocytes retrieved with different regimens. Despite these limitations, this prospective study was undertaken over a period of 18 months, wherein all the information was recorded precisely. Each patient was followed up till the end of pregnancy, observed clinically and ovarian response was measured objectively. Thus, the data collected lead to some important conclusion.\n\nCONCLUSION\nThe treatment outcome of gonadotropin regimens is better than CC in terms of ovarian response and pregnancy rate. The successful pregnancy rate and ongoing pregnancy rate were high with long agonist regimen. However, we failed to establish the drug treatment as positive predictor for successful treatment outcome. Further research to identify predictors of successful treatment in women undergoing ovulation induction with appropriate sample size will be helpful in this regard.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nWe are thankful to the Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Studies, Civil Hospital, Ahmedabad, for giving permission to carry out the study and the patients for their participation and consistent support.\n==== Refs\nREFERENCES\n1 Zegers-Hochschild F Adamson GD de Mouzon J Ishihara O Mansour R Nygren K The international committee for monitoring assisted reproductive technology (ICMART) and the World Health Organization (WHO) revised glossary on ART terminology, 2009 Hum Reprod 2009 24 2683 7 19801627 \n2 Roupa Z Polikandrioti M Sotiropoulou P Faros E Koulouri A Wozniak G Causes of infertility in women at reproductive age Health Sci J 2009 3 80 7 \n3 Aubuchon M Burney RO Schust DJ Yao MW Infertility and assisted reproductive technology Berek & Novak's Gynecology 2012 15th ed New Delhi Lippincott Williams & Wilkins, Wolters Kluwer Business 1257 70 \n4 Norman RJ Dewailly D Legro RS Hickey TE Polycystic ovary syndrome Lancet 2007 370 685 97 17720020 \n5 Al-Inany HG Abou-Setta AM Aboulghar MA Mansour RT Serour GI Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: A meta-analysis Reprod Biomed Online 2008 16 81 8 18252052 \n6 Coomarasamy A Afnan M Cheema D van der Veen F Bossuyt PM van Wely M Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: A systematic review and meta-analysis Hum Reprod 2008 23 310 5 18056719 \n7 Leão Rde B Esteves SC Gonadotropin therapy in assisted reproduction: An evolutionary perspective from biologics to biotech Clinics (Sao Paulo) 2014 69 279 93 24714837 \n8 Legro RS Obesity and PCOS: Implications for diagnosis and treatment Semin Reprod Med 2012 30 496 506 23074008 \n9 Hart R Hickey M Franks S Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome Best Pract Res Clin Obstet Gynaecol 2004 18 671 83 15380140 \n10 Karnath BM Signs of hyperandrogenism in women Hosp Physician 2008 44 25 30 \n11 Hsu WC Araneta MR Kanaya AM Chiang JL Fujimoto W BMI cut points to identify at-risk Asian Americans for type 2 diabetes screening Diabetes Care 2015 38 150 8 25538311 \n12 Dasari P Pranahita G The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS J Hum Reprod Sci 2009 2 18 22 19562069 \n13 Pasquali R Pelusi C Genghini S Cacciari M Gambineri A Obesity and reproductive disorders in women Hum Reprod Update 2003 9 359 72 12926529 \n14 Moy I Ekpo G Pavone M Milad M The use of Clomiphene citrate for ovulation induction: When, why, and how? Contemporary Ob/Gyn 2011 56 4 42 52 \n15 Palatnik A Strawn E Szabo A Robb P What is the optimal follicular size before triggering ovulation in intrauterine insemination cycles with clomiphene citrate or letrozole? An analysis of 988 cycles Fertil Steril 2012 97 1089 94.e1 22459633 \n16 Shalom-Paz E Marzal A Wiser A Hyman J Tulandi T Does optimal follicular size in IUI cycles vary between clomiphene citrate and gonadotrophins treatments? Gynecol Endocrinol 2014 30 107 10 24266698 \n17 Schimmer BP Parker KL Contraception and pharmacotherapy of obstetrical and gynecological disorders Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011 New York McGraw-Hill 1833 47 \n18 Al-Inany HG Abou-Setta AM Aboulghar M Gonadotrophin-releasing hormone antagonists for assisted conception: A Cochrane review Reprod Biomed Online 2007 14 640 9 17509210 \n19 Ombelet W Martens G De Sutter P Gerris J Bosmans E Ruyssinck G Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: A cohort study Hum Reprod 2006 21 1025 32 16339165 \n20 Orvieto R Meltcer S Homburg R Nahum R Rabinson J Ashkenazi J What is the preferred GnRH analogue for polycystic ovary syndrome patients undergoing controlled ovarian hyperstimulation for in vitro fertilization? Fertil Steril 2009 91 1466 8 18774558\n\n",
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"keywords": "Anovulatory infertility; clomiphene citrate; gonadotropins; pregnancy outcome",
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"title": "Treatment Outcome of Ovulation-inducing Agents in Patients with Anovulatory Infertility: A Prospective, Observational Study.",
"title_normalized": "treatment outcome of ovulation inducing agents in patients with anovulatory infertility a prospective observational study"
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"abstract": "Immune thrombocytopenic purpura (ITP) is primarily characterized by immune-mediated destruction of platelets in circulation. Major treatment options range from careful observation, steroids, immunosuppressive medications, immunoglobulins to splenectomy. Interestingly and rarely, ITP has also been reported after solid organ transplantation in patients receiving immunosuppressive medications. While the incidence of new onset ITP after solid organ transplant is comparatively well documented, new onset ITP after renal transplant has only been reported in two patients. Both these patients underwent renal transplant for underlying Immunoglobulin-A (IgA) nephropathy and were treated effectively with steroids. We present successful management of the first reported case of new-onset ITP presenting after renal transplant in a patient with underlying diabetic nephropathy. The case report discusses the potential management strategies in such a novel scenario aiming simultaneously for a well-functioning renal graft, adequate hemostasis, minimum therapy- related morbidity and least cost implications for the patient.\n\n\n\nA 43-year-old male with hypertension and diabetes mellitus (DM), complicated by nephropathy and retinopathy, underwent pre-emptive living related renal transplant by donation from his 33-year-old wife. His immediate post-transplant period was unremarkable. Six months after the transplant, he presented with isolated thrombocytopenia. An extensive workup revealed no clinical or laboratory evidence of unusual substance intake, infection, hemolysis, microangiopathy, autoimmune disease or hematological malignancy. Eight months after the transplant, while the patient was maintained on steroids, cellcept and tacrolimus, his platelet count dipped to 13,000/microL and he had an episode of mild epistaxis. He was administered steroids in line with the adult ITP management protocol. Steroids were well tolerated, and platelet counts showed a good response to therapy. Steroids were then successfully tapered over the next ten weeks with steady and acceptable platelet counts and graft function.\n\n\n\nThe case report discusses the diagnostic considerations and successful management of new-onset post-renal transplant ITP. It also highlights the various therapeutic options available in the medical armamentarium including shuffling of immunosuppressive drugs, rituximab, thrombopoietin receptor agonists (TPO's) and splenectomy for their potential use in complicated scenarios like relapsing, or steroid-refractory post renal transplant ITP.",
"affiliations": "Department of Nephrology, KRL General Hospital, Islamabad, Pakistan. muhammadrashyd@gmail.com.;Department of Nephrology, KRL General Hospital, Islamabad, Pakistan.;Department of Nephrology, KRL General Hospital, Islamabad, Pakistan.;Rawalpindi Medical College, Rawalpindi, Pakistan.",
"authors": "Rashid|Raja Muhammad|RM|;Nabi|Zahid|Z|;Ansari|Ahmad Zaki|AZ|;Qaiser|Quratul-Ain|QA|",
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"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 86810.1186/s12882-018-0868-7Case ReportImmune thrombocytopenic purpura presenting in a patient after renal transplant for diabetic nephropathy Rashid Raja Muhammad +923215393907muhammadrashyd@gmail.com 1Nabi Zahid dr_zahidnabi@hotmail.com 1Ansari Ahmad Zaki zakiansari88@gmail.com 1Qaiser Quratul-ain qurratulainqaiser_khan@hotmail.com 21 Department of Nephrology, KRL General Hospital, Islamabad, Pakistan 2 0000 0004 0401 3757grid.415712.4Rawalpindi Medical College, Rawalpindi, Pakistan 20 3 2018 20 3 2018 2018 19 6910 9 2017 8 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nImmune thrombocytopenic purpura (ITP) is primarily characterized by immune-mediated destruction of platelets in circulation. Major treatment options range from careful observation, steroids, immunosuppressive medications, immunoglobulins to splenectomy. Interestingly and rarely, ITP has also been reported after solid organ transplantation in patients receiving immunosuppressive medications. While the incidence of new onset ITP after solid organ transplant is comparatively well documented, new onset ITP after renal transplant has only been reported in two patients. Both these patients underwent renal transplant for underlying Immunoglobulin-A (IgA) nephropathy and were treated effectively with steroids. We present successful management of the first reported case of new-onset ITP presenting after renal transplant in a patient with underlying diabetic nephropathy. The case report discusses the potential management strategies in such a novel scenario aiming simultaneously for a well-functioning renal graft, adequate hemostasis, minimum therapy- related morbidity and least cost implications for the patient.\n\nCase Presentation\nA 43-year-old male with hypertension and diabetes mellitus (DM), complicated by nephropathy and retinopathy, underwent pre-emptive living related renal transplant by donation from his 33-year-old wife. His immediate post-transplant period was unremarkable. Six months after the transplant, he presented with isolated thrombocytopenia. An extensive workup revealed no clinical or laboratory evidence of unusual substance intake, infection, hemolysis, microangiopathy, autoimmune disease or hematological malignancy. Eight months after the transplant, while the patient was maintained on steroids, cellcept and tacrolimus, his platelet count dipped to 13,000/microL and he had an episode of mild epistaxis. He was administered steroids in line with the adult ITP management protocol. Steroids were well tolerated, and platelet counts showed a good response to therapy. Steroids were then successfully tapered over the next ten weeks with steady and acceptable platelet counts and graft function.\n\nConclusions\nThe case report discusses the diagnostic considerations and successful management of new-onset post-renal transplant ITP. It also highlights the various therapeutic options available in the medical armamentarium including shuffling of immunosuppressive drugs, rituximab, thrombopoietin receptor agonists (TPO’s) and splenectomy for their potential use in complicated scenarios like relapsing, or steroid-refractory post renal transplant ITP.\n\nKeywords\nRenal transplantImmune thrombocytopenic purpura (ITP)ImmunosuppressionPost-transplant thrombocytopeniaissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nImmune thrombocytopenic purpura (ITP) is primarily characterized by immunologically mediated destruction of platelets in circulation at a rate surpassing production by compensating bone marrow [1]. In adults, the incidence is variably reported to be 22 to 39 individuals per million per year and prevalence being 50 to 100 individuals per million per year in USA and Europe respectively [2]. Clinical presentation varies between asymptomatic isolated thrombocytopenia, mucocutaneous bleeding and bruising. There is no gold standard for diagnosis. However, isolated thrombocytopenia, normal peripheral smear, with exclusion of apparent conditions and drugs, helps in the clinical diagnosis [1] Treatment options range from careful observation steroid administration, immunosuppressive drug treatment to splenectomy. Infrequently, ITP has also been reported after solid organ transplantation in patients already on immunosuppressive drugs [2–5]. Here we present the case of a middle- aged man with diabetic nephropathy who underwent living related renal transplant and developed isolated thrombocytopenia six months later. After extensive workup, he was successfully treated along the lines of new- onset ITP post renal transplant.\n\nCase Presentation\nA 43-year-old male with hypertension and diabetes mellitus (DM), complicated by diabetic nephropathy and retinopathy, underwent preemptive living related renal transplant by donation from his 33-year-old wife on 6th of May 2015. Neither the donor, nor the recipient had any history of autoimmune diseases or blood dyscrasias and both were IgG seropositive for Cytomegalovirus (CMV) and Epstein–Barr virus (EBV). Prior to transplantation, there was no history of blood or blood product transfusion. HLA tissue typing revealed antigen match at loci A*03, B*57, DRB1*03 and DQB1*05. The patient received Basiliximab at induction as per protocol and was maintained on a triple immunosuppressive regimen of tacrolimus, mycophenolate and steroids. Tacrolimus trough levels were successfully maintained between 7 to 12 ng/ml and his immediate post-transplant period was uneventful. Steroids were tapered over a period of 8 weeks to a dose of 5 mg once daily. He received standard prophylaxis with valganciclovir, nystatin oral drops and trimethoprim-sulfamethoxazole.\n\nSix months post-transplant, upon follow- up, there was no history of any preceding or current fever, flu- like illness, cough, dyspepsia, gastrointestinal discomfort, altered bowel habits, rash, skin discoloration, body aches or joint pains. He denied taking any non-prescribed drugs including herbal, homeopathic or traditional medications. His blood sugars were adequately controlled. The examination was unremarkable for petechiae, bruises, edema, lymphadenopathy, hepatomegaly or splenomegaly. Laboratory reports were normal except for isolated thrombocytopenia with a platelet count of 40, 000/microL (40, 000/microL, 40 × 109/L, and 40,000 × 109/mL). Blood work showed a normal white blood cell count (9.2 × 103/microL), normal hemoglobin level (14.5 g/dl) and an absence of sinister cells or fragmentation in the peripheral smear. His renal function tests (creatinine 1.2 mg/dl), liver function tests, and electrolytes were normal.\n\nAfter reconfirming the low platelet count in citrated sample, extensive work- up was carried out to ascertain the cause. C - reactive protein (CRP) was within limits and blood and urine cultures showed no growth. Viral serologies and PCR based detection was negative for hepatitis B, hepatitis C, CMV and EBV. Serological workup was negative for Human Immunodeficiency Virus (HIV) and Brucella. Malaria was tested negative by smear and ICT method. Serology and stool antigen tests were negative for H. pylori. Autoimmune workup including ESR, antinuclear antibody (ANA), anti-double stranded DNA antibody (anti- dsDNA), extractable nuclear antigens profile (ENA profile), Coomb’s test (DAT) and lactate dehydrogenase (LDH) levels were normal. The patient was euthyroid clinically and biochemically. Abdominal imaging was also normal.\n\nThe drug chart was reviewed, and the dose of mycophenolate was reduced from 1 g/day to 500 mg/day without any effect on platelet counts, which remained within 40,000/microL (40× × 109/L) to 50,000/microL (50 × 109/L). While the bone marrow biopsy was being arranged, the dose of prednisolone was increased from 5 mg/day to 10 mg/day on December 10, 2015. Platelets showed a subsequent transient increase from 54,000/microL to 81,000/microL. In liaison with the hematologist, bone marrow biopsy was performed on December 23, 2015. It was negative for any infiltrative lesions and was consistent with peripheral destruction. In the month of January, while patient was still being maintained on 10 mg prednisolone, his platelets showed a progressive downward trend. While all other blood indices and chemistry parameters remained normal, he was re- admitted with platelet count of 29,000/microL. On January 16, 2016, his platelet counts dropped to 13,000/microL and he had an episode of mild epistaxis. 250 mg of pulse methylprednisolone was administered on Day 1 followed by 100 mg on Day 2. His platelet counts jumped to 48,000/microL on Day 3 and 80,000/microL on Day 5. His oral prednisolone was subsequently increased to 70 mg per day and TMP-SMX prophylaxis was reinstituted. The platelet counts showed adequate response and were within safe limits within 2 weeks. His blood sugars were well controlled with up- titration of both basal and bolus insulin. Steroids were gradually tapered over the next 10 weeks during which platelet counts remained steady and within safe limits (ranging from 90,000/microL to 180,000/microL). Mycophenolate was increased to 1 g per day upon tapering of the steroids. The patient was maintained on prednisolone 5 mg daily with excellent graft function and acceptable platelet counts for almost an entire year of follow-up (Fig. 1).Fig. 1 Platelet counts over time and response to treatment. Normal platelet counts are taken to be 150–450 × 103/microL. (SI units 150–450 × 109/L). Hemoglobin, RFT’s and LFT’s remained normal throughout this period\n\n\n\nDiscussion and conclusion\nBarring isolated thrombocytopenia, post-renal transplant cytopenias including anemias, bicytopenias and pancytopenias are relatively well studied and documented. The cause of thrombocytopenia is generally connected with suppression of other cell lines and includes immunosuppressive or antimicrobial drugs, infections, sepsis and malignancies [6]. The prevalence of thrombocytopenia < 100,000/microL (< 100 × 109/L) and severe thrombocytopenia < 50,000microL(< 50 × 109/L) after renal transplant, without specifying whether isolated or otherwise, was reported to be around 30% and 4% respectively in the adult Chinese population [7]. ITP in the setting of other solid organ transplants is comparatively well- reported. The incidence of new onset ITP post-orthotopic liver transplant was reported to be 0.7% in 1105 liver transplant patients over a period of 15 years at Ann Arbor University. Such cases are, however reported very rarely after renal transplant [2–5].\n\nIncluding the present case, all reported cases of new onset ITP post renal transplant, have been diagnosed in middle aged men. In the general population, however, ITP is more prevalent in 30- to 60-year-old females [2, 4, 5]. Orchard TR et al. reported successful treatment of ITP with steroids in a 33-year-old patient with IgA nephropathy who developed thrombocytopenia nine months after his kidney transplant while he was taking cyclosporine, prednisolone and azathioprine [4]. Talaulikar D. et al also reported ITP in a post- renal transplant setting in a 42-year-old male which was managed effectively with steroids [5]. Our case is the first reported instance of new- onset ITP in a patient with renal transplant for diabetic nephropathy.\n\nThe diagnosis of ITP is suggested by isolated thrombocytopenia with the peripheral blood smear helping to exclude microangiopathic hemolytic anemia, thrombotic thrombocytopenic purpura, platelet clumping, and hemolysis. Clinically apparent conditions involving viral infection, medications, malignancy, systemic disease, disseminated intravascular coagulation (DIC), and sepsis need to be ruled out and excluded. Hepatitis C and Human Immunodeficiency Virus testing is recommended for all adult patients with ITP [1]. Bone marrow biopsy is not mandatory but verifies ample megakaryocyte lineages and excludes infiltrative disorders and malignancy [1, 3, 8]. Routine testing for platelet specific antibodies is still not recommended for diagnosis and management of ITP [1, 3, 9]. In refractory cases, proponents find potential utility of a positive glycoprotein antibodies test from a reference laboratory, where available, as an adjunct to the clinical diagnosis [9]. Rapid response to steroids, when observed, is also suggestive of ITP and renders alloimmune thrombocytopenia less likely. Transplant- mediated alloimmune thrombocytopenia (TMAT) is another very rare entity causing isolated thrombocytopenia. Its clinical course is, however, explosive: generally presenting in early post-transplant period and refractory to usual medical interventions [10].\n\nWhile encountering cytopenias, the usual suspects in clinical practice are drugs and infections. We reviewed our patient’s chart carefully and tailored the prescription to the minimum number of drugs required. The dose of mycophenolate was reduced to half without any effect on cell indices. We emphasized strict dietary and lifestyle modifications, thereby withdrawing rosuvastatin and ranitidine without any subsequent effect on platelet counts. Our patient demonstrated no clinical signs of illness, infection or malignancy. His graft function and blood pressure remained stable. While excluding infection, it is important to keep local disease burdens in mind. Cases of thrombocytopenia have been reported with malaria, H. pylori and tuberculosis; which were excluded clinically and on laboratory and radiological parameters. H. pylori was tested negative by serology and stool antigen test. In addition to serologies, where pertinent, our work up included PCR based detection for common infections including CMV, Hepatitis B and Hepatitis C. Where clinically relevant and available, testing for Varicella zoster and Parvo-virus B19 could be considered. The donor was also evaluated, revealing normal blood indices and no evidence of infection in vaginal and urethral cultures. In periodic re- assessments during follow-up, the patient did not demonstrate any other disease indicators like anemia, leucopenia or lymph node enlargement.\n\nThe treatment of ITP in adults requires individualized comprehensive assessment of the patient’s occupation, bleeding risk, co- morbidities, therapy related side effects, cost implications and preference of the patient. Therapy is generally recommended for patients with a platelet count below 30,000/microL (< 30 × 109/L). Aside from thrombopoietin receptor agonists (TPO’s), most ITP therapies inhibit active B cells, T cells and/or monocytic-macrophage system. Steroids are the mainstay of treatment and act on the immune system globally by not only functionally diminishing reactivity of T- and B-cell; but also, by inducing tolerance patterns in dendritic cells, cytokines and T cells [11]. IVIG and anti- D can also be used in special circumstances. Second line options include splenectomy, rituximab and thrombopoietin receptor agonists. Rituximab in combination with steroids has been shown to diminish B cell lines while considerably increasing regulatory T cells [11]. Individual successes have been reported, albeit inconsistently, with azathioprine, cyclosporine, mycophenolate, cyclophosphamide, vincristine and danazol. Regardless of the therapy selected, the goal is to achieve patient- specific acceptable platelet counts that are sufficient to prevent bleeding; rather than attempting to bring the counts to normal ranges. Our patient showed a good response to steroid therapy and we were able to taper them to 5 mg over the course of 10 week. Platelet counts remained above 50,000/microL (50 × 109/L) throughout the course of follow-up, demonstrating sustained response to therapy. Strict lifestyle modification, dietary instructions, and close monitoring with appropriate titration of insulin kept his sugars within acceptable limits during the intensive steroid therapy phase. Since he is a driver by profession, he was counseled to switch from driving on highways to driving only on local routes, thereby minimizing the potential risk of high speed trauma. There was no resultant decline in his quality of life due to low platelet counts.\n\nIn adults with ITP, spontaneous remissions are reported in 10% of the patients, usually within the first six months. One- third to two- thirds of these patients will have persistent or chronic ITP with acceptable platelet counts either after first line therapy or after spontaneous remission [12, 13]. When treatment is needed, the longer duration of steroid therapy required in adults poses additional management challenges in relapses of new onset ITP post-transplant. Such challenges will exponentially increase if relapse is either steroid- dependent or refractory to steroids. The therapy thenceforth will have to be tailored to maintain a well-functioning renal graft, adequate hemostasis and minimum therapy- related morbidity to patient. Talaulikar D. et al. successfully treated relapse in their patient with intermediate low- dose steroids [5]. For our patient, the goal will be to keep the platelet counts above 30,000/microL (30 × 109/L) with the least number of medications possible. In the case of a first relapse, steroid therapy may suffice. IVIG with low- dose steroids are another option for such patients and will work best if disease remits early in its natural course. There is anecdotal evidence from local experience that azathioprine has a better response in ITP in our population. Switching from mycophenolate to azathioprine is another consideration with the aim of modifying the immune response that may allow sustained and acceptable platelet response in our patient. For steroid dependent or steroid refractory disease in our case, splenectomy can be reserved as the last resort considering allograft medications, local infection burden in hospital and patient preference. Recent reports show good short- term and modest long-term responses in ITP with rituximab alone or in conjunction with other agents as an option to avoid splenectomy. In fact, rituximab and splenectomy have both been used with some success for treating refractory ITP in the post- liver transplant setting [2].\n\nUncommonly, uremia and ITP can coexist in a single patient. Patients in remission, or those with platelet counts more than 75,000/microL (75 × 109/L), may choose dialysis or renal transplant with necessary adjustments. Severe thrombocytopenia, however, poses additional bleeding risks in either renal replacement modality. Isolated reports show that post-transplant immunosuppressive medication resulted in stable platelet counts in patients with ITP who underwent renal transplant [14]. Simultaneous splenectomy and renal transplant have also been carried out for steroid refractory ITP and chronic renal failure [15]. Post renal transplant ITP cases like these can help patients make informed decisions equipped with the knowledge of the possibility of persistence of ITP post-transplant; and can also help guide immunosuppressive regimens in such exceptional scenarios.\n\nOur case report highlights successful management of ITP with steroids in the setting of renal transplant and diabetic nephropathy. It would be interesting to see how the natural course of disease differs in post renal transplant setting than in normal adults. In addition to posing management challenges, such novel cases also open avenues for translational research and advancement in understanding of disease pathology and treatment responses.\n\nAbbreviations\nANAAntinuclear antibody\n\nAnti- dsDnaAnti-double stranded DNA antibody\n\nCMVCytomegalovirus\n\nCRPC - reactive protein\n\nDICDisseminated intravascular coagulation\n\nDMDiabetes mellitus\n\nEBVEpstein–Barr virus\n\nENA profileExtractable nuclear antigens profile\n\nESRErythrocyte sedimentation rate\n\nHIVHuman immunodeficiency virus\n\nITPImmune thrombocytopenic purpura\n\nLDHLactate dehydrogenase\n\nTMATTransplant mediated alloimmune thrombocytopenia\n\nTMP-SMXTrimethoprim-Sulphamethoxazole\n\nTPO’sThrombopoietin receptor agonists\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo support/funding was claimed or received by any author from any source for this work.\n\nAvailability of data and materials\nIf needed, the relevant material can be provided by corresponding author on reasonable request.\n\nAuthors’ contributions\nRMR, ZN were involved in diagnosis, management and follow-up of the patient since beginning. RMR, ZN, ZAA and QQ all contributed substantially and significantly to the literature review, drafting of the initial manuscript of case report, critical revision and its final version. All authors have participated sufficiently in the work to take public responsibility for the content. All the authors have contributed, read and approved the final and revised manuscript.\n\nEthics approval and consent to participate\nThe case report has been approved by hospital Ethics review committee; approval number: ERC/P-17/09/01. Written and informed consent was taken by patient to participate. No experimental medical intervention or experimental treatment was used for the particular clinical setting.\n\nConsent for publication\nThe case report does not include any specific identifiable personal details, images or videos. Written informed consent for publication of clinical details was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Neunert C Lim W Crowther M Cohen A Solberg L Jr Crowther MA The 1. American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia Blood 2011 117 16 4190 4420 10.1182/blood-2010-08-302984 21325604 \n2. Taylor RM Bockenstedt P Su GL Marrero JA Pellitier SM Fontana RJ Immune thrombocytopenic purpura following liver transplantation: a case series and review of the literature Liver Transpl 2006 12 781 791 10.1002/lt.20715 16628698 \n3. Diaz GC Prowda J Lo IJ Transplantation-mediated alloimmune thrombocytopenia: guidelines for utilization of thrombocytopenic donors Liver Transpl 2008 14 1803 10.1002/lt.21539 19025920 \n4. Orchard TR Neild GH Immune thrombocytopenic purpura presenting in an immunosuppressed patient after renal transplantation Nephrol Dial Transplant 1997 12 2436 2438 10.1093/ndt/12.11.2436 9394342 \n5. Talaulikar D Falk M Talaulikar G Pidcock M Immunethrombocytopenia after renal transplantation for IgA nephropathy Acta Haematol 2007 117 65 67 10.1159/000096855 17106188 \n6. Yang Y Yu B Chen Y Blood disorders typically associated with renal transplantation Front Cell Dev Biol 2015 3 18 10.3389/fcell.2015.00018 25853131 \n7. Xie L He S Fu L The prevalence and risk factors of thrombocytopenia after living-related renal transplantation in Chinese adult recipients Transplant Proc 2013 45 197 199 10.1016/j.transproceed.2012.09.113 23375299 \n8. Cines DB Blanchette VS Immune thrombocytopenic purpura N Engl J Med 2002 346 995 1008 10.1056/NEJMra010501 11919310 \n9. British Committee for Standards in Haematology General Haematology Task Force Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy Br J Haematol 2003 120 574 596 10.1046/j.1365-2141.2003.04131.x 12588344 \n10. West KA Anderson DR McAlister VC Hewlett TJ Belitsky P Smith JW Alloimmune thrombocytopenia after organ transplantation N Engl J Med 1999 341 1504 1507 10.1056/NEJM199911113412004 10559451 \n11. Johnsen J Pathogenesis in immune thrombocytopenia: new insights Hematology Am Soc Hematol Educ Program 2012 2012 306 312 23233597 \n12. Neylon AJ Saunders PW Howard MR Proctor SJ Taylor PR Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients Br J Haematol 2003 122 6 966 974 10.1046/j.1365-2141.2003.04547.x 12956768 \n13. Rodeghiero F Stasi R Gernsheimer T Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group Blood 2009 113 2386 2393 10.1182/blood-2008-07-162503 19005182 \n14. Einollahi B Renal transplantation and idiopathic thrombocytopenic purpura: two case reports Transplant Proc 2009 41 7 2923 10.1016/j.transproceed.2009.07.010 19765475 \n15. Hwang EM Woo HY Choi BS Yang CW Kim YS Moon IS Bang BK Renal transplantation in a patient with idiopathic thrombocytopenic purpura Korean J Intern Med 2005 20 1 92 95 10.3904/kjim.2005.20.1.92 15906962\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "19(1)",
"journal": "BMC nephrology",
"keywords": "Immune thrombocytopenic purpura (ITP); Immunosuppression; Post-transplant thrombocytopenia; Renal transplant",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D003928:Diabetic Nephropathies; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D016553:Purpura, Thrombocytopenic, Idiopathic",
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"pages": "69",
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"pmid": "29554892",
"pubdate": "2018-03-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Immune thrombocytopenic purpura presenting in a patient after renal transplant for diabetic nephropathy.",
"title_normalized": "immune thrombocytopenic purpura presenting in a patient after renal transplant for diabetic nephropathy"
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"abstract": "Metformin is one of the most widely prescribed medications for type 2 diabetes. While extremely rare, metformin has been reported to cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. In this paper, we present a case of a patient with previously undiagnosed glucose-6-phosphate dehydrogenase deficiency who presented with hemolysis likely induced by metformin. The patient concurrently presented with idiopathic Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Metformin causing hemolysis is extremely rare but considering the severe outcomes, it is something that medical practitioners need to be aware of.",
"affiliations": "Internal Medicine, The University of Western Australia (UWA) Medical School, Perth, AUS.;Internal Medicine, Texila American University, Texas, USA.;Internal Medicine, Xavier University School of Medicine, Oranjestad, ABW.;Family Medicine, Western Australian General Practice Education and Training (WAGPET), Bentley, AUS.",
"authors": "Roy Choudhury|Avijoy|A|;Gadaga|Cecilia|C|;Moodley|Layuren|L|;Moodley|Aru|A|",
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"doi": "10.7759/cureus.18506",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18506\nInternal Medicine\nAllergy/Immunology\nHematology\nMetformin-Induced Hemolysis in a Patient With Glucose-6-Phosphate Dehydrogenase Deficiency Presenting With Concurrent Idiopathic Steven-Johnson Syndrome/Toxic Epidermal Necrolysis\nMuacevic Alexander\nAdler John R\nRoy Choudhury Avijoy 1\nGadaga Cecilia 2\nMoodley Layuren 3\nMoodley Aru 45\n1 Internal Medicine, The University of Western Australia (UWA) Medical School, Perth, AUS\n2 Internal Medicine, Texila American University, Texas, USA\n3 Internal Medicine, Xavier University School of Medicine, Oranjestad, ABW\n4 Family Medicine, Western Australian General Practice Education and Training (WAGPET), Bentley, AUS\n5 Medicine, The University of Notre Dame Australia, Fremantle, AUS\nAvijoy Roy Choudhury avrchoudhury@gmail.com\n5 10 2021\n10 2021\n13 10 e185065 10 2021\nCopyright © 2021, Roy Choudhury et al.\n2021\nRoy Choudhury et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/72228-metformin-induced-hemolysis-in-a-patient-with-glucose-6-phosphate-dehydrogenase-deficiency-presenting-with-concurrent-idiopathic-steven-johnson-syndrometoxic-epidermal-necrolysis\nMetformin is one of the most widely prescribed medications for type 2 diabetes. While extremely rare, metformin has been reported to cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. In this paper, we present a case of a patient with previously undiagnosed glucose-6-phosphate dehydrogenase deficiency who presented with hemolysis likely induced by metformin. The patient concurrently presented with idiopathic Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Metformin causing hemolysis is extremely rare but considering the severe outcomes, it is something that medical practitioners need to be aware of.\n\nglucose-6-phosphate-dehydrogenase deficiency (g6pd)\n: metformin\nhemolytic anemia\ntoxic epidermal necrolysis (ten)\nsteven johnson syndrome\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nMetformin is an oral medication that is commonly used in the treatment of type 2 diabetes mellitus. The common adverse effects of metformin include gastrointestinal symptoms, vital B12 deficiency, and lactic acidosis [1]. That being said, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemolytic anemia is a rare complication that may arise [2,3]. In this case report, we outline a patient with a previously undiagnosed G6PD deficiency that had an episode of hemolytic anemia following the administration of metformin. Furthermore, the patient had a concurrent episode of idiopathic Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). This report aims to alert that metformin can induce hemolysis in patients with G6PD deficiency. Furthermore, this report also aims to emphasize the importance of investigating G6PD deficiency in patients presenting with hemolytic anemia.\n\nCase presentation\n\nA 35-year-old African American female with a past medical history of type 2 diabetes mellitus, hypertension, and iron-deficient anemia presented to the hospital with fever, chills, and a diffuse erythematous rash which got worse after taking her current usual medications which are metformin, losartan, and simvastatin. The patient had been taking metformin, losartan, and simvastatin for greater than 12 months. Approximately 12 hours following the initial presentation, the erythematous rash became more extensive and skin peeling was present. Nikolsky sign was positive. Mucosal membrane involvement was present with severe conjunctivitis characterized by conjunctival injections and photophobia.\n\nComprehensive investigations were conducted for this patient which included a complete blood count. The patient had lab results conducted eight weeks prior by her primary care physician. The lab results from eight weeks prior showed the patient’s hemoglobin as 12.9 g/dL and her platelet count as 125,000 mm3. In comparison to those results, the patient had drastic falls in her hemoglobin and platelet levels on initial presentation as her hemoglobin was 10.0 g/dL and her platelet count was 90,000 mm3. Furthermore, following the administration of the patient’s regular medications, there was an even further fall in the patient’s hemoglobin and platelet levels. These results showed a hemoglobin level of 8.2 g/dL and a platelet level of 60,000 mm3 (Table 1). A direct Coombs test was conducted, which was negative ruling out Evans Syndrome. Furthermore, an indirect Coombs test was conducted which positive thus suggested that hemolysis was present. Furthermore, bilirubin levels were increased from eight weeks prior to initial presentation and further increased during lab results completed following administration of the patient's regular medications (Table 1). The results from other blood labs including lipid screen, glucose, HbA1C, urea, electrolytes, and creatinine were stable. \n\nTable 1 Blood laboratory results of the patient\n\n \t8 Weeks Prior to Admission\tAt Admission\tFollowing Administration of Regular Medication\t\nNa+\t141 mEq/L\t136 mEq/L\t140 mEq/L\t\nK+\t 4.5 mEq/L\t 4.3 mEq/L\t4.3 mEq/L\t\nCl-\t101 mEq/L\t100 mEq/L\t107 mEq/L\t\nGlucose (serum)\t81 mg/dL\t93 mg/dL\t89 mg/dL\t\nBilirubin (total)\t2.1 mg/dL\t3.8 mg/dL\t7.0 mg/dL\t\nCreatinine (serum)\t1.0 mg/dL\t1.1 mg/dL\t0/87 mg/dL\t\nBlood Urea Nitrogen\t12.2 mg/dL\t13.0 mg/dL\t12.7 mg/dL\t\nCholesterol\t150 mg/dL\t155 mg/dL\t146 mg/dL\t\nTriglycerides \t92 mg/dL\t89 mg/dL\t95 mg/dL\t\nHemoglobin\t12.9 g/dL\t10.0 g/dL\t8.2 g/dL\t\nMean Corpuscular Volume\t69.2 μm3\t68.8 μm3\t68.8 μm3\t\nWhite Blood Cell Count\t8,900/mm3\t16,000/mm3\t16.000/mm3\t\nPlatelet Count\t125,000/mm3\t90,000/mm3\t60,000/mm3\t\n\nFurther investigating the patient’s hemolysis, testing was conducted which showed that the patient had a G6PD deficiency with a level of less than 8.8 units per gram of hemoglobin. Following this finding, the hemolysis was diagnosed as metformin-induced hemolytic anemia in a patient with G6PD deficiency. The metformin was ceased and the patient's hemolytic anemia improved. \n\nLooking at the erythematous rash, SJS with an overlap of TEN was suspected resulting in detailed differential analysis. The patient denied taking any sulfur-containing drugs, sulfate antibiotics, or hydralazine. The patient did not have any porphyria as per the uroporphyrinogen test and the paraneoplastic of the young was statistically unlikely. Herpes simplex virus screen, hepatitis C virus screen, and mycoplasma screen were all negative. Streptococcal scalded skin syndrome was ruled out as presentation had mucosal involvement with conjunctivitis. The patient had no history of malignancy and there was no family history of SJS or TEN. Furthermore, the patient had no immunosuppressive conditions and was taking no immunosuppressive medication. Following a thorough investigation, idiopathic SJS/TEN was diagnosed.\n\nIn treating the SJS/TEN overlap, the patient was stabilized and the patient underwent skin grafts to treat the condition.\n\nDiscussion\n\nMetformin is a biguanide and the first-line pharmacological treatment for type 2 diabetes mellitus. The drug acts on the liver where it inhibits gluconeogenesis while also having insulin sensitivity enhancement effects [1]. Common adverse effects of metformin include gastrointestinal symptoms such as mild anorexia, nausea, abdominal discomfort, and diarrhea. Vitamin B12 deficiency is also an adverse effect of metformin while lactic acidosis is a rare, but potentially fatal, complication [4].\n\nIn patients with G6PD deficiency, there have been reports of metformin inducing hemolytic anemia. G6PD deficiency is an X-linked recessive disorder resulting in an inborn error of metabolism that predisposes to the breakdown of red blood cells [5]. Hemolysis in patients with G6PD deficiency is commonly caused by bacterial or viral infections. Many drugs also induce hemolysis in patients with G6PD deficiency with the common drugs being dapsone, flutamide, mafenide cream, methylene blue, nalidixic acid, nitrofurantoin, phenazopyridine, primaquine, rasburicase, sulfacetamide, sulfamethoxazole, and sulfanilamide. Fava beans are also a common trigger for hemolysis in G6PD deficient patients. Triggers such as certain drugs, fava beans, or infections result in the build-up of reactive oxygen species inside the cell and with a deficiency of G6PD, these reactive oxygen species cannot be broken down. This build-up of reactive oxygen species results in hemolysis [6].\n\nThe incidence of metformin inducing hemolytic anemia in G6PD deficient patients is very low, but it has been reported in case reports in the past. A common feature in the majority of the reports is that the hemolysis took place within the first 12 days of starting metformin [2,3]. Developing an undeniable diagnosis of metformin causing hemolysis is impossible but, in this case, considering the lack of commonly known triggers, it is a likely cause of the hemolytic anemia. Although very rare, medical practitioners should be aware of metformin inducing hemolytic anemia as it can lead to serious and potentially fatal outcomes.\n\nThere have been no reports relating metformin administration causing SJS or TEN. A hypothesis was presented in 2007 which suggested G6PD deficiency could be a risk factor for the development of TEN but this was not followed further, and no further evidence has been presented on this concept [7]. SJS/TEN is commonly triggered by certain medications or infections. The common medications include allopurinol, nevirapine, aromatic antiseizure medication, and antibacterial sulfonamides while Mycoplasma pneumoniae is a common infectious cause [8,9]. That being said, over 33% of presentations of SJS or TEN have been idiopathic [10]. Considering this patient had no significant risk factors for SJS or TEN, such as HIV infection, systemic lupus erythematosus, malignancy, or family history of SJS/TENS, a definite cause could not be found. As a result, the diagnosis of idiopathic SJS/TEN was made.\n\nConclusions\n\nWe have reported the case of a 35-year-old female with previously undiagnosed G6PD deficiency who presented with hemolysis likely related to the administration of metformin. Furthermore, this patient concurrently presented with idiopathic SJS/TEN. Hemolysis induced by metformin is extremely rare but it has been reported in the literature. Despite the rare nature of the occurrence, medical practitioners should be aware of this adverse effect of metformin as it has severe outcomes.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 The mechanisms of action of metformin Diabetologia Rena G Hardie DG Pearson ER 1577 1585 60 2017 28776086\n2 Metformin-induced hemolytic anemia in a patient with glucose-6-phosphate dehydrogenase deficiency Diabetes Care Meir A Kleinman Y Rund D Da'as N 956 957 26 2003 12610074\n3 Metformin-induced hemolytic anemia in a patient with glucose-6-phosphate dehydrogenase deficiency Am J Ther Ruggiero NA Kish TD Lee ML 0 8 23 2016\n4 Metformin in 2019 JAMA Flory J Lipska K 1926 1927 21 2019\n5 Glucose-6-phosphate dehydrogenase deficiency Lancet Fiorelli G 64 74 5 2008\n6 Glucose-6-phosphate dehydrogenase deficiency Hematol Oncol Clin North Am Luzzatto L Nannelli C Notaro R 373 393 30 2016 27040960\n7 Glucose-6-phosphate-dehydrogenase deficiency is a possible risk factor for the development of toxic epidermal necrolysis Med Hypotheses Namazi MR 466 467 68 2007 17011137\n8 Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol Mockenhaupt M Viboud C Dunant A 35 44 128 2008 17805350\n9 Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic Mayo Clin Proc Wetter DA Camilleri MJ 131 138 85 2010 20118388\n10 ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis Clin Pharmacol Ther Sassolas B Haddad C Mockenhaupt M 60 68 88 2010 20375998\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": ": metformin; glucose-6-phosphate-dehydrogenase deficiency (g6pd); hemolytic anemia; steven johnson syndrome; toxic epidermal necrolysis (ten)",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e18506",
"pmc": null,
"pmid": "34754666",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "20375998;17805350;28776086;27040960;31009043;12610074;17011137;25756470;20118388",
"title": "Metformin-Induced Hemolysis in a Patient With Glucose-6-Phosphate Dehydrogenase Deficiency Presenting With Concurrent Idiopathic Steven-Johnson Syndrome/Toxic Epidermal Necrolysis.",
"title_normalized": "metformin induced hemolysis in a patient with glucose 6 phosphate dehydrogenase deficiency presenting with concurrent idiopathic steven johnson syndrome toxic epidermal necrolysis"
} | [
{
"companynumb": "AU-MACLEODS PHARMACEUTICALS US LTD-MAC2021033461",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "A case of fatty liver of pregnancy with subcapsular hematoma of the liver caused by intravenous heparin treatment is reported. The heparin was given for the thrombophlebitis of leg veins. The patient expired suddenly as a result of rupture of the subcapsular hematoma of the liver causing massive intraperitoneal hemorrhage. The pathophysiology and complications of the fatty liver of pregnancy are discussed.",
"affiliations": null,
"authors": "Roh|L S|LS|",
"chemical_list": "D006493:Heparin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "31(4)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D005234:Fatty Liver; D005260:Female; D006406:Hematoma; D006493:Heparin; D006801:Humans; D008099:Liver; D011247:Pregnancy; D011248:Pregnancy Complications; D011249:Pregnancy Complications, Cardiovascular; D012421:Rupture; D013924:Thrombophlebitis",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1509-13",
"pmc": null,
"pmid": "3783118",
"pubdate": "1986-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Subcapsular hematoma in fatty liver of pregnancy.",
"title_normalized": "subcapsular hematoma in fatty liver of pregnancy"
} | [
{
"companynumb": "US-PFIZER INC-2020487860",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Paracetamol poisoning is manifested by hepatotoxicity, but acute renal failure is very rare, especially when there is no fulminant hepatic damage with encephalopathy or severe haemodynamic alterations. We present here the case of a 22-year-old woman who presented with acute renal failure after the ingestion of 11.5 g of acetaminophen. The clinical course and laboratory data were consistent with tubular necrosis. The patient required hemodialysis, but finally renal function returned to normal. The acetaminophen pharmacology and the differential diagnosis of acute azotemia in paracetamol overdosage are reviewed.",
"affiliations": "Sección de Nefrología, Hospital San Pedro de Alcántara, Avda. Millán Astray, s/n. 10003 Cáceres.",
"authors": "Herrero|J L|JL|;Castellano|I|I|;Gómez-Martino|J R|JR|;Novillo|R|R|;Covarsí|A|A|",
"chemical_list": "D000082:Acetaminophen",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0211-6995",
"issue": "21(6)",
"journal": "Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia",
"keywords": null,
"medline_ta": "Nefrologia",
"mesh_terms": "D000082:Acetaminophen; D058186:Acute Kidney Injury; D000328:Adult; D001780:Blood Coagulation Tests; D056486:Chemical and Drug Induced Liver Injury; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D007683:Kidney Tubular Necrosis, Acute; D008111:Liver Function Tests; D009325:Nausea; D006435:Renal Dialysis; D013406:Suicide, Attempted; D014839:Vomiting",
"nlm_unique_id": "8301215",
"other_id": null,
"pages": "592-5",
"pmc": null,
"pmid": "11881430",
"pubdate": "2001",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute kidney failure caused by paracetamol poisoning.",
"title_normalized": "acute kidney failure caused by paracetamol poisoning"
} | [
{
"companynumb": "ES-RANBAXY-2014RR-91401",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nChildren with nephrotic syndrome can develop life-threatening complications, including infection and thrombosis. While AKI is associated with adverse outcomes in hospitalized children, little is known about the epidemiology of AKI in children with nephrotic syndrome. The main objectives of this study were to determine the incidence, epidemiology, and hospital outcomes associated with AKI in a modern cohort of children hospitalized with nephrotic syndrome.\n\n\nMETHODS\nRecords of children with nephrotic syndrome admitted to 17 pediatric nephrology centers across North America from 2010 to 2012 were reviewed. AKI was classified using the pediatric RIFLE definition.\n\n\nRESULTS\nAKI occurred in 58.6% of 336 children and 50.9% of 615 hospitalizations (27.3% in stage R, 17.2% in stage I, and 6.3% in stage F). After adjustment for race, sex, age at admission, and clinical diagnosis, infection (odds ratio, 2.24; 95% confidence interval, 1.37 to 3.65; P=0.001), nephrotoxic medication exposure (odds ratio, 1.35; 95% confidence interval, 1.11 to 1.64; P=0.002), days of nephrotoxic medication exposure (odds ratio, 1.10; 95% confidence interval, 1.05 to 1.15; P<0.001), and intensity of medication exposure (odds ratio, 1.34; 95% confidence interval, 1.09 to 1.65; P=0.01) remained significantly associated with AKI in children with nephrotic syndrome. Nephrotoxic medication exposure was common in this population, and each additional nephrotoxic medication received during a hospitalization was associated with 38% higher risk of AKI. AKI was associated with longer hospital stay after adjustment for race, sex, age at admission, clinical diagnosis, and infection (difference, 0.45 [log]days; 95% confidence interval, 0.36 to 0.53 [log]days; P<0.001).\n\n\nCONCLUSIONS\nAKI is common in children hospitalized with nephrotic syndrome and should be deemed the third major complication of nephrotic syndrome in children in addition to infection and venous thromboembolism. Risk factors for AKI include steroid-resistant nephrotic syndrome, infection, and nephrotoxic medication exposure. Children with AKI have longer hospital lengths of stay and increased need for intensive care unit admission.",
"affiliations": "Due to the number of contributing authors, the affiliations are provided in the Supplemental Material. rheau002@umn.edu.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.;Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.",
"authors": "Rheault|Michelle N|MN|;Zhang|Lei|L|;Selewski|David T|DT|;Kallash|Mahmoud|M|;Tran|Cheryl L|CL|;Seamon|Meredith|M|;Katsoufis|Chryso|C|;Ashoor|Isa|I|;Hernandez|Joel|J|;Supe-Markovina|Katarina|K|;D'Alessandri-Silva|Cynthia|C|;DeJesus-Gonzalez|Nilka|N|;Vasylyeva|Tetyana L|TL|;Formeck|Cassandra|C|;Woll|Christopher|C|;Gbadegesin|Rasheed|R|;Geier|Pavel|P|;Devarajan|Prasad|P|;Carpenter|Shannon L|SL|;Kerlin|Bryce A|BA|;Smoyer|William E|WE|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.06620615",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "10(12)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "acute kidney injury; child; dialysis; hospitalization; humans; incidence; length of stay; nephrotic syndrome; nephrotoxicity; risk factors",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D007223:Infant; D007902:Length of Stay; D016014:Linear Models; D008297:Male; D008499:Medical Records; D015999:Multivariate Analysis; D009404:Nephrotic Syndrome; D009656:North America; D016017:Odds Ratio; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "2110-8",
"pmc": null,
"pmid": "26450933",
"pubdate": "2015-12-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "951142;25649155;3781676;17396113;17331245;11068633;12777562;19158356;19651590;20124891;21332335;20936523;21212419;21412214;21663616;22240130;22344511;22200895;23471414;23314441;23434062;23940245;23833312;24100738;24037143;24009223;24785560;25024752;23394211;25280497;7468609",
"title": "AKI in Children Hospitalized with Nephrotic Syndrome.",
"title_normalized": "aki in children hospitalized with nephrotic syndrome"
} | [
{
"companynumb": "US-JNJFOC-20160225587",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Thrombotic complications are common in patients with severe COVID-19 pneumonia with important consequences on the diagnostic and therapeutic management. We report a consecutive series of five patients on long-term oral anticoagulation therapy who presented to our hospital for severe COVID-19 pneumonia associated with segmental acute pulmonary embolism despite adherence to therapy and with an adequate anticoagulant range at the time of the event. Four patients were receiving a direct oral anticoagulant (two with edoxaban, one with rivaroxaban and one with apixaban) and one patient a vitamin K antagonist. No significant thrombotic risk factors, active cancer, or detectable venous thromboembolism were present. In all cases, elevated d-dimer and fibrinogen levels with a parallel rise in markers of inflammation were documented. The combination of these findings seems to support the hypothesis that considers the local vascular damage determined by severe viral infection as the main trigger of thrombi detected in the lungs, rather than emboli from peripheral veins.",
"affiliations": "Cardiology Unit, Cremona Hospital, Cremona, Italy.;Maxillo-Facial Surgery Unit, Head and Neck Department, Santi Paolo e Carlo University Hospital, Università degli Studi di Milano, Milan, Italy.;Pneumology Unit, Cremona Hospital, Cremona, Italy.;Pneumology Unit, Cremona Hospital, Cremona, Italy.;Cardiology Unit, Cremona Hospital, Cremona, Italy.;Cardiology Unit, Cremona Hospital, Cremona, Italy.;Cardiology Unit, Cremona Hospital, Cremona, Italy. gbdanzi@gmail.com.",
"authors": "Di Tano|Giuseppe|G|;Dede|Meghi|M|;Pellicelli|Irene|I|;Martinelli|Enrico|E|;Moschini|Luigi|L|;Calvaruso|Elva|E|;Danzi|Gian Battista|GB|http://orcid.org/0000-0003-0897-8006",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-021-02589-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": null,
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Anticoagulant; Infectious diseases; Pulmonary embolism",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": null,
"nlm_unique_id": "9502018",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34708314",
"pubdate": "2021-10-27",
"publication_types": "D016428:Journal Article",
"references": "24859362;32219356;32422076;28249326;32421381;32374815;23809127;32473124;32291094;18955643;32325026;32320517;32227120;32297089;29433148;22797452;28483766;32349132;28405675;32311448;32220112;31402914;32330083;29562325",
"title": "Pulmonary embolism in patients with COVID-19 pneumonia on adequate oral anticoagulation.",
"title_normalized": "pulmonary embolism in patients with covid 19 pneumonia on adequate oral anticoagulation"
} | [
{
"companynumb": "IT-DSJP-DSE-2022-113129",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EDOXABAN"
},
"drugadditional": "3",
"... |
{
"abstract": "Coronavirus Disease-2019 (COVID-19), an infectious disease associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global emergency with high mortality. There are few effective treatments, and many severe patients are treated in an intensive care unit (ICU). The purpose of this study was to evaluate whether the Japanese Kampo medicine ninjin'yoeito (NYT) is effective in treating ICU patients with COVID-19. Nine patients with confirmed SARS-CoV-2 infection admitted to the ICU were enrolled in this study. All patients underwent respiratory management with invasive mechanical ventilation (IMV) and enteral nutrition. Four patients received NYT (7.5 g daily) from an elemental diet tube. We retrospectively examined the prognostic nutritional index (PNI), length of IMV, length of ICU stay, length of hospital stay, rate of tracheostomy, and mortality rate. The median age of the enrolled participants was 60.0 years (4 men and 5 women). The median body mass index was 27.6. The most common comorbidity was diabetes (4 patients, 44%), followed by hypertension (3 patients, 33%) and chronic kidney disease (2 patients, 22%). The median length of IMV, ICU stay, and hospital stay were all shorter in the NYT group than in the non-NYT group (IMV; 4.0 days vs 14.3 days, ICU; 5.3 days vs 14.5 days, hospital stay; 19.9 days vs 28.2 days). In the NYT and non-NYT groups, the median PNI at admission was 29.0 and 31.2, respectively. One week after admission, the PNI was 30.7 in the NYT group and 24.4 in non-NYT group. PNI was significantly (p = 0.032) increased in the NYT group (+13.6%) than in the non-NYT group (-22.0%). The Japanese Kampo medicine NYT might be useful for treating patients with severe COVID-19 in ICU. This study was conducted in a small number of cases, and further large clinical trials are necessary.",
"affiliations": "Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan; Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan. Electronic address: hong_shim@yahoo.co.jp.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Infectious Diseases, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Emergency and Critical Care Medical center, Osaka City General Hospital, Osaka, Japan.;Department of Breast Surgical Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan.;Department of Infectious Diseases, Osaka City General Hospital, Osaka, Japan.;Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan.",
"authors": "Aomatsu|Naoki|N|;Shigemitsu|Kazuaki|K|;Nakagawa|Hidenori|H|;Morooka|Takaya|T|;Ishikawa|Junichi|J|;Yamashita|Tomoya|T|;Tsuruoka|Ayumu|A|;Fuke|Akihiro|A|;Motoyama|Koka|K|;Kitagawa|Daiki|D|;Ikeda|Katsumi|K|;Maeda|Kiyoshi|K|;Shirano|Michinori|M|;Rinka|Hiroshi|H|",
"chemical_list": "D004365:Drugs, Chinese Herbal; C000709707:ninjin'yoeito",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.npep.2021.102201",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0143-4179",
"issue": "90()",
"journal": "Neuropeptides",
"keywords": "COVID-19; Intensive care unit; Kampo; Ninjin'yoeito; Pneumonia; Prognostic nutritional index; SARS-CoV-2",
"medline_ta": "Neuropeptides",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D002318:Cardiovascular Diseases; D003131:Combined Modality Therapy; D015897:Comorbidity; D003920:Diabetes Mellitus; D004365:Drugs, Chinese Herbal; D004750:Enteral Nutrition; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007564:Japan; D007674:Kidney Diseases; D007902:Length of Stay; D008297:Male; D020835:Medicine, Kampo; D008875:Middle Aged; D015596:Nutrition Assessment; D012121:Respiration, Artificial; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "8103156",
"other_id": null,
"pages": "102201",
"pmc": null,
"pmid": "34753072",
"pubdate": "2021-12",
"publication_types": "D016422:Letter",
"references": null,
"title": "Efficacy of Ninjin'yoeito in treating severe coronavirus disease 2019 in patients in an intensive care unit.",
"title_normalized": "efficacy of ninjin yoeito in treating severe coronavirus disease 2019 in patients in an intensive care unit"
} | [
{
"companynumb": "JP-GILEAD-2022-0566958",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "REMDESIVIR"
},
"drugadditional": "4",
... |
{
"abstract": "Neuropsychiatric and gastrointestinal side effects of opioids are well documented, but self-reported hearing disturbance from opioids is often unrecognized. Two cases are presented illustrating a possible association between auditory symptoms and opioid toxicity. Possible mechanisms are discussed.",
"affiliations": null,
"authors": "Cran|Alison|A|;Kiely|Fiona|F|;O'Brien|Tony|T|",
"chemical_list": "D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D004091:Hydromorphone",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2014.959233",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "28(4)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "auditory symptoms; hearing disturbance; opioid; toxicity",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D005260:Female; D006311:Hearing Disorders; D006801:Humans; D004091:Hydromorphone; D055104:Infusions, Subcutaneous; D008875:Middle Aged",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "378-81",
"pmc": null,
"pmid": "25299483",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Auditory symptoms as an unrecognized manifestation of opioid toxicity: two case reports.",
"title_normalized": "auditory symptoms as an unrecognized manifestation of opioid toxicity two case reports"
} | [
{
"companynumb": "GB-WATSON-2015-20574",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE"
},
"drugadditional": null,
... |
{
"abstract": "A lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump.\n\n\nCONCLUSIONS\nAnti-insulin antibodies may result in low levels of free insulin.Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.",
"affiliations": "Harrogate District Hospital Harrogate, HG2 7SX UK.;Leeds Children's Hospital NHS Trust Leeds UK.;Leeds Children's Hospital NHS Trust Leeds UK.;Wellcome Trust Cambridge University Hospital Cambridge UK.;Clinical Biochemistry Department Addenbrooke's Hospital Cambridge UK.;SAS Peptides Hormone Section Royal Surrey County Hospital Surrey UK.;Blood Sciences Department Leeds Teaching Hospitals NHS Trust Leeds UK.",
"authors": "Jassam|N|N|;Amin|N|N|;Holland|P|P|;Semple|R K|RK|;Halsall|D J|DJ|;Wark|G|G|;Barth|J H|JH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-13-0086",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol EDM13008610.1530/EDM-13-0086Diabetes, Rare diseases/syndromesAnalytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome Challenges in a patient with type 1 diabetesJassam N Amin N 1Holland P 1Semple R K 2Halsall D J 3Wark G 4Barth J H 5Harrogate District HospitalHarrogate, HG2 7SXUK1 Leeds Children's Hospital NHS TrustLeedsUK2 Wellcome TrustCambridge University HospitalCambridgeUK3 Clinical Biochemistry DepartmentAddenbrooke's HospitalCambridgeUK4 SAS Peptides Hormone SectionRoyal Surrey County HospitalSurreyUK5 Blood Sciences DepartmentLeeds Teaching Hospitals NHS TrustLeedsUKCorrespondence should be addressed to N Jassam Email: Nuthar.Jassam@hdft.nhs.uk01 4 2014 2014 2014 13008616 2 2014 25 2 2014 © 2014 The authors2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nA lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump.\n\nLearning points\n\nAnti-insulin antibodies may result in low levels of free insulin.\n\nPolyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.\n\nIn this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.\n\nIt is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.\n\nA prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.\n==== Body\nBackground\nInsulin autoimmune syndrome (IAS or Hirata's disease) is a common cause of hypoglycaemia and mild insulin resistance that has most frequently been described in Japan, but is very rare within the Caucasian population (1). In this condition, circulating insulin autoantibodies are generated against endogenous insulin in patients who have not been exposed to exogenous insulin (2).\n\nAmong diabetic patients treated with recombinant human insulin, antibodies created against exogenous insulin are also a common phenomenon and hypoglycaemia has been seen in cases where insulin antibodies are present in the circulation (3). Hypoglycaemia in insulin-treated patients may occur because of the release of the hormone from the circulating insulin–antibody complex, but in general, these antibodies rarely affect the course of the disease, the daily insulin requirements or the glycaemic control (4). However, there have been a few cases worldwide where patients with type 1 diabetes treated with recombinant human insulin have developed a high titre of circulating insulin antibodies. The presence of these antibodies has led to unstable glycaemic control, resulting in a severe form of insulin resistance (5)\n(6). Previous treatment has been with double filtration plasmapheresis followed by prednisolone and/or mycophenolate mofetil (5)\n(6).\n\nInsulin resistance associated with s.c. insulin administration is another uncommon condition that complicates T1DM management (7). This condition is characterised by decreased sensitivity to s.c., but not i.v. insulin. The pathophysiology of subcutaneous insulin resistance (SIR) is not well understood. Other than immune-mediated insulin resistance, mechanisms such as increased enzymatic activity leading to rapid insulin degradation at the injection site, poor insulin diffusion or insulin sequestration in the adipose tissue have been proposed but not sufficiently documented (8)\n(9).\n\nIn this paper, we report a patient with type 1 diabetes with a form of immune-mediated insulin resistance, in which the insulin resistance has been developed as a result of the presence of circulating insulin antibodies, with possible tissue resistance to subcutaneous insulin. We have described the clinical course of this patient, with use of surrogate markers to monitor disease activity and treatment modalities used to maintain normoglycaemia.\n\nCase presentation\nA lean 15-year-old white Caucasian female was diagnosed with type 1 diabetes. At the time of diagnosis, the patient presented with polyuria, polydipsia and a random glucose of 20 mmol/l. She tested positive for anti-gliadin antibodies and islet cell antibodies. She had no significant illness prior to this and there was no family history of diabetes or any other autoimmune diseases. Examination found no features of insulin resistance. She had good glycaemic control during the first 6 months following diagnosis. Her plasma HbA1c was maintained at 58 mmol/mol with s.c. Mixtard 30, in a dose of 32 units twice daily, which was increased to four times a day within two months of diagnosis. She had never received animal-derived insulin preparation.\n\nAfter 8 months from the time of diagnosis, the patient reported cyclical swings in her insulin requirements according to her menstrual cycle. Her insulin requirements in the first 2 weeks of the cycle were around 60 units/day. This was followed by a week where the insulin requirement rose to 90–120 units/day, and within 4 months her insulin requirements were 280 units/day, with little effect on blood glucose levels. This period was usually followed by a week when she required no insulin to be administered (average glucose of 3.2 mmol/l).\n\nAfter 2 months, the cyclical swings of insulin became worse. Her insulin requirements continued to rise up to 300 U/day. These periods were usually preceded by intervals of hyperglycaemia and ketosis that resulted in repeated admission to the intensive care unit, where the patient was managed with i.v. insulin. Furthermore, the period when insulin was not required became shorter and was followed by long periods of hypoglycaemia. The hypoglycaemic episodes were very severe, with un-recordable glucose concentrations, and the patient required continuous infusions with 15–20% dextrose at an infusion rate of 200 ml/h for up to 2 weeks. Any interruption in i.v. infusion of dextrose led to the immediate recurrence of hypoglycaemia. These episodes became recurrent and nocturnal. Surreptitious insulin self-administration or insulin administration by proxy was considered but no evidence was found.\n\nInvestigation\nIn view of the cyclical swings in insulin requirements, a number of laboratory tests were performed. Biochemical tests for luteinising and follicle hormones, thyroid hormones, cortisol and growth hormone were all within the normal range. During episodes of severe hypoglycaemia, when i.v. insulin administration had been stopped, blood insulin concentrations were markedly elevated at 10 750 pmol/l, with appropriate C-peptide levels of <94 pmol/l. Insulin and C-peptide levels vary greatly depending on glucose levels, but in patients with no anti-insulin antibodies the ratio is typically maintained at 1:5–1:10 (insulin:C-peptide). In patients with anti-insulin antibodies, the half-life for insulin becomes much longer, making the results more difficult to interpret.\n\nIn the insulin immunoassay, the high titre of the circulating anti-insulin antibodies is considered to be the interfering substance (10), hence insulin measurement alone becomes unreliable. Instead, insulin recovery as a percentage of free insulin (before polyethylene glycol (PEG) 6000 precipitation) to total insulin after PEG precipitation is required to give an accurate functioning insulin level. On the patient's admission to our centre, free insulin recovery was remarkably low (it varied from 9 to 17%) and the patient was strongly positive for anti-insulin antibodies.\n\n\nFigure 1 illustrates the Scatchard analysis of the anti-insulin antibodies in this patient. The results revealed the presence of two populations of polyclonal IgG antibodies. One population had high affinity (K\na ≈2×1010/M) with low capacity (0.009 nm in the assay, ∼0.8 nm antibody in the serum) and the other had low affinity (K\na ≈6×107/M) but higher capacity (0.13 nm in the assay, ∼12 nm antibody in the serum). However, half maximal inhibition of 125I-insulin binding occurs with ∼0.1 nm insulin, suggesting that most of the binding in this assay is due to high-affinity binding sites. The shape of the curve is relatively shallow with complete displacement occurring over more than a 100-fold concentration of unlabelled insulin, suggesting that insulin is binding to polyclonal antibodies. This analysis showed that the characteristics of circulatory antibodies are similar to those associated with insulin autoimmune syndrome (IAS). These studies were conducted after trials of plasmapheresis, immunoglobulins, prednisolone and methotrexate to improve glycaemic control. Rituximab had not yet been used.\n\nFigure 1 Scatchard analysis of the insulin autoantibodies in this patient using 125I human insulin. B:F, bound:free ratio. The specific binding is expressed as a percentage of the total insulin. The Scatchard plots of insulin–antibody binding data showed a bimodal distribution, suggesting that two classes of antibodies exist. Two orders of sites could be inferred from this plot – a high-affinity population of binding sites with a K\na of ∼2×1010/M and a low capacity and a lower affinity population with a K\na of ∼6×107/M and a higher capacity.\n\n\nFigure 2 illustrates the affinity of these antibodies in binding to different insulin preparations. There was no demonstrable difference in the ability of the tested insulin preparations to compete with the labelled hormones for antibody-binding sites, indicating that our patient had a similar affinity for all the tested insulin preparations.\n\nFigure 2 The affinity of binding various insulin preparations to insulin autoantibodies positive sample. Displacement of 125I binding to the patient serum by various types of insulin. The specific binding (i.e. NSB in the presence of 10 μM insulin has been subtracted) is expressed as a percentage of the total insulin. Binding of human 125I-insulin is decreased with increasing concentrations of all the insulin preparations tested, with a very similar half maximal inhibition of 125I-insulin binding for the human analogues and bovine insulin (0.07–0.1 nM).\n\n\nFigure 3 shows insulin recovery, episodes of hypoglycaemia and concentration of insulin antibodies in response to different treatment modalities over the first 14 months of hospitalisation. The different treatment modalities are outlined in the section below.\n\nFigure 3 Insulin recovery in relation to different treatment regimes and the concentration of insulin antibodies over the first 14 months of hospitalisation. The broken horizontal line indicates a normal recovery. The vertical lines represent the hypoglycaemic episodes. The width of each line is an estimate for the duration of hypoglycaemic period. The widest line represents a 2-week period.\n\nSubsequent to all immunosuppressant therapies, and 9–12 months after use of rituximab, tissue-resistant tests were performed (Fig. 4a and b). The first test was conducted over 24 h (Fig. 4a) and the second over 36 h (Fig. 4b). The glucose values in Fig. 4b represent the progressive increase in glucose concentration despite insulin administration, indicating that insulin may have been trapped in the subcutaneous tissue and released later in the circulation. This is outlined in further detail in the discussion section.\n\nFigure 4 (a and b) The insulin analogue, NovoRapid, concentration in the patient's circulation during 24 h tissue resistance test (a) and during a prolonged test duration (b). The solid circle in (b) represents the insulin level before insulin injection. The open circle represents the insulin level after insulin injection. NovoRapid of 20 units was injected in the 24 h test and 10 U were injected after each meal in the 3 days duration test. NovoRapid of 10 U is equivalent to 300 pmol/l. The glucose levels documented are the average glucose concentrations on each of the 3 days.\n\nTreatment\nOwing to the presence of circulating antibodies, it was elected to treat the patient as having IAS. Hence, she had three sessions of double-filtration plasmapheresis and was started on 60 mg prednisolone. During this time, she had three episodes of severe hypoglycaemia. Prednisolone treatment worsened glycaemic control, hence the dose was gradually reduced to 5 mg daily.\n\nAlthough plasmapheresis successfully removed insulin antibodies from the circulation (as indicated by insulin recovery >70% and negative anti-insulin antibodies), this effect was short lived and antibodies reappeared in the circulation a few hours after the plasmapheresis session or after s.c. insulin administration.\n\nImmunoglobulin infusion and 20 mg methotrexate weekly were also tried and were found to be unsuccessful in reducing the severity of the nocturnal hypoglycaemia or degree of insulin resistance. In view of the failure of all the treatment modalities, a decision was made to give the patient rituximab.\n\nThe patient was given the first dose of rituximab and started on methylprednisolone. Subsequent monitoring showed that within 6 months the circulating antibodies disappeared. A >70% insulin recovery with a negative insulin antibody titre was sustained for the second year of hospitalisation (Fig. 3). Although the nocturnal hypoglycaemia became less severe and shorter in interval, the patient experienced five episodes over the subsequent 14 months and insulin resistance to subcutaneous insulin did not change.\n\nDuring this time in an attempt to improve the patient's glycaemic control, i.v. Actrapid and the insulin analogue, glargine, administrated subcutaneously, were used to manage the patient. Although, the anti-insulin antibodies were diminished from the circulation, this treatment modality resulted in worsening glycaemic control and precipitated hypoglycaemia lasting for 3 days.\n\nOver the subsequent years, episodes of hypoglycaemia diminished and she could be managed purely with continuous subcutaneous insulin infusion (CSII) via an insulin pump. In total, the patient was hospitalised for 28 months before becoming stable enough for discharge.\n\nOutcome and follow-up\nAfter 60 months from the time of use of rituximab and methylprednisolone, the patient has become stable and uses a CSII via an insulin pump to manage her type 1 diabetes. She has had no further periods of hospitalisation for over 5 years and her insulin requirement is ∼38 units/day.\n\nDiscussion\nThis is a complex case of immune-mediated insulin resistance presented with unusually severe hypoglycaemia. This young lady with type 1 diabetes initially presented with circulating anti-insulin antibodies. Anti-insulin antibodies to human insulin preparation in diabetic children are not an uncommon phenomena and the presence of these antibodies in the patient's circulation is associated with an increase in the frequency of hypoglycaemia (8)\n(11). The anti-insulin antibody characteristics are one of the causative factors of hypoglycaemic episodes. The characteristics of anti-insulin antibodies have been thoroughly studied in IAS. It is evident that high-affinity insulin antibodies frequently induce insulin resistance, whereas the presence of low-affinity antibodies induce hypoglycaemia due to the dissociation of the high amount of insulin from the insulin–antibody complex (12)\n(13). However, in diabetes, only a few studies have focused on the characteristics of these antibodies (6). In this case, anti-insulin antibodies interfered with the pharmacological action of administrated insulin resulting in hypoglycaemia and insulin resistance. The autoimmune hypothesis for the origin of the anti-insulin antibodies in this patient was tested by characterising those antibodies and studying their association constant and binding capacity. The characterisation of anti-insulin antibodies in this patient confirmed the existence of polyclonal insulin antibodies. This finding is consistent with the concept that the antibodies to exogenous insulin are generally considered to be polyclonal and consist of various components with different affinities and capacities (14). Furthermore, the values of association affinity constant and capacity reported in this case were similar to those reported in association with IAS in non-diabetics (15). The diagnosis of IAS as the sole cause of the patient symptoms was refuted after she still had an ongoing insulin requirement despite lack of insulin antibodies in the circulation.\n\nIndeed, the clinical history always suggested dual pathology as the patient maintained a high sensitivity to i.v. insulin but not to s.c. insulin. This phenomenon is consistent with SIR, which complicated the case history of this patient.\n\nIn 1979, Paulsen et al. defined SIR according to three criteria:\n\n\nresistance to the action of subcutaneous insulin but maintaining sensitivity to i.v. insulin;\n\nlack of increase in the circulatory insulin after subcutaneous insulin and\n\nincreased insulin degrading activity in the subcutaneous tissue (16).\n\n\n\n\nWhile the last criterion represents a small percentage of cases of published SIR, the first criterion has been met in our case. Fulfilment of the second criteria is less clear in this case. Our data from the first tissue resistance test (Fig. 4A), which was performed over 24 h, revealed a normal response with an insulin peak at around 40 min. This was a similar finding to that in normal diabetics as presented by Hedman et al. (18). When this test has been repeated but over a period of three days (Fig. 4B), the patient showed no rise in circulating insulin but a concomitant rise in glucose. On the third day and while the same dose of insulin has been given subcutaneously, a massive peak of insulin, inappropriate to the administered dose, appeared in the circulation, with a concurrent fall in glucose concentration. Although only based on the clinical history of one patient we may conclude that in immune-mediated SIR and where there is a gradual build up to subcutaneous insulin, an insulin tissue resistance protocol performed over few days is more appropriate than the 24 h test.\n\nGiven our finding, we hypothesise that the mechanism causing insulin resistance starts when the subcutaneously administrated insulin is captured in the tissues. Few case reports have linked SIR to rapid insulin degradation at the injection site (17). This mechanism is very unlikely given the evidence that supports the subsequent release of insulin into the circulation.\n\nWe postulate two mechanisms that may explain insulin resistance and hypoglycaemia in this patient. The first is consistent with the presence of anti-insulin antibodies or receptors, at the tissue level. We hypothesise that tissue antibodies were formed through an immune reaction against exogenous insulin. The gradual rise in requirement of insulin over time followed by a sudden appearance of insulin in the circulation is consistent with an immune-mediated process, where a gradual filling up to antibody-binding sites leads to a saturation point at which the bound insulin and insulin antibodies are freed into the circulation. However, the mechanism that governs the insulin antibodies and insulin release process is not understood. The administered insulin is subsequently captured by circulating insulin antibodies. The buffering effect of the circulating insulin antibodies worsens insulin resistance and contributes to the increase in insulin requirements. The fasting state encourages the release of a large amount of the bound insulin and results in the nocturnal hypoglycaemia. What is not known is whether the circulating antibodies were dissociated from the tissue antibodies or they were produced separately, although insulin recovery studies during plasmapheresis showed the immediate return of insulin antibodies after s.c. insulin administration. However, autoimmune disorders sometimes coexist in one patient and this case may represent the coexistence of dual pathologies.\n\nThis hypothesis is further supported by the reduction in length and severity of hypoglycaemia when the patient was anti-insulin antibody negative. Indeed, at this phase, the glycaemic control was adequately managed with i.v. insulin on its own. Hypoglycaemia usually appeared a few days or weeks after s.c. insulin administration, indicating that the autoimmune reaction to subcutaneous insulin was resolving.\n\nThe second postulated mechanism is consistent with insulin sequestration in the derma or adipose tissue and subsequent release into the circulation and the presence of circulating insulin antibodies can be a concurrent finding that complicated the tissue resistance picture. However, evidence from the clinical presentation and patient response to immunosuppression therapy is in favour of the earlier hypothesis. Although the second mechanism appears less likely, it cannot be eliminated.\n\nThe mechanism of the immunogenicity of the exogenous human anti-insulin antibody is still unknown. Several factors are considered to influence the production of insulin antibodies, such as genetic factors, mode of insulin administration, degree of purity and species of insulin. It also appears that different insulin analogues induced different immune reactions in this patient. That was evident by the severity and the length of hypoglycaemic episode after administration of long-acting insulin in this patient.\n\nThe use of differential insulin assays with different specificities for different types of exogenous insulin was an important factor that helped explaining the kinetics of administered insulin analogues. Using these assays, we first demonstrated that high levels of insulin analogue, NovoRapid, were detectable during episodes of hypoglycaemia, although this was not administered on the same day. This observation, together with those from the prolonged tissue resistant test, was important in understanding the mechanism of the disease, informing management and education of the patient and family. The abnormal response of the prolonged tissue resistant tests is consistent with a gradual build-up of tissue resistance. Evidence from early clinical presentation showed a gradual increase in insulin requirement and the concomitant rise in glucose concentrations over periods of days preceded a period of severe hypoglycaemia. This indicates that the more the site of injection was exposed to subcutaneous insulin, the more severe the picture of insulin resistance was. Over the 28 months of hospitalisation, it becomes apparent that tissue resistance to subcutaneous insulin worsened after a period of regular s.c. injection and regressed following a period of discontinuation. Indeed, the 24 h tissue resistance test was preceded by a 2 weeks period of discontinuation of s.c. injections, which may explain the normal response seen from this test. The tissue resistance tests and the differential insulin assay results elucidated the skin involvement in the disease mechanism.\n\nIt is known that genetic predisposition is important in the pathogenesis of IAS. This has been suggested by an apparent HLA association with IAS cases in which typing has been performed. It has been found that 96% of IAS Japanese patients possessed the DR4, Cw4 and B15 antigens and almost all of them carried HLA-DRB1*0406, HLA-DQA1*0301/HLA-DQB1*0302\n(1). Although our patient was positive for DR4, DNA sequencing indicated that the HLA-DRB1*0406 allele was not present. In the Caucasian population, of the seven cases studied, four possessed DR4 and carried HLA-DRB1*0401 and three had non-DR4 phenotypes either with HLA-DRB1*0101, HLA-DRB1*1501 or HLA-DRB1*0701. Our patient's HLA typing would seem to support the hypothesis of IAS in that she is positive for DR4 (HLA-DRB1*0401) and HLA-DRB1*0101\n(19).\n\nVarious treatment modalities for SIR such as immunosuppression, plasmapheresis, protease inhibitors, insulin with heparin, peritoneal insulin administration, insulin analogue, inhaled insulin and β-cell transplantation have been proposed but were inconsistently effective, which may reflect several pathophysiologies for this condition.\n\nTreating IAS patients with steroids, immunoglobulin infusions and plasmapheresis (6) is well established. In our patient, treatment with steroids partially lowered the insulin antibodies titre but worsened glycaemic control. Treatment with plasmapheresis failed to sustain a response due to recurrence of insulin autoantibodies after s.c. insulin administration. I.v. insulin administration improved the glycaemic control but was complicated by central line infection episodes. The immunoglobulin infusion had no impact on the course of the disease. Therefore, a potent immunosuppressant drug rituximab was administrated. Rituximab is a B-cell-depleting agent, with potential risk and side effects. This treatment was associated with a gradual disappearance of anti-insulin antibodies. Indeed, it took a few months before the insulin antibodies were diminished and 14 months after rituximab administration before the hypoglycaemic spells faded and the insulin resistance resolved. After 3 years, good glycaemic control was maintained.\n\nIt is not clear if the hyperglycaemic episodes were related to the SIRS or from IAS. Both IAS and SIR can be associated with hypo- and hyperglycaemia, and we cannot be certain to which the hyperglycaemia was attributable. Episodes of hyperglycaemia frequently preceded the episodes of hypoglycaemia, even after eradication of circulating anti-insulin antibodies, suggesting that hyperglycaemia may have been attributable to SIR as well as IAS.\n\nIn conclusion, this was a challenging clinical scenario where immune-mediated tissue resistance and circulatory insulin antibodies may underline the pathophysiology in this patient. It was the first time that insulin recovery studies were used routinely as a surrogate marker of disease activity. The laboratory had a major role in this case and the use of the differential insulin assays has shed the light on the kinetics of insulin resistance in this patient. Furthermore, it is obvious from this case that a short tissue resistant test as proposed by Pualsen et al. (16) is not sufficient to exclude SIR. A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR.\n\nPatient's perspective\nWhat I thought was a simple chronic condition of type 1 diabetes suddenly changed my way of life completely. Within months of my diagnosis with diabetes I was regularly admitted into my local hospital with fluctuating blood sugar levels. I was having seizures due to low blood sugar levels followed by episodes of ketosis with high blood sugar levels. Being diagnosed with diabetes was one thing but less than a year later I had a unique condition which did not appear to have a name nor could anyone answer any of our questions and that was the difficult part. Everything appeared to be a risk and a guessing game but I was fortunate to have Dr P Holland as my consultant, a remarkable dedicated and caring consultant who was always open and honest with my family and me along the way which made the journey that little bit easier. I put my life in his hands and trusted him completely. I did feel like I was in a bubble for the duration of my hospital stay but my condition is continuing to improve and I am thoroughly enjoying getting a part of my life back.\n\nPatient consent\nConsent has been obtained from the patient.\n\nAuthor contribution statement\nN Jassam provided biochemistry advice and helped in writing the article; N Amin contributed to the writing of the article and was the, clinician involved in care of patient. P Holland is the named physician of patient. R K Semple provided advice about the investigation, management of the patient and helped in the writing of the article. D J Halsall provided advice and development of insulin assays. G Wark contributed to sample analysis and data processing. J H Barth provided biochemistry advice.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \nUchigata \nY \n & \nHirata \nY \n. 1999 Insulin autoimmune syndrome (IAS, Hirata disease) . Annales de Médecine Interne . 155 : 245 –253 10445096 \n2 \nUchigata \nY \n, \nEguchi \nY \n, \nTakayama-Hasumi \nS \n & \nOmori \nY \n. 1994 Clinical characteristics of 197 patients with insulin autoimmune syndrome in Japanese . Diabetes Research and Clinical Practice . 22 : 89 –94 \n10.1016/0168-8227(94)90040-X 8200300 \n3 \nVan Haeften \nTW \n. 1989 Clinical significance of insulin antibodies in insulin-treated diabetic patients . 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Diabetes Care . 27 : 2243 –2244 \n10.2337/diacare.27.9.2243 15333492 \n10 \nCasesnovaes \nA \n, \nMauri \nM \n, \nDominguez \nJR \n, \nAlfayate \nR \n & \nPico \nAM \n. 1998 Influence of antiinsulin antibodies on insulin immunoassay in the autoimmune insulin syndrome . Annals of Clinical Biochemistry . 35 : 768 –774 \n10.1177/000456329803500610 9838991 \n11 \nSeewi \nO \n, \nJaeger \nC \n, \nBretzel \nRG \n & \nSchonau \nE \n. 2008 Insulin binding to antibodies is a risk factor for inexplicable severe hypoglycaemia in children with type I diabetes mellitus . Experimental and Clinical Endocrinology & Diabetes . 116 : 1 –5 \n10.1055/s-2007-1004565 17973211 \n12 \nDozio \nN \n, \nScavini \nM \n, \nBeretta \nA \n, \nSarugeri \nE \n, \nSartori \nS \n, \nBelloni \nC \n, \nDosio \nF \n, \nSavi \nA \n, \nFazio \nF \n, \nSodoyez \nJC \n & \nPozza \nG \n. 1998 Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycaemic syndrome . Journal of Clinical Endocrinology and Metabolism . 83 : 643 –648 \n10.1210/jcem.83.2.4599 9467587 \n13 \nKure \nM \n, \nKatsura \nY \n, \nKosano \nH \n, \nNoritake \nM \n, \nWatanabe \nT \n, \nIwaki \nY \n, \nNishigori \nH \n & \nMatsuoka \nT \n. 2005 A trial to assess the amount of insulin antibodies in diabetic patients by surface plasmon resonance . Internal Medicine . 44 : 100 –106 \n10.2169/internalmedicine.44.100 15750268 \n14 \nKumar \nD \n. 1986 Insulin antibodies: an analysis of immunoglobulin G sub-classes . Diabetes . 35 : 189A \n15 \nGoldman \nJ \n, \nBaldwin \nD \n, \nRubenstein \nAH \n, \nKlink \nDD \n, \nBlackard \nWG \n, \nFisher \nLK \n, \nRoe \nTF \n & \nSchnure \nJJ \n. 1979 Characterisation of circulating insulin and proinsulin binding antibodies in autoimmune hypoglycaemia . Journal of Clinical Investigation . 63 : 1050 –1059 \n10.1172/JCI109374 447827 \n16 \nPaulsen \nEP \n, \nCourtney \nJW \nIII\n & \nDuckworth \nWC \n. 1979 Insulin resistance caused by massive degradation of subcutaneous insulin . Diabetes . 28 : 640 –645 \n10.2337/diab.28.7.640 109340 \n17 \nChalmers \nT \n. 1987 Subcutaneous insulin resistance syndrome . New England Journal of Medicine . 316 : 49 –51 \n10.1056/NEJM198701013160112 3537795 \n18 \nHedman \nCA \n, \nLindström \nT \n & \nArnqvist \nHJ \n. 2001 Direct comparison of insulin Lispro and Aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes . Diabetes Care . 24 : 1120 –1121 \n10.2337/diacare.24.6.1120 11375381 \n19 \nCavaco \nB \n, \nUchigata \nY \n, \nPorto \nT \n, \nAmparo-Santos \nM \n, \nSobrinho \nL \n & \nLeite \nV \n. 2001 Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies . European Journal of Endocrinology . 145 : 311 –316 \n10.1530/eje.0.1450311 11517012\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-0573",
"issue": "2014()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": null,
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": "130086",
"pmc": null,
"pmid": "24711924",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "10445096;15750268;15333492;2676431;8200300;18484562;3537795;11375381;18547238;9028697;11517012;2237267;109340;14631332;9467587;447827;15894868;9838991",
"title": "Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome.",
"title_normalized": "analytical and clinical challenges in a patient with concurrent type 1 diabetes subcutaneous insulin resistance and insulin autoimmune syndrome"
} | [
{
"companynumb": "GB-NOVOPROD-523667",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN HUMAN"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nThe combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients.\n\n\nMETHODS\nIn this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing.\n\n\nRESULTS\nBetween July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free survival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group).\n\n\nCONCLUSIONS\nLenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment.\n\n\nBACKGROUND\nCelgene Corporation.",
"affiliations": "Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany. Electronic address: anna-maria.fink@uk-koeln.de.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Gemeinschaftspraxis für Hämatologie und Onkologie, Leipzig, Germany.;Zentrum für Innere Medizin, Hämatologie/Onkologie, Stauferklinikum Schwäbisch-Gmünd, Germany.;Internistische Gemeinschaftspraxis, Magdeburg, Germany.;Onkologische Gemeinschaftspraxis, Dresden, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany; Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany.;3rd Department for Hematology and Oncology, Hanusch Hospital, Vienna, Austria.;Strategic Research Program on CLL, Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy.;Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain; on behalf of the Spanish Group of CLL (GELLC).;Department of Hematology, Academic Medical Center Amsterdam, University of Amsterdam, Netherlands; on behalf of the Dutch-Belgium HOVON CLL study group.;Department of Internal Medicine III, University of Ulm, Ulm, Germany.;Campus Kiel, 2nd Deptartment of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Department of Internal Medicine III, University of Ulm, Ulm, Germany.;Department of Internal Medicine III, University of Ulm, Ulm, Germany.;Campus Kiel, 2nd Deptartment of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany.;Campus Kiel, 2nd Deptartment of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany; Department of Medicine III-Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.;Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital of Cologne, Cologne, Germany.",
"authors": "Fink|Anna Maria|AM|;Bahlo|Jasmin|J|;Robrecht|Sandra|S|;Al-Sawaf|Othman|O|;Aldaoud|Ali|A|;Hebart|Holger|H|;Jentsch-Ullrich|Kathleen|K|;Dörfel|Steffen|S|;Fischer|Kirsten|K|;Wendtner|Clemens-Martin|CM|;Nösslinger|Thomas|T|;Ghia|Paolo|P|;Bosch|Francesc|F|;Kater|Arnon P|AP|;Döhner|Hartmut|H|;Kneba|Michael|M|;Kreuzer|Karl-Anton|KA|;Tausch|Eugen|E|;Stilgenbauer|Stephan|S|;Ritgen|Matthias|M|;Böttcher|Sebastian|S|;Eichhorst|Barbara|B|;Hallek|Michael|M|",
"chemical_list": "D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(17)30171-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "4(10)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D018450:Disease Progression; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D016019:Survival Analysis; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e475-e486",
"pmc": null,
"pmid": "28916311",
"pubdate": "2017-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study.",
"title_normalized": "lenalidomide maintenance after first line therapy for high risk chronic lymphocytic leukaemia cllm1 final results from a randomised double blind phase 3 study"
} | [
{
"companynumb": "DE-CELGENEUS-062-21880-14070017",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null... |
{
"abstract": "Lamotrigine is an effective antiepileptic drug with few adverse effects. Nystagmus is one of the commonly observable signs of lamotrigine overdose, which may result from central nervous system involvement. However, the physiologic basis of lamotrigine-induced nystagmus is not fully understood. Here we report a patient who presented with lamotrigine-associated nystagmus that was probably related to cerebellar dysfunction.",
"affiliations": "Department of Neurology, Chungnam National University College of Medicine, Korea.",
"authors": "Oh|Sun-Young|SY|;Kim|Ji Soo|JS|;Lee|Young Hoon|YH|;Lee|Ae Young|AY|;Kim|Jei|J|;Kim|Jae Moon|JM|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3988/jcn.2006.2.4.283",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1738-6586",
"issue": "2(4)",
"journal": "Journal of clinical neurology (Seoul, Korea)",
"keywords": "Downbeat nystagmus; Lamotrigine toxicity; Perverted head-shaking nystagmus",
"medline_ta": "J Clin Neurol",
"mesh_terms": null,
"nlm_unique_id": "101252374",
"other_id": null,
"pages": "283-5",
"pmc": null,
"pmid": "20396535",
"pubdate": "2006-12",
"publication_types": "D016428:Journal Article",
"references": "15716057;15699406;7288469;13822287;11185974;300801",
"title": "Downbeat, positional, and perverted head-shaking nystagmus associated with lamotrigine toxicity.",
"title_normalized": "downbeat positional and perverted head shaking nystagmus associated with lamotrigine toxicity"
} | [
{
"companynumb": "KP-CIPLA LTD.-2016KR02339",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "Erectile dysfunction (ED), defined as the inability to achieve or sustain an erection firm enough for sexual intercourse, is common in men older than 50 years of age whose medical history includes diabetes mellitus. This case report describes a male patient treated with hyperbaric oxygen (HBO₂) therapy as part of a comprehensive wound treatment plan for an open right foot wound. The patient's medical history included Type 1 diabetes mellitus and chronic ED refractory to previous trials of phosphodiesterase type 5 inhibitors. The patient completed a total of 60 HBO₂ treatments over a 15-week period. He reported an improvement in his ED symptoms after the first 20 hyperbaric treatments, with morning tumescence being the first sign of a change. Patient continued to report morning tumescence 24 weeks after final HBO₂ treatment.",
"affiliations": "Baylor Scott and White Comprehensive Wound Center, Irving, Texas U.S.;Baylor Scott and White Comprehensive Wound Center, Irving, Texas U.S.",
"authors": "Cormier|Jolene|J|;Theriot|Maxine|M|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-2936",
"issue": "43(4)",
"journal": "Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc",
"keywords": "erectile dysfunction; hyperbaric oxygen",
"medline_ta": "Undersea Hyperb Med",
"mesh_terms": "D007172:Erectile Dysfunction; D006801:Humans; D006931:Hyperbaric Oxygenation; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D000068581:Tadalafil; D016896:Treatment Outcome; D000069058:Vardenafil Dihydrochloride",
"nlm_unique_id": "9312954",
"other_id": null,
"pages": "463-465",
"pmc": null,
"pmid": "28763176",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Patient diagnosed with chronic erectile dysfunction refractory to PDE 5 Inhibitor therapy reports improvement in function after hyperbaric oxygen therapy.",
"title_normalized": "patient diagnosed with chronic erectile dysfunction refractory to pde 5 inhibitor therapy reports improvement in function after hyperbaric oxygen therapy"
} | [
{
"companynumb": "US-BAYER-2018-000337",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TADALAFIL"
},
"drugadditional": null,
"... |
{
"abstract": "The case of a patient who experienced serious adverse effects following a potential overdose of Patent Blue V dye (PVB) is presented here. A 65-year-old woman developed cardiac arrythmias and circulatory instability 35 minutes after receiving 100 mg PVB during breast cancer surgery. An allergic reaction was assumed and treated accordingly. Intraoperatively, both epinephrine and norepinephrine infusions were required to support circulation. However, mast-cell tryptase levels were normal and subsequent allergy testing for all potential allergens was negative. This case highlights that life-threatening reactions to perioperative PVB should not always be attributed to anaphylaxis; systemic toxicity could occur with an overdose.",
"affiliations": "From the Department of Anesthesia and Pain Management, Maroondah Hospital, Eastern Health, Melbourne, Victoria, Australia.",
"authors": "Wu|Aihua|A|",
"chemical_list": "D004396:Coloring Agents; D012394:Rosaniline Dyes; C008769:sulfan blue",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001413",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "15(3)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D004396:Coloring Agents; D005260:Female; D006801:Humans; D016462:Mammaplasty; D012394:Rosaniline Dyes; D021701:Sentinel Lymph Node Biopsy",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01413",
"pmc": null,
"pmid": "33684092",
"pubdate": "2021-03-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potential Patent Blue V Overdose in a Patient Undergoing Free-Flap Breast Reconstruction: A Case Report.",
"title_normalized": "potential patent blue v overdose in a patient undergoing free flap breast reconstruction a case report"
} | [
{
"companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-05710",
"fulfillexpeditecriteria": "2",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nPauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING.\n\n\nMETHODS\nCase series.\n\n\nMETHODS\n74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis.\n\n\nRESULTS\nMedian age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed.\n\n\nCONCLUSIONS\nRetrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits.\n\n\nCONCLUSIONS\nWithin the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.",
"affiliations": "Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France.;Department of Pathology, Center Hospitalier Universitaire de Nantes, Nantes, France.;Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France; Centre de Recherche en Transplantation et en Immunologie, UMR 1064, INSERM, Université de Nantes, France.;Department of Nephology, CHU Angers, Angers, France.;Department of Nephrology and Renal Transplantation, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, INSERM U955, Université Paris Est Créteil, Paris, France.;Department of Nephrology, CHU Rouen, Rouen, France.;Department of Nephrology, CHU Bordeaux, Bordeaux, France.;Department of Nephrology and Internal Medicine, Centre Hospitalier de Valenciennes, Valenciennes, France.;Department of Nephrology, Centre Hospitalier de Boulogne-sur-Mer, Boulogne sur Mer, France.;Department of Nephrology, Hôpital Européen Georges-Pompidou, Université Paris Descartes, Paris, France.;Department of Nephrology, CHU Bichat, Paris, France.;Department of Nephrology, CHU Amiens, Amiens, France.;Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France.;Department of Nephrology, CHU Rennes, Rennes, France.;Department of Nephrology, CHU Tours, Tours, France.;Department of Nephrology, Groupe Hospitalier Universitaire Pitié-Salpêtrière, Paris, France.;Department of Nephrology, Centre Hospitalier de Saint Nazaire, Saint Nazaire, France.;Department of Nephrology, Centre Hospitalier de Saint Malo, Saint Malo, France.;Department of Nephrology, CHU Poitiers, Poitiers, France.;Centre ECHO, Site Confluent-Rezé, Nantes, France.;Department of Nephrology, CHU Montpellier, Montpellier, France.;Department of Pathology, Center Hospitalier Universitaire de Nantes, Nantes, France; Centre de Recherche en Transplantation et en Immunologie, UMR 1064, INSERM, Université de Nantes, France. Electronic address: karine.renaudin@chu-nantes.fr.;Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France; Centre de Recherche en Transplantation et en Immunologie, UMR 1064, INSERM, Université de Nantes, France. Electronic address: fadi.fakhouri@unil.ch.",
"authors": "Ronsin|Charles|C|;Georges|Marie|M|;Chapelet-Debout|Agnès|A|;Augusto|Jean-François|JF|;Audard|Vincent|V|;Lebourg|Ludivine|L|;Rubin|Sebastien|S|;Quemeneur|Thomas|T|;Bataille|Pierre|P|;Karras|Alexandre|A|;Daugas|Eric|E|;Titeca-Beauport|Dimitri|D|;Boffa|Jean-Jacques|JJ|;Vigneau|Cécile|C|;Halimi|Jean-Michel|JM|;Isnard-Bagnis|Corinne|C|;Durault|Sandrine|S|;Renaudineau|Eric|E|;Bridoux|Frank|F|;Testa|Angelo|A|;Le Quintrec|Moglie|M|;Renaudin|Karine|K|;Fakhouri|Fadi|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2021.03.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": null,
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Acute kidney injury (AKI); antineutrophil cytoplasmic antibodies (ANCA); case series; crescent; infection; kidney biopsy; malignancy; pauci-immune necrotizing glomerulonephritis (PING); renal disease; vasculitis",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": null,
"nlm_unique_id": "8110075",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34119564",
"pubdate": "2021-06-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ANCA-Negative Pauci-Immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification.",
"title_normalized": "anca negative pauci immune necrotizing glomerulonephritis a case series and a new clinical classification"
} | [
{
"companynumb": "FR-CELLTRION HEALTHCARE HUNGARY KFT-2021FR008709",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Elimination of a rifamycin from the treatment regimen for tuberculosis negatively impacts outcomes. Cross-reactivity between the rifamycins after drug eruptions is unclear. We report 6 consecutive human immunodeficiency virus-infected patients with rifampicin-associated drug rash with eosinophilia and systemic symptoms (DRESS) syndrome confirmed on diagnostic rechallenge. The patients subsequently tolerated rifabutin. These data inform clinical management of tuberculosis-associated drug reactions.",
"affiliations": "Division of Dermatology; Lung Infection and Immunity Unit.;Division of Infectious Disease and HIV Medicine, Department of Medicine.;Department of Paediatrics and Child Health , University of Cape Town , South Africa.;Division of Dermatology.;Division of Dermatology.;Division of Dermatology.;Lung Infection and Immunity Unit.",
"authors": "Lehloenya|Rannakoe J|RJ|;Dlamini|Sipho|S|;Muloiwa|Rudzani|R|;Kakande|Betty|B|;Ngwanya|Mzudumile R|MR|;Todd|Gail|G|;Dheda|Keertan|K|",
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"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 2741919010.1093/ofid/ofw130ofw130Brief ReportsTherapeutic Trial of Rifabutin After Rifampicin-Associated DRESS Syndrome in Tuberculosis-Human Immunodeficiency Virus Coinfected Patients Lehloenya Rannakoe J. 12Dlamini Sipho 3Muloiwa Rudzani 4Kakande Betty 1Ngwanya Mzudumile R. 1Todd Gail 1Dheda Keertan 21 Division of Dermatology2 Lung Infection and Immunity Unit3 Division of Infectious Disease and HIV Medicine, Department of Medicine4 Department of Paediatrics and Child Health, University of Cape Town, South AfricaCorrespondence: K. Dheda, Department of Medicine, Division of Dermatology, Cape Town, Western Cape 7925, South Africa (keertan.dheda@uct.ac.za).9 2016 20 6 2016 3 3 ofw13025 5 2016 14 6 2016 © The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.Elimination of a rifamycin from the treatment regimen for tuberculosis negatively impacts outcomes. Cross-reactivity between the rifamycins after drug eruptions is unclear. We report 6 consecutive human immunodeficiency virus-infected patients with rifampicin-associated drug rash with eosinophilia and systemic symptoms (DRESS) syndrome confirmed on diagnostic rechallenge. The patients subsequently tolerated rifabutin. These data inform clinical management of tuberculosis-associated drug reactions.\n\nalternativerifabutinrifampicin-associated drug eruptiontuberculosis HIV coinfection cover-dateSummer 2016\n==== Body\nTuberculosis (TB) is a major cause of mortality in sub-Saharan Africa [1]. The upsurge in the incidence of TB in recent years has been driven by the human immunodeficiency virus (HIV) pandemic. In 2013, 61% of new cases of TB in South Africa were coinfected with HIV [2]. Cutaneous adverse drug reactions (CADRs) are generally more common in persons infected with HIV, including those associated with 1st-line anti-TB drugs (FLTDs) [3].\n\nAll FLTDs can cause a wide variety of CADRs, including drug rash with eosinophilia and systemic symptoms (DRESS syndrome), a severe form of CADR with mortality of up to 10% [4]. The diagnosis of DRESS syndrome warrants interruption of treatment that may impact cure and survival [3]. We have previously shown that diagnostic rechallenge in the context of FLTD, even in severe CADR such as DRESS syndrome and toxic epidermal necrolysis, is usually successful, and the majority of rechallenge reactions are nonlife threatening. Rechallenge facilitates detection of the offending drug allowing its removal from the treatment regimen while retaining the other FLTD within the treatment regimen [5]. This improves outcomes in the management of TB, because 2nd-line drugs are less efficacious and are associated with higher toxicity profiles [3].\n\nThe rifamycins are a class of synthetic antibiotics particularly effective against mycobacteria. Rifampicin, rifabutin, rifapentine, and rifaximin are the currently available rifamycins. Their inclusion in the treatment regimen for TB has been shown to shorten the duration of therapy, improve cure rates, and lower relapse rates [6]. Thus, elimination of rifampicin in the context of CADR often impacts negatively on treatment outcomes. For that reason, it would be useful if rifampicin could be substituted with an alternative rifamycin.\n\nHowever, there are limited data about the cross-reactivity among the rifamycins in the context of CADR. We report the successful switch to rifabutin as an alternative to rifampicin in a series of patients with rifampicin-associated DRESS syndrome.\n\nMETHODS\nThe subjects included in this study had initially presented to the dermatology ward at Groote Schuur Hospital, a tertiary center in Cape Town, South Africa, with CADR while on FLTDs between November 2013 and June 2015. They were all enrolled in a larger randomized controlled trial comparing sequential, additive, and incremental dosing versus sequential, additive, and full therapeutic dose reintroduction of FLTD in CADR. That study, now completed, was approved by the institutional Human Research Ethics Committee (Reference: 246/2009). The methods used in the parent study have previously been described [7, 8]. Eighty-eight patients were rechallenged with rifampicin in the parent study, and 19 of 88 (22%) patients reacted to rifampicin. Based on recently published literature, the last 6 consecutive cases of the 19 who reacted to rifampicin were switched to rifabutin [9, 10].\n\nOn admission, the anti-TB drugs were stopped when TB-associated CADR was suspected. Before rechallenge, all patients were investigated to confirm active TB. Once the CADR had resolved and laboratory parameters returned to baseline, three 2nd-line anti-TB drugs (SLTDs) to which the patient has not previously been exposed were initiated as bridge therapy. This was to minimize the risk of developing mycobacterial resistance during the prolonged rechallenge process with the individual drugs. This was followed by a diagnostic workup (patch testing followed by a skin prick test and an oral rechallenge) to pinpoint the offending FLTD. Depending on the sensitivities of the patient's strain of TB, isoniazid followed by rifampicin, pyrazinamide, and ethambutol were reintroduced consecutively and additively. A rechallenge reaction after any of these modalities lead to immediate withdrawal of the drug from the treatment regimen. The last 6 cases of the study that developed rechallenge reactions to rifampicin were switched to oral therapeutic dose of rifabutin after completion of the rechallenge process. The other FLTD that did not induce a rechallenge reaction were continued uninterrupted. Laboratory parameters and clinical features usually associated with a drug reaction were closely monitored for 96 hours after initiating rifabutin.\n\nRESULTS\nThe demographic and clinical characteristics of the 6 patients with DRESS syndrome that developed rechallenge reactions to rifampicin and subsequently tolerated rifabutin are summarized in Table 1. All 6 participants were TB and HIV coinfected (median CD4 count 111 cells/mm3). Three of them had pulmonary TB and 3 had disseminated disease. One had previous TB before the current episode, and none had a previous drug reaction. Five of the 6 participants were determined not to be resistant to rifampicin by GeneXpert MTB/RIF assay before they were started on anti-TB therapy. Two were on antiviral therapy (ART), which was initially interrupted but reinitiated uneventfully. Four of the 6 were on co-trimoxazole for Pneumocystis jiroveci pneumonia prophylaxis at the onset of CADR, which was stopped and not reinitiated. All 6 fulfilled the diagnostic criteria of DRESS syndrome at initial presentation as defined by Bocquet et al [11].\nTable 1. Demographic and Clinical Characteristics of Six Cases of Tuberculosis-Associated DRESS That Developed Rechallenge Reactions to Rifampicin and Tolerated Rifabutin\n\nCase\tAge in Years\tGender\tCD4 Count (Cells/mm3)\tARV\tFeature of DRESS at Initial Presentation\t1st-Line Agents Rechallenged\t2nd-Line Agents Used\tHypersensitivity Reactions to 1st- and/or 2nd-Line Agents\tCTCAE Criteria Severity Grading of Rechallenge Reaction to 1st-Line Agents\t\n1\t36\tM\t63\tYes\tRash, eosinophilia, oedema, ×fever >38°C, ALT > 5 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, ETH, KNM\tRIF: itch, morbilliform rash, hepatitis eosinophilia, INH: hepatitis, eosinophilia\tModerate\t\n2\t23\tF\t401\tNo\tRash, eosinophilia, oedema, fever >38°C, ALT > 5 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, ETH, KNM, CPM,\tRIF: itch, morbilliform rash, hepatitis, eosinophilia, oedema\nMOX: morbilliform rash, hepatitis, oedema, fever, nausea, vomiting\tMild\t\n3\t31\tF\t457\tNo\tRash, atypical lymphocytes, oedema, fever >38°C, ALT > 2 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, ETH, KNM TER,\tRIF: itch, morbilliform rash, hepatitis, eosinophilia MOX: intense itch morbilliform rash, fever,\tMild\t\n4\t35\tF\t74\tNo\tRash, eosinophilia, oedema, fever >38°C, ALT > 5 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, ETH, KAN\tRIF: itch, morbilliform rash, oedema, INH: hepatitis, fever, nausea, diarrhoea\tMild\t\n5\t49\tM\t32\tNo\tRash, eosinophilia, oedema, fever >38°C, ALT > 5 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, TER, KAN, ETH\tRIF: morbilliform rash, eosinophilia, fever, diarrhoea, hypotension MOX: eosinophilia, fever, diarrhea\tSevere\t\n6\t44\tF\t153\tYes\tRash, eosinophilia, anaemia, oedema, fever >38°C, ALT > 5 × ULN, lymphadenopathy\tRIF, INH, PZA, ETH\tMOX, TER, KAN, ETH\tRIF: itch, morbilliform rash, hepatitis eosinophilia, oedema\nPZA: itch morbilliform rash, MOX and/or TER and/or ETH: itch, erythematous rash, hepatitis, oedema, eosinophilia\tModerate\t\nAbbreviations: ALT, alanine aminotransferase; AMK, amikacin; ARV, antiretroviral therapy; CADR, cutaneous adverse drug reactions; CPM, capreomycin; CTCAE, common terminology criteria for adverse events (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death); DRESS, drug rash with eosinophilia and systemic symptoms; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KNM, kanamycin; MOX, moxifloxacin; PZA, pyrazinamide; RIF, rifampicin; TER, terizidone; ULN, upper limit of normal.\n\n\n\nThe rechallenge reactions to rifampicin were characterized by a rash in 6 of 6 (100%), itch and eosinophilia in 5 of 6 (83%) each, hepatitis in 4 of 6 (67%), edema in 3 of 6 (50%), and fever, hypotension, and diarrhea once. They were treated with potent topical steroids until resolution. None received systemic steroids. All 6 cases developed multiple drug hypersensitivity to at least 2 anti-TB drugs (Table 1). Three of the 6 cases reacted to 2 FLTD and required more than the standard 6 months of treatment. The other 3 reacted to rifampicin and at least 1 SLTD, but they were successfully rechallenged with the other 3 FLTDs (isoniazid, pyrazinamide, and ethambutol). Consequently, the latter 3 cases needed standard 6 months of TB treatment after successful replacement of rifampicin with rifabutin.\n\nDISCUSSION\nWe report successful switch to rifabutin as an alternative to rifampicin in 6 consecutive cases of rifampicin-associated DRESS syndrome, effectively normalizing the duration of therapy. The major concern in rechallenging with structurally similar drugs is the possibility of cross-reactivity. Cross-reactivity in DRESS syndrome is well described for several structurally similar compounds such as aromatic anticonvulsants and sulfonamide antibiotics, the latter particularly in persons infected with HIV [12]. However, there have been reports of successful switch to rifabutin in rifampicin-associated hepatotoxicity and hypersensitivity reactions, although a significant proportion reacted to both drugs [9, 10, 13]. Our findings suggest that that the 2 drugs in HIV-infected persons with DRESS may not cross-react in the context of DRESS. It is still unknown whether this applies to Stevens Johnson syndrome and lichenoid drug eruption, other forms of CADR associated with FLTD [3]. Larger studies are needed to confirm these findings.\n\nA systematic review by Davies et al [14] found no significant differences in cure rates, relapse rates, and adverse event profiles between those receiving either one of the 2 rifamycins, rifampicin or rifabutin, in their treatment regimen. The 2 drugs have a comparable efficacy in the treatment of TB in persons infected with HIV [15]. However, drug interactions between rifabutin and ART have to be considered in this subgroup. Efavirenz, which forms the backbone of 2nd-line ART regimen in South Africa, significantly reduces plasma levels of rifabutin. Thus, higher doses of rifabutin are required when the drug is used with efavirenz [16]. We used this higher dosing in all of our 6 patients who also initiated an efavirenz-containing regimen. The switch to rifabutin in our patients facilitated an optimal treatment regimen despite the loss of an important FLTD.\n\nCross-resistance between the 2 rifamycins, estimated to go up to 90%, is another concern in re-exposing a patient to a potentially life-threatening rechallenge reaction [17]. Therefore, it is prudent to ascertain that rifampicin-sensitive strains of TB are being treated, as was the case in 5 of our cases. The other case with disseminated disease was initiated on therapy based on clinical features only.\n\nThe major limitation of our study is the small sample size. Confirmation of rifampicin-associated DRESS syndrome by diagnostic rechallenge is still infrequently performed considering the severity of the reaction. Larger studies in multiple centers are needed to confirm our findings. It is also not clear whether these findings are applicable in non-HIV-infected persons or other severe forms of CADRs.\n\nCONCLUSIONS\nIn summary, we show that rifabutin is a viable replacement in rifampicin-associated DRESS syndrome in patients coinfected with TB and HIV. Our findings, if confirmed in larger cohorts and different clinical settings, will allow patients with rifampicin-associated DRESS to remain on optimum treatment, improving cure rates and compliance.\n\nAcknowledgments\nPotential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1 Dheda K , Barry CE III, Maartens G \nTuberculosis . Lancet \n2016 ; 387 :1211 –26 .26377143 \n2 World Health Organization . Global tuberculosis report 2015: World Health Organization ; 2015 \nAvailable at: http://www.who.int/tb/publications/global_report/en/. Accessed 16 March 2016. \n3 Lehloenya RJ , Dheda K \nCutaneous adverse drug reactions to anti-tuberculosis drugs: state of the art and into the future . Expert Rev Anti Infect Ther \n2012 ; 10 :475 –86 .22512756 \n4 Walsh SA , Creamer D \nDrug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking . Clin Exp Dermatol \n2011 ; 36 :6 –11 .21143513 \n5 Lehloenya RJ , Todd G , Badri M , Dheda K \nOutcomes of reintroducing anti-tuberculosis drugs following cutaneous adverse drug reactions . Int J Tuberc Lung Dis \n2011 ; 15 :1649 –57 .22118173 \n6 Joint Tuberculosis Committee of the British Thoracic Society . Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998 . Thorax \n1998 ; 53 :536 –48 .9797751 \n7 Lehloenya RJ , Todd G , Wallace J et al \nDiagnostic patch testing following tuberculosis-associated cutaneous adverse drug events induces systemic reactions in HIV-infected persons . Br J Dermatol \n2016 ; doi:10.1111/bjd.14492 .\n8 Lehloenya RJ , Muloiwa R , Dlamini S et al \nLack of cross-toxicity between isoniazid and ethionamide in severe cutaneous adverse drug reactions: a series of 25 consecutive confirmed cases . J Antimicrob Chemother \n2015 ; 70 :2648 –51 .26142408 \n9 Chien JY , Chien ST , Huang SY , Yu CJ \nSafety of rifabutin replacing rifampicin in the treatment of tuberculosis: a single-centre retrospective cohort study . J Antimicrob Chemother \n2014 ; 69 :790 –6 .24243988 \n10 Horne DJ , Spitters C , Narita M \nExperience with rifabutin replacing rifampin in the treatment of tuberculosis . Int J Tuberc Lung Dis \n2011 ; 15 :1485 –9 .22008761 \n11 Bocquet H , Bagot M , Roujeau JC \nDrug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS) . Semin Cutan Med Surg \n1996 ; 15 :250 –7 .9069593 \n12 Holtzer CD , Flaherty JF Jr, Coleman RL \nCross-reactivity in HIV-infected patients switched from trimethoprim-sulfamethoxazole to dapsone . Pharmacotherapy \n1998 ; 18 :831 –5 .9692656 \n13 Tattevin P , Revest M , Dupont M et al \nA regimen containing rifabutin for the treatment of tuberculosis in patients intolerant to rifampin . Clin Infect Dis \n2003 ; 36 :127 –8 .12491218 \n14 Davies G , Cerri S , Richeldi L \nRifabutin for treating pulmonary tuberculosis . Cochrane Database Syst Rev \n2007 ; 4 :CD005159 .17943842 \n15 Schwander S , Rusch-Gerdes S , Mateega A et al \nA pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis . Tuber Lung Dis \n1995 ; 76 :210 –8 .7548903 \n16 Weiner M , Benator D , Peloquin CA et al \nEvaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis . Clin Infect Dis \n2005 ; 41 :1343 –9 .16206114 \n17 Gao L , Xiao HP , Hu ZY et al \n[Cross-resistance between rifampin and rifabutin in multidrug resistant Mycobacterium tuberculosis complex strains] . Zhonghua Jie He He Hu Xi Za Zhi \n2012 ; 35 :333 –5 .22883990\n\n",
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"abstract": "We describe the case of a pregnant woman diagnosed with breast cancer at 26 weeks' gestation. The tumor was positive for estrogen and progesterone receptors and negative for overexpression of c-erbB-2 protein. Neoadjuvant FAC (fluorouracil, adriamycin, cytoxan) chemotherapy was started at 29 weeks' gestation. At 37 weeks, delivery was induced and the patient gave born to a healthy female baby weighing 2350 g, after which she was given a further cycle of chemotherapy and weekly paclitaxel. Clinical and radiological remission was achieved. Resection of the breast tissue showed complete pathological response and negative lymph nodes. This case illustrates how the integrated work of different specialists can obtain excellent oncological and obstetrical results in the care of pregnant women with breast cancer.",
"affiliations": "Breast Unit, Service of Obstetrics and Gynecology, Hospital Vail d'Hebron, Autonomous University of Barcelona, Barcelona, Spain. ocordoba@vhebron.net",
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"title": "Complete pathological remission in a patient with hormone-receptor positive and c-erbB-2 expression-negative breast cancer treated with FAC chemotherapy during pregnancy.",
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"abstract": "Myelodysplastic syndromes (MDS) are a heterogeneous group clonal disorders of hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis that lead to variable grades of impaired blood cell production. Chromosomal aberrations are often detected in MDS patients and thus cytogenetic analysis is useful for the diagnosis of these disorders. Common recurring chromosomal defects, such as the -5/5q- and -7/7q- are relatively well characterized cytogenetic abnormalities in MDS, however, the biological significance of uncommon cytogenetic alterations is unknown. We report here, two cases of peripheral blood and bone marrow hypereosinophilia in patients with MDS harboring the unbalanced translocation der(1;7)(q10;p10), a poorly characterized cytogenetic abnormality that is found in certain myeloid malignancies, including MDS. The patients reported here presented hypereosinophilia that was refractory to steroids and cytotoxic therapy, leading to severe target tissue damage that ultimately resulted in fatal end-organ failure. Potential roles of the der(1;7)(q10;p10) aberrations in the pathogenesis of aggressive eosinophilia and disease prognosis are discussed here.",
"affiliations": "Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, Japan.;Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, Japan.",
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"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2018.03031ImmunologyCase ReportSevere Eosinophilia in Myelodysplastic Syndrome With a Defined and Rare Cytogenetic Abnormality Rai Shinya Espinoza J. Luis *Morita Yasuyoshi Tanaka Hirokazu Matsumura Itaru Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osaka-Sayama, JapanEdited by: Shigeharu Ueki, Akita University, Japan\n\nReviewed by: Dalil Hannani, UMR5525 Techniques de l'Ingénierie Médicale et de la Complexité Informatique, Mathématiques et Applications, Grenoble (TIMC-IMAG), France; Kushagra Bansal, Harvard Medical School, United States\n\n*Correspondence: J. Luis Espinoza luis@med.kindai.ac.jpThis article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology\n\n09 1 2019 2018 9 303105 7 2018 07 12 2018 Copyright © 2019 Rai, Espinoza, Morita, Tanaka and Matsumura.2019Rai, Espinoza, Morita, Tanaka and MatsumuraThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Myelodysplastic syndromes (MDS) are a heterogeneous group clonal disorders of hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis that lead to variable grades of impaired blood cell production. Chromosomal aberrations are often detected in MDS patients and thus cytogenetic analysis is useful for the diagnosis of these disorders. Common recurring chromosomal defects, such as the −5/5q- and −7/7q- are relatively well characterized cytogenetic abnormalities in MDS, however, the biological significance of uncommon cytogenetic alterations is unknown. We report here, two cases of peripheral blood and bone marrow hypereosinophilia in patients with MDS harboring the unbalanced translocation der(1;7)(q10;p10), a poorly characterized cytogenetic abnormality that is found in certain myeloid malignancies, including MDS. The patients reported here presented hypereosinophilia that was refractory to steroids and cytotoxic therapy, leading to severe target tissue damage that ultimately resulted in fatal end-organ failure. Potential roles of the der(1;7)(q10;p10) aberrations in the pathogenesis of aggressive eosinophilia and disease prognosis are discussed here.\n\neosinophiliacytogenetic (CG) analyseseosinophilic pneumoniamyelofibrosismembranoproliferative glomerulonephritis (MPGN)myelodisdplastic/myeloproliferative disorders\n==== Body\nIntroduction\nEosinophilia, defined as a peripheral blood eosinophil count exceeding 500 μl, can be associated with a large number of disorders and is causally classified into two general categories, (1) primary eosinophilia that results from disorders that are intrinsic to the eosinophil lineage and (2) secondary eosinophilia, which is caused by factors outside the eosinophil lineage (1). In most cases secondary eosinophilia represents a reaction to the overproduction of the eosinophilopoietic cytokines such as interleukin 3 (IL-3), interleukin 15 (IL-5), and granulocyte colony stimulating factor (GM-CSF), such as the eosinophilia observed in response to allergens, drugs or parasitic infections. Secondary eosinophilia may also develop in the context of autoimmune disorders or certain malignancies such as Hodgkin's lymphomas (2, 3).\n\nMyeloid neoplasms, including myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML) and MDS are well-known causes of primary eosinophilia, in which defined clonal disorders of HSC lead to the overproduction of eosinophils (4). Hence, myeloid malignancies carrying dysregulated fusion tyrosine kinase genes (TK), including platelet-derived growth factor (PDGF-AB), fibroblast growth factor receptor 1 (FGFR1), and the PCM1-JAK2 fusion product has been recently recognized by the World Health Organization (WHO) category of myeloid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2. These distinctive group of myeloid neoplasms present with eosinophilia, ranging from a mild increase in eosinophil count to a marked eosinophilia that can be directly responsible for target organ damage (1). Hypereosinophilia (HE) is defined as a persistent eosinophil count in the peripheral blood that exceeds 1,500 μl and may be associated with life-threatening organ damage as a result of tissue infiltration by eosinophils and the release of their granular contents (5, 6).\n\nMDS are clonal disorders of HSCs characterized by the ineffective blood cells production leading to variable grades of cytopenias in the circulating blood (7). Overall, the incidence of MDS ranges from 3 to 5 per 100,000 individuals, however, in individuals over 70 years old, the incidence increases to about 50 per 100,000 inhabitants (8).\n\nTypically, the bone marrow (BM) of patients with MDS shows increased cellularity with variable grade of dysplasia of bone marrow cells, ranging from erythroid hyperplasia to defective maturation in the myeloid series an increase in the number of blasts, thus patients with MDS have an exceptional increased risk for progression to AML and although most MDS cases arise de novo, some cases are caused by mutagenic insults, such as the prolonged exposure of the BM to cytotoxic chemotherapy (9–11).\n\nChromosomal abnormalities are detected in approximately 30–70% of MDS patients and the presence of cytogenetic abnormalities correlates with disease prognosis, consequently, disease karyotype constitutes an important component of the International Prognostic Scoring System (IPSS) and the revised IPSS-R (IPSS-R), which are the most broadly utilized scoring tools for assessing prognosis in patients with MDS (11, 12). Notably, the prognostic relevance of cytogenetic abnormalities in MDS is largely limited to the most frequent ones, including del(5q),−7/del(7q),−8,-18/del (18q), del (20q),-5,-Y,-17/del (17p) (12, 13) and hence the biological relevance of less common chromosomal alterations in MDS is poorly understood. This is particularly important considering that over 600 different cytogenetic categories had been identified in MDS patients (14).\n\nThe unbalanced translocation, der(1;7)(q10;p10), is a rare cytogenetic abnormality that is detectable in some myeloid malignancies, including MDS (1–3%), AML (1–2%), and MPN (1%) (15, 16). MDS patients harboring this translocation appear to have specific molecular and clinical features, however, given its scarceness compared with better characterized cytogenetic groups found in AML/MDS, several aspects of this entity have not been described (15, 17).\n\nHere, we report two MDS cases with (1;7)(q10;p10) translocation in previously healthy men who presented with severe hypereosinophilia and target organ damage leading to fatal complications. In both cases, a large number of eosinophils were detectable in the peripheral blood and BM and eosinophilia was refractory to the treatment with corticosteroids.\n\nCase 1\nA previously healthy 67-year old male presented to another hospital complaining of dry cough, wheezing and mild dyspnea. Physical examination was unremarkable, except for the signs of bronchoconstriction. The laboratory tests revealed a marked increase in the number of eosinophils in the peripheral blood and thus a diagnosis of eosinophilic asthma was made. He was given inhaled bronchodilators and corticosteroids which induced a moderate improvement of symptoms. Four months later his symptoms worsened and was then diagnosed as Chronic Eosinophilic Pneumonia and oral methylprednisolone was added, which induced a minor improvement of symptoms without affecting eosinophilia. In addition, dry cough and respiratory discomfort reoccurred along with tapering the methylprednisolone to 10 mg/day. He was referred to our hospital in July 2016 for further evaluation. He had no smoking history and his medical history was unremarkable. On examination, vital signs were stable except for requiring 1L of nasal cannula oxygen. The SaO2 was 96% on 1L oxygen. He had decreased breath sounds in the lower right lung field with fine crackles. He had no raised JVP, murmurs, gallop or peripheral edema. Chest x-ray revealed right ground glass opacities (GGOs). A high-resolution CT scan revealed GGOs surrounded by consolidation in the right lower lung field.\n\nMain laboratory findings were as follows: WBC 7,770/μl, with eosinophils 52.3%; red blood cells (RBC) 366 × 104/μl; hemoglobin (Hb) 8.6 g/dl; Platelets (Plt) 25.5 × 104/μl; C-reactive protein 2.66 mg/dl (normal <0.3 mg/dl); lactate dehydrogenase (LDH) 243 IU/L (normal range <225 IU/L); IgE 254 IU/ml (normal <232 IU/ml); Soluble IL-2 receptor (sIL-2R) 495 U/ml (normal 150–505 U/ml); serum thymus and activation-regulated chemokine (TARC) 119 pg/mL (Table 1).\n\nTable 1 Laboratory test at the diagnosis in case 1.\n\n(Peripheral blood)\t(Biochemistry)\t\t\t\nWBC\t7,700/μL\tCRP\t2.66 mg/dL\tANA\tNegative\t\nStab\t5.0%\tCa\t8.8 mg/dL\tJo-1-Ab\tNegative\t\nSeg\t33.5%\tUA\t4.8 mg/dL\tRF\t<7.0 U/mL\t\nEo\t53.5%\tBUN\t12.0 mg/dL\tPR-ANCA\t<1.0 U/mL\t\nBaso\t4.0%\tCrea\t0.90 mg/dL\tMPO-ANCA\t<1.0 EU\t\nMono\t2.5%\tTP\t6.6 g/dL\tTARC\t119 pg/mL\t\nLymph\t1.5%\tAlb\t3.5 g/dL\t\t\t\nRBC\t366 × 104/μL\tAST\t15 U/L\t\t\t\nHGB\t8.6 g/dL\tALT\t11 U/L\t(Arterial blood gas analysis)\t\nPLT\t25.5 × 104/μL\tLDH\t243 U/L\tpH\t7.549\t\n(Infectious marker)\tALP\t176 U/L\tpCO2\t27.1 mmHg\t\t\nHBs-Ag\t(–)\tT-Cho\t156 mg/dL\tpO2\t68.2 mmHg\t\nHBs-Ab\t(–)\tTG\t86 mg/dL\tHCO3\t23.1 mmol/L\t\nHCV-Ab\t(–)\tsIL-2R\t495 U/mL\t\t\t\nHIV-Ab\t(–)\tIgE\t254 IU/mL\t\t\t\nANA, anti-nuclear antibody; RF, rheumatoid factor; PR3-ANCA, proteinase3-antineutrophil cytoplasmic antibody; MPO-ANCA, myeroperoxidase-antineutrophil cytoplasmic antibody; TARC, Thymus and activation-regulated chemokine.\n\nBone marrow (BM) aspirate demonstrated infiltration of eosinophils (26.2% of the total BM cells) without dysplasia. The percentage of blast cells in the BM was 2.4% with trilineage dysplasia seen in megakaryocytes, as well as in myeloid and erythroid lineages (Figures 1A,B). Chromosomal analysis of BM cells showed 46, XY, +1, der(1;7) (q10;p10) in 13 of 20 metaphases (Figure 2). He was negative for PDGFRA, PDGFRB rearrangement or FGFR1, or with JAK2 mutations. Accordingly, a diagnosis of MDS (refractory cytopenias with multilineage dysplasia type) was made, and consequently was categorized as intermediate risk, according to IPSS-R and intermediate-1 risk according to the IPSS scoring.\n\nFigure 1 Bone marrow eosinophilia. A representative Wright-Giemsa stain, (×400) of bone marrow aspirate smears from case 1. Notice the presence of various immature eosinophils, including eosinophilic band and Polymorphonuclear eosinophils (A), as well as eosinophilic myelocyte and eosinophilic metamyelocyte (B).\n\nFigure 2 Chromosomal analysis of case 1. A representative metaphase chromosomal analysis of the bone marrow cells derived from case 1. Arrows indicate the allelic imbalance of trisomy 1q and monosomy 7q.\n\nThe patient was treated with 75 mg/m2 azacitidine (AZA) once daily for five consecutive days on a 28-day cycle based (Figure 3). After the first cycle of AZA, the number of eosinophils further increased (WBC 6,570/μl with eosinophils 60.2%), which coincided with the tapering of 10 mg/day. After completing the second cycle of AZA treatment and increasing prednisolone to 30 mg/day, we noticed a substantial decrease in the right lung infiltrate. However, before starting the third cycle of AZA, dyspnea, cough and wheezing significantly worsened and a new infiltrate was detected in the left lower lung field (Figure 4). The infiltrate was refractory to various antimicrobial regimens combined with methylprednisolone and the patient's condition deteriorated, leading to respiratory failure and death.\n\nFigure 3 The clinical course of case 1. The X axis indicate the time (days). AZA, azacitidine; WBC, white blood cells; PLS, prednisolone.\n\nFigure 4 Representative chest computer tomography of case 1, showing consolidation in the right lower lung field at day 60 and consolidation in the left lower lung field at day 120.\n\nCase 2\nA 23-year old male presented to our hospital in April 2005 with maculopapular rash involving >50% of his body and intermittent fever of several weeks of evolution. He had no significant past medical history and denied symptoms of fatigue, body weight loss, or night sweats. Physical examination was unremarkable, except for the presence of a maculopapular rash covering nearly 50% of the skin surface.\n\nLaboratory findings were as follows: WBC 24,300/μl with eosinophils 39.0%; RBC 263 × 104/μl; Hb 10.0 g/dl; Plt 12.5 × 104/μl; C-reactive protein 1.66 mg/dl (normal <0.3 mg/dl); LDH 363 IU/L (normal range <225 IU/L); creatinine 0.95 mg/dl and estimated glomerular filtration rate (eGFR) of 65.7 ml/min/1.73 m2 (according to the modification of the CKD Epidemiology Collaboration Equation for Japanese); IgE 1,156 IU/ml (normal <232 IU/mL). A BM aspirate demonstrated significant infiltration of eosinophils (23% of total BM cells) without dysplasia and a 0.3% of blast cells with dysplasia in the erythroid lineages. Chromosomal analysis of BM cells showed 46, XY, +1, der(1;7) (q10;p10) in 4 of 20 metaphases (Figure 5). He was negative for PDGFRA, PDGFRB rearrangement or FGFR1, or with JAK2 mutations.\n\nFigure 5 Chromosomal analysis of case 2. A representative metaphase chromosomal analysis of the bone marrow cells derived from case 2. Arrows indicate the allelic imbalance of trisomy 1q and monosomy 7q.\n\nA diagnosis of MDS (Refractory anemia type) with hypereosinophilic syndrome (HES) was made and was subsequently categorized as low risk according to IPSS-R and intermediate-1 according to the IPSS scoring.\n\nHe was initially treated with methylprednisolone (1.0 mg/kg/day) in an attempt to control HES. Within approximately 1 week, significant improvement in the clinical condition was observed, and eosinophil count returned to normal values. However, the maculopapular rash and eosinophilia reoccurred along with tapering the methylprednisolone to 25 mg/day along with a rapid and progressive increase in the serum levels of creatinine (7.61 mg/dl) (Table 2 and Figure 6). A renal biopsy was performed for histopathological diagnosis, which showed globally sclerotic glomerulus in four out of 14 glomeruli analyzed by light microscopy. The remaining 10 glomeruli appeared enlarged and the marked diffuse thickening of glomerular basement membranes (GBM) and mesangial cell proliferation were also noted. Mesangial interposition neither endocapillary hypercellularity nor crescent formation in these glomeruli were noted periodic acid methenamine silver staining revealed duplication of the capillary wall (Figure 7). A Congo red staining for amyloid protein was negative. A diagnosis of membranoproliferative glomerulonephritis (MPGN) was made, however the patient's condition deteriorated and died from septicemia.\n\nTable 2 Laboratory test at the diagnosis of MPGN in case 2.\n\n(Peripheral blood)\t(Biochemistry)\t\t\t\nWBC\t22,300/μL\tCRP\t15.18 mg/dL\tANA\tNegative\t\nStab\t1.3%\tCa\t7.6 mg/dL\tRF\t<7.0 U/mL\t\nSeg\t43.3%\tUA\t4.8 mg/dL\tC3\t73 mg/dL\t\nEo\t26.0%\tBUN\t53.0 mg/dL\tC4\t25 mg/dL\t\nBaso\t0.0%\tCrea\t7.61 mg/dL\tCH50\t40.1 U/mL\t\nMono\t9.3%\tTP\t5.3 g/dL\tPR-ANCA\t<1.0 U/mL\t\nLymph\t4.3%\tAlb\t2.4 g/dL\tMPO-ANCA\t<1.0 EU\t\nRBC\t290 × 104/μL\tAST\t22 U/L\tAnti-GBM\t<2.0 U/mL\t\nHGB\t9.4 g/dL\tALP\t37 U/L\t(Urinalysis)\t\nPLT\t17.8 × 104/μL\tLDH\t536 U/L\tpH\t5.5\t\n(Infectious marker)\tALP\t700 U/L\tProtein\t3+\t\t\nHBs-Ag\t(–)\tT-Cho\t204 mg/dL\tSugar\t±\t\nHBs-Ab\t(–)\tHDL-Cho\t29 mg/dL\tRBC\t30–49/HPF\t\nHCV-Ab\t(–)\tTG\t182 mg/dL\tWBC\t1–4/HPF\t\nHIV-Ab\t(–)\tsIL-2R\t4,273 U/mL\t(Urine chemistry)\t\n\t\tIgG\t502 mg/dL\tNAG\t10.0 U/L\t\n\t\tIgA\t130 mg/dL\tβ-2MG\t54,985 μg/day\t\n\t\tIgM\t79 mg/dL\tProtein\t7.9 g/day\t\n\t\tIgE\t6,760 IU/mL\t\t\t\nC3, complement 3; C4, complement 4; CH50, complement hemolytic activity; Anti-GBM, anti-glomerular basement membrane.\n\nFigure 6 The clinical course of case 2. The X axis indicate the time (days). WBC, white blood cells; PLS, prednisolone.\n\nFigure 7 Representative images of periodic acid methenamine silver staining (high magnification) of renal specimen from patient 2 showing duplication of the capillary wall consistent with membranoproliferative glomerulonephritis.\n\nDiscussion\nCytogenetic aberrations are frequently detectable in patients with MDS. Some of those molecular changes have been linked to disease pathogenesis and their presence is utilized for assessing disease prognosis (13). Here we report two male patients who presented with de novo MDS, harboring the unbalanced translocation der(1;7)(q10;p10) associated with aggressive hypereosinophilic syndromes. In both cases, eosinophilia was not responsive to corticosteroids treatment and ultimately lead to severe target tissue damage and fatal end-organ failure.\n\nIn contrast to other hematological malignancies, in which specific chromosomal arrangements are distinctive molecular features of the disease, MDS are frequently associated with a variable number of cytogenetic abnormalities, which appear to determine the heterogeneous clinical phenotype of these disorders (18, 19).\n\nA recurrent molecular characteristic of MDS is the loss of genetic material, via deletions and monosomies, while the gain of genetic material is uncommon. Consequently, such a loss of genetic material is consistent with the assumption that the deletion or inactivation of tumor suppressor genes, rather than the activation of oncogenes, constitutes the main molecular mechanism implicated in the development of MDS (12, 20).\n\nThe unbalanced translocation, der(1;7)(q10;p10), is a nonrandom chromosomal abnormality that occurs through a mitotic recombination between chromosome 1 and chromosome 7 that generates two copies of chromosome 1 and a single copy of the intact chromosome 7 leading to an allelic imbalance of trisomy 1q and monosomy 7q. (15–17).\n\nThere is some controversy regarding the prognosis of der(1;7)(q10;p10). Early reports involving small numbers of patients with der(1;7)(q10;p10) suggested this entity correlates with unfavorable prognosis and increased risk of progression to AML (21, 22), however, in subsequent studies that included relatively larger number of cases, the presence of this translocation in MDS indeed correlated with a better clinical outcome, with patients showing milder anemia and lower blast counts at diagnosis and a tendency to have less trilineage dysplasia and a slower progression to AML (15, 17). Similarly, in a more recent study, newly diagnosed MDS patients with der(1;7)(q10;p10) were less likely to have excess blasts or multilineage dysplasia and overall showed higher hemoglobin levels compared to patients with monosomy 7 or those with 7q. However, the three groups were otherwise similar in regard to other laboratory and clinical features, including overall survival (23). These findings are consistent with the results of large study involving a cohort of 1,593 MDS patients (944 Germans and 695 Japanese). In this study, clinical outcomes of der(1;7)(q10;p10) patients were significantly better than those having−7/del(7q) or 1q gain alone. Interestingly, der(1;7)(q10;p10) was found to be 10 times more frequent in Japanese than in Germans (4.5 vs. 0.43%) and the strong male predominance (86% of cases) of this entity was also confirmed (Okuda et al. The 80th annual meeting of the Japanese Society of Hematology, 2018, abstract OS3-5C-3).\n\nMost MDS patients develop symptoms related to cytopenias and anemia, although isolated neutropenia and thrombocytopenia can also occur. In addition, some MDS patients may also present with eosinophilia (7). Among 288 patients with de novo MDS retrospectively analyzed by Matsushima and colleagues, 36 (12.5%) fulfilled the criterion for BM eosinophilia (eosinophils in BM exceeding 5%) and those with BM eosinophilia showed a higher tendency to evolve to AML and had a worst overall survival. In the same study, specific cytogenetic aberrations, especially, abnormalities in chromosome 7, complex karyotypes and i(17q), were associated with an increase in BM eosinophils (24). Nonetheless, it must be noted that the frequency of eosinophilia in MDS der(1;7)(q10;p10) has not been comprehensively investigated, likely due to the rarity of this entity. In the study by Slovak and colleagues, none of the 12 MDS patients with der(1;7)(q10;p10) showed eosinophilia (17). On the other hand, Sanada and colleagues documented eosinophilia in the peripheral blood of six out of 77 patients with der(1;7)(q10;p10), however none of those patients had eosinophilia in the BM (15).\n\nThe optimal treatment for MDS patients with der(1;7)(q10;p10) is another important aspect that has not been defined and patients are currently managed following the current treatment algorithm for MDS. In isolated case reports, the response with AZA was good (Imi et al. The 75th annual meeting of the Japanese Society of Hematology, 2013, abstract PS2-90), although the limited number of cases and the lack of controlled studies is a handicap to assume that AZA is the optimal treatment for this entity. In the cases reported here, AZA was ineffective in case 1 and by the time of diagnosis of case 2, AZA has not been approved for clinical use in Japan.\n\nCorticosteroids are the first line therapy for all types of hypereosinophilia preventing end-organ damage caused by these disorders, however recent studies suggest that certain subtypes are less responsive to these agents and many either exhibit resistance or relapse during steroid tapering or withdrawal (4, 25, 26), as observed in the case presented here. On the other hand, tyrosine kinase inhibitors are highly effective in those cases harboring fusion gene as a cause of hypereosinophilia. For example, imatinib is the drug of choice for patients with FIP1L1-PDGFRA and ruxolitinib is the first drug of choice in hypereosinophilia driven by gain of function mutations involving JAK/STAT axis (4, 25, 26). None of those mutations were detectable in the cases presented here. Novel monoclonal antibodies capable of depleting circulating eosinophils, such as mepolizumab (targeting IL-5), omalizumab (anti-IgE), and dupilumab (anti-IL4α receptor subunit) have been recently approved by the FDA have therapeutic potential for the management of hypereosinophilia, especially those cases refractory to corticosteroids and not associated with tyrosine kinase mutations (25, 26).\n\nDoes der(1;7)(q10;p10) translocation play a role in the pathogenesis of MDS or in the development of eosinophilia? So far, no specific molecular targets have been identified for this translocation and it is unknown if the loss of 7q and/or gain of 1q play a direct role in the pathogenesis of this entity. It is plausible that those chromosomal aberrations may generate genetic rearrangement of genes encoding eosinophilopoietic cytokines. Alternatively, prominent eosinophilia has been reported in myeloid leukemia with translocations or deletions of chromosome 7 (27). Interestingly, the deletion of the long arm of chromosome 7 (7q) has been reported in association with eosinophilia in isolated cases of myeloid malignancies such as myelomonocytic leukemia with BM eosinophilia (28).\n\nMDS with der(1;7)(q10;p10) has distinctive clinical and pathological characteristics, however, this translocation is found in a very small fraction of patients, and its pathogenic relevance to MDS and eosinophilia is unclear. Newer high-resolution whole-genome molecular approaches, such as comparative genomic hybridization and gene expression microarray studies, are expected to provide a more comprehensive analysis to unravel a potential role of this particular cytogenetic abnormality in disease pathogenesis.\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of Kindai University ethical committee. The protocol was approved by the Kindai University ethical committee. Written informed consent in accordance with the Declaration of Helsinki was obtained from the patient for analysis, publication of this report, and any accompanying images.\n\nAuthor Contributions\nSR collected information and data and wrote the manuscript. JE conceived the study and wrote the manuscript. YM collected data. HT collected and analyzed data. IM analyzed data and supervised the study.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This work was made possible by institutional funding.\n==== Refs\nReferences\n1. Gotlib J . World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management . Am J Hematol. (2017 ) 92 :1243 –59 . 10.1002/ajh.24880 29044676 \n2. Butt NM Lambert J Ali S Beer PA Cross NC Duncombe A . 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "9()",
"journal": "Frontiers in immunology",
"keywords": "cytogenetic (CG) analyses; eosinophilia; eosinophilic pneumonia; membranoproliferative glomerulonephritis (MPGN); myelodisdplastic/myeloproliferative disorders; myelofibrosis",
"medline_ta": "Front Immunol",
"mesh_terms": "D000368:Aged; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D004198:Disease Susceptibility; D004802:Eosinophilia; D004804:Eosinophils; D006801:Humans; D059785:Karyotype; D007958:Leukocyte Count; D008297:Male; D009190:Myelodysplastic Syndromes; D010641:Phenotype; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "3031",
"pmc": null,
"pmid": "30687305",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10861810;29957243;9283595;28496445;29680938;19857474;21669051;29742289;28112388;12846884;29624895;29728319;29259972;26940274;17315020;20002154;2306683;26486351;27230620;27819178;22565657;12506028;19665067;28028030;25960862;29044676;29312946;29791902",
"title": "Severe Eosinophilia in Myelodysplastic Syndrome With a Defined and Rare Cytogenetic Abnormality.",
"title_normalized": "severe eosinophilia in myelodysplastic syndrome with a defined and rare cytogenetic abnormality"
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"abstract": "We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Dexamethasone co-administration further diminished lymphocyte counts. Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib.",
"affiliations": "Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.",
"authors": "Sondermann|Wiebke|W|;Griewank|Klaus G|KG|;Schilling|Bastian|B|;Livingstone|Elisabeth|E|;Leyh|Julia C|JC|;Rompoti|Natalia|N|;Cosgarea|Ioana|I|;Schimming|Tobias|T|;Schadendorf|Dirk|D|;Zimmer|Lisa|L|;Hillen|Uwe|U|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D003907:Dexamethasone; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0124590",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2589784310.1371/journal.pone.0124590PONE-D-14-57255Research ArticleCorticosteroids Augment BRAF Inhibitor Vemurafenib Induced Lymphopenia and Risk of Infection Lymphopenia with Vemurafeni and CorticosteroidsSondermann Wiebke Griewank Klaus G. *Schilling Bastian Livingstone Elisabeth Leyh Julia C. Rompoti Natalia Cosgarea Ioana Schimming Tobias Schadendorf Dirk Zimmer Lisa Hillen Uwe *\nDepartment of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany\nHaass Nikolas K. Academic Editor\nUniversity of Queensland Diamantina Institute, AUSTRALIA\nCompeting Interests: Wiebke Sondermann has received honoraria from Roche and travel support from Bristol-Myers Squibb. Bastian Schilling has received honoraria from Roche and travel support as well research funding from Bristol-Myers Squibb. Elisabeth Livingstone has received honoraria from Roche, Bristol-Myers Squibb, Amgen, Boehringer Ingelheim, Merck Sharp & Dohme, and Merck, and travel support from Bristol-Myers Squibb. Lisa Zimmer has received honoraria from Roche, Bristol-Myers Squibb, Boehringer Ingelheim and Amgen, and travel support from Merck Sharp & Dohme and Bristol-Myers Squibb. Uwe Hillen has received honoraria from Roche. Dirk Schadendorf is on the advisory board or has received honoraria from Roche, Genentech, Novartis, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck Sharp & Dohme. The remaining authors have declared no conflicts of interest. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: WS KGG BS LZ UH. Performed the experiments: WS BS JCL NR IC TS. Analyzed the data: WS KGG BS EL DS LZ UH. Contributed reagents/materials/analysis tools: WS KGG BS EL. Wrote the paper: WS KGG BS EL JCL NR IC TS DS LZ UH.\n\n* E-mail: klaus.griewank@uk-essen.de (KGG); uwe.hillen@uk-essen.de (UH)21 4 2015 2015 10 4 e012459021 12 2014 16 3 2015 © 2015 Sondermann et al2015Sondermann et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Dexamethasone co-administration further diminished lymphocyte counts. Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib.\n\nThe authors have no support or funding to report. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nMelanoma is a particularly malignant cutaneous neoplasm and responsible for a considerable mortality worldwide[1]. In the United States, 9710 people were expected to die of melanoma in 2014[2]. Until recently, effective therapies for metastatic disease were not available. With the introduction of BRAF V600 inhibitors (BRAFi) and immunotherapies targeting CTLA-4 and PD-1, a convincing survival benefit of patients with metastasized disease receiving these treatments has been observed[3–9].\n\n\nBRAF mutations occur in around 40–60% of melanomas and the majority of these mutations affect the V600 amino acid residue, leading to a constitutively active BRAF kinase[10]. BRAFi such as vemurafenib (VEM) and dabrafenib (DAB) have shown convincing therapeutic responses in a large number of patients receiving therapy. Although around 80% of treated patients benefit from BRAFi monotherapy[3, 11], the average duration of response before tumors become therapy resistant is around 6 months.\n\nIn patients receiving immunotherapies such as CTLA-4 or PD-1 antibodies, the response rates of patients profiting from treatment is lower than for those receiving BRAFi[7, 8, 12]. However, a proportion of patients receiving immunotherapies and showing objective responses can benefit for a number of years from therapy[13, 14]. This differs from patients receiving BRAFi monotherapy where long term responses are an exception. However, the recent introduction of regimens combining BRAF with MEK inhibitors have shown a considerably increased duration of therapy responses[15, 16].\n\nOne potential treatment strategy would be to combine immunotherapeutic agents with BRAFi. Reports of BRAFi increasing expression of tumor antigens[17] provide further support that a beneficial synergistic effect could be achieved by combination therapy. Unfortunately, one trial aiming to combine these therapies was terminated due to the high level of liver toxicities observed[18].\n\nRecently, we described lymphopenias in patients treated with VEM[19]. This was not observed in DAB treated patients. A mean decrease in lymphocyte numbers of ~25% was noted in patients receiving VEM. The CD4 T cell population was particularly affected, showing a significant decrease in cell number. An altered phenotype with a higher proportion of CCR7+CD45RA+ (naïve) and lower proportion of CCR7+CC45RA- (central memory) cells, as well as altered cytokine profiles with lower secretion of interleukin-9 and interferon-gamma, was also noted.\n\nLymphocyte counts can also be affected by systemic application of corticosteroids. Corticosteroids are frequently given to oncology patients with symptomatic hepatic or brain metastases as these often significantly impede the patients´ quality of life (i.e. pain, paralysis, epileptic seizures, etc.). Corticosteroids reduce tumor-associated inflammation and can significantly and rapidly improve symptoms caused by increased tissue pressure. Corticosteroids are generally potent immunosuppressive agents and patients receiving treatment have an increased risk of infection.\n\nThe aim of our study was to retrospectively analyze to which extent patients treated with the BRAFi VEM or DAB received corticosteroids, how this treatment affected lymphocyte counts and whether this had a relevant impact on clinical parameters such as infections\n\nMaterials and Methods\nPatient Selection\n102 patients, who had received a BRAFi between May, 2010 and July, 2014 in the Department of Dermatology, University Hospital Essen were retrospectively selected for study inclusion. Patients were excluded from analysis if they had been enrolled in a clinical trial where it was not known whether they had received a BRAFi as monotherapy or in combination with a MEK inhibitor. Patients who had received BRAF and MEK inhibitor combination therapy in the context of an early access program were also excluded. The study was conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board of the University of Duisburg-Essen approved the study (IRB protocol number 12-4961-BO). All patients included in the study provided written informed consent. Patient written consent was also granted for medical images published in the study.\n\nWhite blood counts (WBC)\nWBC were performed by routine clinical lab analysis on a Sysmex XE-5000 (Sysmex, Norderstedt, Germany) automated hematology analyzer. Lymphopenia was defined as a lymphocyte count of <1/nl (nanoliter) and was termed as “mild” or “severe” based on the CTCAE (Common Terminology Criteria of Adverse Events) version 4.0 criteria (“mild” = CTCAE grade 1 (lymphocyte count <LLN [Lower limit of normal]- 0,8/nl) or 2 (<0,8/nl- 0,5/nl), “severe” = CTCAE grade 3 (<0,5/nl- 0,2/nl) or 4 (<0,2/nl). Pre-therapy lymphocyte counts were defined as the last measured lymphocyte count within 4 weeks of initiating BRAFi therapy. The lowest lymphocyte count measured within the first 12 weeks of therapy was defined as the lymphocyte nadir. Neutrophil and eosinophil counts measured at the same time points were also assessed.\n\nStatistical Analyses\nVarious parameters of the patient cohort were investigated, including age at therapy initiation and gender, number of patients receiving VEM or DAB, as well as DEX co-medication. Additionally, impact of DEX usage prior to BRAFi therapy, especially with regard to lymphocyte counts prior to BRAFi treatment, was explored. Lymphocyte counts before and during therapy were taken into account and the amount of mild or severe lymphopenia in the following groups (all, BRAFi mono, BRAFi+DEX, VEM, VEM+DEX, DAB, DAB+DEX) documented. The difference (delta) between lymphocyte counts before and during therapy was calculated. Neutrophil and eosinophil counts were analyzed similarly to lymphocyte counts,\n\nChi-square and Fisher´s exact test were used to test for differences between groups for categorical variables, Mann-Whitney-U-test and one-sample t-test for continuous variables. All statistical tests were two-sided with a rejection of the null hypothesis at p<0.05. Analyses were performed with SPSS Statistics software (version 22; SPSS Chicago, IL, USA).\n\nResults\nTumors and patients\nIn total, 102 patients with BRAFi therapy were included in the study, of which 41 (40.8%) were female and 61 (59.8%) were male. The average age at onset of therapy was 51.5 years (median: 53.2, range: 20–90). 25 (24.5%) patients received co-medication with DEX (BRAFi+DEX). VEM was taken by 66 (64.7%) patients, DEX co-administered in 13 (19.7%) cases. DAB was given to 36 (35.3%) patients, of which 12 (33.3%) received DEX co-medication (Table 1). Overall, DEX was administered in 25 cases, 22 (88%) to treat brain metastasis, 1 (4%) for liver capsule tension, 1 (4%) to improve general physique and 1 (4%) to treat vemurafenib induced arthralgia. All doses of DEX applied were supraphysiological. The average dosage given was 7.4 mg (median 8 mg, range 1–24 mg).\n\n10.1371/journal.pone.0124590.t001Table 1 Overview of basic patient characteristics sorted by groups.\n\t\tall patients\tall BRAFi\tVEM\tDAB\t\n\t\t\tmono\t+ DEX\tmono\t+ DEX\tmono\t+ DEX\t\ntotal\t\t102\t77\t25\t53\t13\t24\t12\t\nage at therapy initiation (years)\t51,5\t53.2\t53.5\t56.2\t56,1\t46.4\t50.7\t\nsex female/male\tabsolute\t41/61\t32/45\t9/16\t22/31\t7/6\t10/14\t2/10\t\n\t\n%\n\t\n40.8/ 59.8\n\t\n41.6/ 58.4\n\t\n36/ 64\n\t\n41.5/ 58.5\n\t\n53.8/ 46.2\n\t\n41.7/ 58.3\n\t\n16.7/ 83.3\n\t\nno LP\tabsolute\t51\t41\t10\t20\t2\t21\t8\t\n\t\n%\n\t\n50\n\t\n53.2\n\t\n40\n\t\n37.7\n\t\n15.4\n\t\n87.5\n\t\n66.7\n\t\nLP\tabsolute\t51\t36\t15\t33\t11\t3\t4\t\n\t\n%\n\t\n50\n\t\n46.8\n\t\n60\n\t\n62.3\n\t\n84.6\n\t\n12.5\n\t\n33.3\n\t\nLP grade 1+2\tabsolute\t37\t30\t7\t28\t5\t2\t2\t\n\t\n%\n\t\n72.5\n\t\n83.3\n\t\n46.7\n\t\n84.8\n\t\n45.5\n\t\n66.7\n\t\n50\n\t\nLP grade 3+4\tabsolute\t14\t6\t8\t5\t6\t1\t2\t\n\t\n%\n\t\n27.5\n\t\n16.7\n\t\n53.3\n\t\n15.2\n\t\n54.5\n\t\n33.3\n\t\n50\n\t\nmean lymph. prether. /nl\t1.37\t1.45\t1.09\t1.37\t1.05\t1.64\t1.14\t\nmean lymph. under ther. /nl\t1.11\t1.21\t0.82\t1.02\t0.59\t1.62\t1.08\t\nmean delta lymphocytes/nl\t-0.25\t-0.25\t-0.27\t-0.35\t-0.46\t-0.2\t-0.06\t\nabsolute number of infections\t9\t2\t7\t1\t6\t1\t1\t\nLP = lymphopenia; grades 1–4 according to CTCAE criteria version 4.1; BRAFi = BRAF inhibitor; VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy.\n\nLymphopenia in the BRAFi group\nPre-therapy lymphocyte counts were significantly lower in the BRAFi+DEX group, than in the BRAFi group (1.09/nl vs. 1.45/nl, p = 0.006). The average difference in lymphocyte counts before and in the first 12 weeks of therapy did not differ significantly between the BRAFi and BRAFi+DEX groups (p = 0.06), however the nadir in the BRAFi+DEX group was significantly lower than in the BRAFi group (0.82/nl versus 1.21/nl, p = 0.012)-\n\nOverall, 51 (50%) of patients developed a lymphopenia. Of these, 36 (46.8% of 77 patients) were in the BRAFi group and 15 (60% of 25 patients) in the BRAFi+DEX group. A severe lymphopenia (CTCAE grade 3 or 4) occurred in 14 of 51 (27.5%) patients. Severe lymphopenias were identified significantly more often in the BRAFi+DEX group (8 of 15 [53.3%]) than in the solely BRAFi treated group (6 of 36 [16.7%], p = 0.02, Table 1).\n\nIn 21 of 25 BRAFi+DEX patients (84%) DEX treatment had started before initiating BRAFi therapy and of these 15 (71.4%) already demonstrated lymphopenia prior to BRAFi therapy.\n\nLymphopenia in VEM and DEX subgroups\nComparisons between different groups (VEM, VEM+DEX, DAB, DAB+DEX—Figs 1 and 2), only showed a significant difference (p = 0.045) in pre-therapeutic lymphocyte values between the DAB+DEX group (1.14/nl) and the DAB group (1.64/nl), but significant differences in lymphocytes counts were found between VEM and DAB groups while under BRAFi therapy (VEM vs. DAB, 1.02/nl vs. 1.62/nl [p<0.01]; VEM+DEX vs. DAB+DEX, 0.59/nl vs. 1.08/nl, [p = 0.022]). Comparisons of lymphocyte counts with and without DEX treatment were also significant (VEM vs. VEM+DEX, 1.02/nl vs. 0.59/nl [p = 0.07] and DAB vs. DAB+DEX, 1.62/nl vs. 1.08/nl [p = 0.038]).\n\n10.1371/journal.pone.0124590.g001Fig 1 Frequency of lymphopenias in various treatment groups.\nShown are the frequencies of lymphopenias patients treated receiving vemurafenib (VEM) or dabrafenib (DAB), with or without concomitant corticosteroid therapy (dexamethasone—DEX). * = p < 0.05 marking statistically significant differences between groups; n = number of patients\n\n10.1371/journal.pone.0124590.g002Fig 2 Mean lymphocyte counts before and during therapy.\nShown are the mean overall lymphocyte counts before and during therapy according to treatment group. VEM- vemurafenib; DAB- dabrafenib; DEX- dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; corresponding symbols (*, #, +, x, °) above bars indicate statistical significant difference between groups (p < 0.05).\n\nComparisons in terms of changes in lymphocyte numbers during the course of therapy showed no significant differences between groups (Fig 2).\n\nThe frequency of lymphopenias was significantly higher in VEM than DAB and VEM+DEX than DAB+DEX treated patients (p<0.0001 and p = 0.009, respectively). Significant differences were not observed between VEM and VEM+DEX or DAB and DAB+DEX groups (Figs 1 and 3).\n\n10.1371/journal.pone.0124590.g003Fig 3 Distribution and degree of lymphopenia in treatment groups.\nShown are the frequency and grade of lymphopenias in patients receiving BRAF inhibitor (vemurafenib or dabrafenib) monotherapy or those receiving both BRAF inhibitor and dexamethasone. VEM- vemurafenib; DAB- dabrafenib; DEX- dexamethasone; delta lymphocytes- difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; CTCAE = Common Terminology Criteria of Adverse Events, version 4.0; corresponding symbols indicate statistically significant difference between groups (p < 0.05).\n\nSevere lymphopenias (CTCAE grade 3 or 4) were detected significantly more often in the VEM+DEX group than in the VEM group (p = 0.01). Comparisons between other groups found no significant differences (Fig 3).\n\nInfections under therapy\nNine patients experienced an infection while under BRAFi therapy. Two of these were severe pneumonia resulting in patient death (Fig 4). An additional patient with pneumonia had a concurrent severe gastrointestinal infection. One patient developed CTCAE grade 3 pyrexia with procalcitonin (PCT) levels increasing massively without an identifiable source of infection. Five mild infections were noted consisting of either cellulitis or mucosal candida infection. Both patients dying from pneumonia had limited lung metastasis. Lymphopenia was observed in all nine cases. Eight of these (89%) had received DEX and seven of these (88%) a therapy with VEM (Table 2).\n\n10.1371/journal.pone.0124590.g004Fig 4 Images of infections occurring under BRAFi and DEX therapy.\n(A) The absolute number and percentage of patients developing infections in different treatment groups is shown. (B) Chest x-ray of a patient under therapy with vemurafenib and dexamethasone showing reticular pulmonary infiltrates (blue arrows). (C) CT scan of the thorax of a patient under therapy with vemurafenib and dexamethasone showing atypical pulmonary infiltrates (blue arrows). VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; * = p< 0.05 marking statistically significant difference between groups; n = number of patients.\n\n10.1371/journal.pone.0124590.t002Table 2 Overview of patients’ characteristics with infections under therapy.\npatient number\t1\t2\t3\t4\t5\t6\t7\t8\t9\t\nage at therapy onset\t61\t27\t48\t77\t79\t78\t40\t41\t62\t\nsex\tmale\tfemale\tfemale\tmale\tmale\tmale\tmale\tfemale\tmale\t\nInfection type\tcellulitis\toropharyngeal candidiasis\tpneumonia\tpneumonia\toropharyngeal candidiasis\tpneumonia and salmonellosis\toropharyngeal candidiasis\turinary tract infection\tsepsis with unknown focus\t\nInfection severity\tbenign\tbenign\tsevere\tsevere\tbenign\tsevere\tbenign\tbenign\tsevere\t\nBRAFi\tVEM\tVEM\tVEM\tVEM\tVEM\tVEM\tVEM\tDAB\tDAB\t\nprevious therapies\tnone\tnone\t1 dose of Ipilimumab\tnone\tnone\tnone\tnone\t2 different chemo-Tx\tnone\t\nDEX dose (mg)\t0\t6\t8\t6\t4\t8\t24\t0\t2\t\nDEX prior to BRAFi\t-\tno\tyes\tyes\tyes\tyes\tyes\t-\tyes\t\nLP prior to BRAFi initiation under DEX\t-\tno\tyes\tyes\tyes\tyes\tyes\t-\tyes\t\nprether. lymph./nl\t1.13\t1.74\t0.6\t0.5\t1.07\t1.49\t0.1\t0.31\t0.81\t\nnadir lymph./nl\t0.96\t1.61\t0.2\t0.09\t0.45\t0.5\t0.18\t0.43\t0.18\t\ndelta lymph./nl\t-0.17\t-0.13\t-0.4\t-0.41\t-0.62\t-0.99\t0.08\t0.12\t-0.63\t\nCTCAE grade LP\t1\t0\t3\t4\t3\t2\t4\t3\t4\t\nInfection outcome\tresolved\tresolved\tfatal\tfatal\tresolved\tresolved\tresolved\tresolved\tresolved\t\nOverall outcome\tdead\talive\tdead\tdead\tdead\tdead\tdead\tdead\tdead\t\nLP = lymphopenia; grade 1–4 according to CTCAE criteria version 4.1; BRAFi = BRAF-inhibitor; VEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapeutic lymphocyte count and lymphocyte count under therapy; severe infection = life-threatening infection.\n\nIn the VEM+DEX group 6 out of 13 patients (46.2%) developed an infection. This rate was significantly higher than in both the VEM group (1 out of 53 patients [1.9%], p<0.0001) and the DAB+DEX group (1 out of 12 [8.3%], p = 0.035), as shown in Fig 4A. Comparisons of groups receiving either VEM or DAB as monotherapy showed no significant difference in infection rate (p = 0.56), nor did a comparison of DAB mono with DAB+DEX (p = 0.61). The dose of DEX given to patients with an infection was not significantly higher than those without an infection (8.29 mg to 7.11 mg, respectively, p = 1.0). Table 3 shows the lymphocyte counts before and under therapy as well as the mean difference in lymphocyte counts in the group with infections and without.\n\n10.1371/journal.pone.0124590.t003Table 3 Mean lymphocyte counts in patient groups with infections.\n\tLymphocytes\t\n\tmean/nl\t\nInfection\tpretherapy\tnadir\tdelta\t\n no (n = 93)\t1.41\t1.17\t-0.24\t\n yes (n = 9)\t0.86\t0.51\t-0.35\t\n\npatients with infection\n\t\t\t\t\n VEM (n = 1)\t1.13\t0.96\t-0.17\t\n VEM+DEX (n = 6)\t0.92\t0.51\t-0.41\t\n DAB (n = 1)\t0.31\t0.43\t0.12\t\n DAB+DEX (n = 1)\t0.81\t0.18\t-0.63\t\n\nsevere infection\n\t0.85\t0.24\t-0.61\t\n\nmild infection\n\t0.87\t0.73\t-0.14\t\nVEM = vemurafenib; DAB = dabrafenib; DEX = dexamethasone; delta lymphocytes = difference between pretherapy lymphocyte count and lymphocyte count under therapy; severe infection = life-threatening infection.\n\nTo assess the effect of lymphopenia duration on infection, patients were grouped into those known as being lymphopenic for ≥ or < 4 weeks. Lymphopenia ≥ 4 weeks was more frequent in patients with infections (7/8 = 87.5%) compared to patients where no infections were observed (28/43 = 65.1%). The difference however, was not statistically significant.\n\nNeutrophils and eosinophils in treatment groups\nAn individual analysis of neutrophil and eosinophil counts in different groups showed that DEX therapy led to statistically significant increases in neutrophil and decreases in eosinophil counts (p<0.0001, S1 Table and S1 Fig). Treatment with VEM or DAB caused a mild, statistically not significant decrease in neutrophil counts and had minimal effects on eosinophil counts (S1 Table and S1 Fig).\n\nSelective analysis of patients receiving DEX co-medication with or without infections showed no statistically significant difference in neutrophil counts before (9.64/nl vs. 10.01/nl, respectively) or under BRAFi therapy (7.56/nl vs. 4.68/nl, respectively). Comparable analysis of eosinophil counts in DEX treated patients with or without infections showed no statistically significant difference before BRAFi therapy (0.02/nl vs. 0.05/nl, respectively), however the difference in eosinophil nadir under BRAFi treatment was statistically significant (0.02/nl vs. 0.06/nl, respectively, p = 0.041).\n\nPrevious therapies\nOverall 77 patients (75.5%) had not previously received systemic therapies for metastasized melanoma prior to BRAFi therapy. Of the 25 patients with prior therapy, 18 (72%) had received conventional chemotherapeutic agents, 7 patients (28%) targeted therapies (non-BRAFi) and 6 patients (24%) immunotherapeutic agents. No statistically significant difference in the median number of previous therapies was observed between patients with and without infection.\n\nDiscussion\nIn our study, we recognize a considerable amount of patients who experienced severe lymphopenias while under BRAFi treatment. Fitting our initial study[19], lymphopenias were primarily noted in VEM treated patients and only rarely affected patients receiving DAB (62.3 vs. 12.5%). The percentage of lymphopenias was further increased in both groups if patients additionally received systemic corticosteroid therapy (84.6% and 33.3%, respectively). This makes it evident, that in patients receiving either corticosteroids, VEM or in particular the combination of VEM and corticosteroids, lymphopenias frequently occur.\n\nLymphopenia, especially severe lymphopenia, is a potentially dangerous condition. It impedes the immune system in establishing a protective immune response, thus predisposing patients to infections with a variety of different pathogens. It is well known that systemic administration of corticosteroids can lead to immunosuppression, by causing lymphopenia and other mechanisms[20, 21]. However, patients with clinical symptoms of metastasis due to increased tissue pressure can benefit strongly from systemic corticosteroids. Corticosteroids are a potent treatment for pain, nerve paralysis or epileptic seizures due to tumor induced pressure in the central nervous system. Another indication for therapy with corticosteroids in oncology patients is severe pain caused by metastasis related liver capsule tension[22]. In these situations, the moderate increase in risk of infection is a minor concern compared to the considerable and rapid treatment benefit that can be achieved.\n\nIdentifying signs of infection can be difficult in patients with advanced disease. As classical clinical signs such as reduced general physique, fever, leucocytosis and elevated CRP (C-reactive protein) levels frequently occur in tumor patients without infection, due to a high tumor burden[23], identification of a pathogen-induced infection may be delayed and only noted at a relatively late stage. This combined with a general state of immunosuppression caused by advanced tumor burden can lead to a particularly severe and potentially fatal course of infection. Patients who develop lymphopenia while receiving VEM and systemic corticosteroids could be at a particularly increased risk for complications.\n\nUnderstanding the extent to which BRAFi and corticosteroid therapy affect lymphocyte counts would be valuable, in particular if it is a simple additive effect, or if the combination results in a more drastic decrease in lymphocyte cell numbers. Given that the patients did not have a baseline lymphocyte count prior to the initiation of dexamethasone the effect of dexamethasone on lymphocyte counts could not be directly evaluated. It is however apparent, that these patients had lower lymphocyte counts at BRAFi therapy initiation (Fig 2), which argues for an effect of DEX. The additional decrease in lymphocyte counts after BRAFi treatment initiation (0.27/nl) is comparable to the decrease in the solely BRAFi treated group (0.25/nl), arguing that the effects of BRAFi and DEX observed are primarily additive.\n\nThe potential effect of neutrophil and eosinophil counts on infections was also addressed in our study. Clear neutrophil count increases and eosinophil count decreases under DEX therapy were noted. VEM and DAB treatment decreased neutrophil cell counts mildly and exerted only minor effects on eosinophil cell counts. Overall, the effect of VEM and DAB on eosinophil and neutrophil counts was relatively comparable. DEX treated patients with and without infection had comparable neutrophil counts within the normal range before and under BRAFi therapy, excluding low neutrophil counts as a causative factor for infection in our study.\n\nA modest statistical significance for lower eosinophil counts in BRAFi and DEX-treated patients with infections than similarly treated patients without infections was noted. This could imply a contribution of low eosinophil counts to infections. However, as VEM or DAB treatment generally showed comparable, minimal effects on eosinophil counts, it seems unlikely effects on eosinophils are responsible for the strong infection bias observed in the VEM and DEX treated patient group. Larger studies analysing more patients will be required to assess if eosinophil counts are truly a relevant factor in these settings.\n\nAn interesting aspect that merits consideration is the effect the induced lymphopenias might have on therapy designs where BRAFi are combined with immunotherapies such as CTLA-4 and PD-1 antibodies. In clinical studies of such treatment regimens, it would seem appropriate to routinely analyse patient lymphocyte counts and in cases where lymphopenia is noted, further application of the immunotherapeutic agent or continuation of systemic steroid therapy should be considered carefully. As seen in the current and our previous study[19], the effects of different BRAFi may vary strongly, indicating that effects observed for one substance, such as VEM, should not be seen as representative for other agents of the same group, e.g. DAB. Based on the results of this and our previous study [19], it would seem apparent, that combining DAB with immunotherapies would have greater potential, as lymphocyte counts and function are seemingly not, or just mildly, affected in comparison to VEM. Not compromising the potential to initiate a strong lymphocytic response would appear vital if patients should profit from combined BRAF inhibitor and immunostimulative therapies.\n\nEven though the observed infection rate was still relatively low (9%), four of these infections were severe and two even fatal. Both fatal infections occurred in patients receiving VEM+DEX with extremely low lymphocyte nadirs (0.2/nl and 0.09/nl). Due to the small number of patients, it cannot be excluded that the occurrence of lymphopenia and severe infections in the same treatment group is purely coincidental. DEX alone is usually given to more severely ill oncology patients. This could be associated with an increased infection rate independent of BRAF inhibitor treatment or lymphopenia. However, the impressive overall frequency of patients with VEM+DEX treatment that developed infections (46.2%, 6 of 13) compared to all other groups, including DAB+DEX, where infections were the exception (Fig 4A), does strongly support that the combination of VEM and DEX increases the risk of infection. At least in our cohort, these infections occasionally proved to be fatal and prophylactic measures need to be implemented early in the future.\n\nThis study is not without limitations. Due to the limited number of patients included, only a few could be analysed that had severe infections. Larger case numbers would be required to allow a significant analysis of these cases. Another aspect that made the evaluation and data interpretation more difficult was that most patients (84%) receiving BRAFi+DEX had already received corticosteroids before initiating BRAFi therapy. Lymphocyte counts prior to corticosteroid therapy were generally not available. Certain infections such as oropharyngeal candidiasis could be primarily DEX induced. A valuable control group would consist of patients having received only DEX, however for obvious ethical reasons such data was not available for a metastasized melanoma patient cohort. To be able to further evaluate the combined effect of BRAFi and corticosteroids on lymphocyte counts and validate our current observations, larger numbers of patients would need to be analysed in an—ideally—prospective study.\n\nOverall, we believe our data points towards an additive effect of the BRAFi VEM with DEX in inducing lymphopenias in treated patients. This effect could be clinically relevant as it might predispose patients with metastatic melanoma, who are already at increased risk for infections, even further. If validated in larger studies, this side effect of BRAFi and corticosteroid treatment should be considered when applying such treatments to advanced oncology patients. While this doesn´t necessarily mean BRAFi generally shouldn´t be combined with corticosteroids, it does suggest that lymphocyte counts should be monitored closely before and during therapy and patients be assessed for clinical signs of infections. In cases where a significant lymphopenia is observed or eminent, one should either try to avoid combining corticosteroids and BRAFi, or consider treating affected patients with a BRAFi having a less profound effect on patients´ lymphocytes.\n\nSupporting Information\nS1 Fig Neutrophil and eosinophil counts before and during therapy.\nShown are the mean overall neutrophil (A) and eosinophil (B) counts before and during therapy according to treatment group. VEM- vemurafenib; DAB- dabrafenib; DEX- dexamethasone; delta = difference between pretherapeutic count and count under therapy; corresponding symbols above bars indicate statistically significant difference between groups (p < 0.05)\n\n(PDF)\n\nClick here for additional data file.\n\n S1 Table Mean neutrophil and eosinophil counts in patient groups with infections.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nLozano R , Naghavi M , Foreman K , Lim S , Shibuya K , Aboyans V , et al\nGlobal and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 . Lancet . 2013 ;380 (9859 ):2095 –128 . Epub 2012/12/19. 10.1016/S0140-6736(12)61728-0 PubMed .23245604 \n2 \nSiegel R , Ma J , Zou Z , Jemal A . Cancer statistics, 2014 . CA: a cancer journal for clinicians . 2014 ;64 (1 ):9 –29 . Epub 2014/01/09. 10.3322/caac.21208 PubMed .24399786 \n3 \nFlaherty KT , Puzanov I , Kim KB , Ribas A , McArthur GA , Sosman JA , et al\nInhibition of mutated, activated BRAF in metastatic melanoma . The New England journal of medicine . 2010 ;363 (9 ):809 –19 . Epub 2010/09/08. 10.1056/NEJMoa1002011 PubMed .20818844 \n4 \nChapman PB , Hauschild A , Robert C , Haanen JB , Ascierto P , Larkin J , et al\nImproved survival with vemurafenib in melanoma with BRAF V600E mutation . The New England journal of medicine . 2011 ;364 (26 ):2507 –16 . Epub 2011/06/07. 10.1056/NEJMoa1103782 PubMed .21639808 \n5 \nRobert C , Thomas L , Bondarenko I , O'Day S , M DJ , Garbe C , et al\nIpilimumab plus dacarbazine for previously untreated metastatic melanoma . The New England journal of medicine . 2011 ;364 (26 ):2517 –26 . Epub 2011/06/07. 10.1056/NEJMoa1104621 PubMed .21639810 \n6 \nDanielli R , Ridolfi R , Chiarion-Sileni V , Queirolo P , Testori A , Plummer R , et al\nIpilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy . Cancer immunology, immunotherapy: CII . 2012 ;61 (1 ):41 –8 . Epub 2011/08/13. 10.1007/s00262-011-1089-0 PubMed .21833591 \n7 \nHamid O , Robert C , Daud A , Hodi FS , Hwu WJ , Kefford R , et al\nSafety and tumor responses with lambrolizumab (anti-PD-1) in melanoma . The New England journal of medicine . 2013 ;369 (2 ):134 –44 . Epub 2013/06/04. 10.1056/NEJMoa1305133 PubMed .23724846 \n8 \nWolchok JD , Kluger H , Callahan MK , Postow MA , Rizvi NA , Lesokhin AM , et al\nNivolumab plus ipilimumab in advanced melanoma . The New England journal of medicine . 2013 ;369 (2 ):122 –33 . Epub 2013/06/04. 10.1056/NEJMoa1302369 PubMed .23724867 \n9 \nTopalian SL , Sznol M , McDermott DF , Kluger HM , Carvajal RD , Sharfman WH , et al\nSurvival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2014 ;32 (10 ):1020 –30 . Epub 2014/03/05. 10.1200/JCO.2013.53.0105 PubMed .24590637 \n10 Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, Malke J, et al. Beyond BRAFV600: clinical mutation panel testing by next-generation sequencing in advanced melanoma. The Journal of investigative dermatology. 2014.\n11 \nHauschild A , Grob JJ , Demidov LV , Jouary T , Gutzmer R , Millward M , et al\nDabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial . Lancet . 2012 ;380 (9839 ):358 –65 . Epub 2012/06/28. 10.1016/S0140-6736(12)60868-X PubMed .22735384 \n12 \nHodi FS , O'Day SJ , McDermott DF , Weber RW , Sosman JA , Haanen JB , et al\nImproved survival with ipilimumab in patients with metastatic melanoma . The New England journal of medicine . 2010 ;363 (8 ):711 –23 . Epub 2010/06/08. 10.1056/NEJMoa1003466 PubMed .20525992 \n13 \nWolchok JD , Weber JS , Maio M , Neyns B , Harmankaya K , Chin K , et al\nFour-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials . Annals of oncology: official journal of the European Society for Medical Oncology / ESMO . 2013 ;24 (8 ):2174 –80 . Epub 2013/05/15. 10.1093/annonc/mdt161 PubMed 23666915 \n14 \nLipson EJ , Sharfman WH , Drake CG , Wollner I , Taube JM , Anders RA , et al\nDurable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody . Clinical cancer research: an official journal of the American Association for Cancer Research . 2013 ;19 (2 ):462 –8 . Epub 2012/11/22. 10.1158/1078-0432.CCR-12-2625 PubMed 23169436 \n15 \nLong GV , Stroyakovskiy D , Gogas H , Levchenko E , de Braud F , Larkin J , et al\nCombined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma . The New England journal of medicine . 2014 ;371 (20 ):1877 –88 . Epub 2014/09/30. 10.1056/NEJMoa1406037 PubMed .25265492 \n16 \nRobert C , Karaszewska B , Schachter J , Rutkowski P , Mackiewicz A , Stroiakovski D , et al\nImproved overall survival in melanoma with combined dabrafenib and trametinib . The New England journal of medicine . 2015 ;372 (1 ):30 –9 . Epub 2014/11/18. 10.1056/NEJMoa1412690 PubMed .25399551 \n17 \nBoni A , Cogdill AP , Dang P , Udayakumar D , Njauw CN , Sloss CM , et al\nSelective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function . Cancer research . 2010 ;70 (13 ):5213 –9 . Epub 2010/06/17. 10.1158/0008-5472.CAN-10-0118 PubMed .20551059 \n18 \nRibas A , Hodi FS , Callahan M , Konto C , Wolchok J . Hepatotoxicity with combination of vemurafenib and ipilimumab . The New England journal of medicine . 2013 ;368 (14 ):1365 –6 . Epub 2013/04/05. 10.1056/NEJMc1302338 PubMed .23550685 \n19 \nSchilling B , Sondermann W , Zhao F , Griewank KG , Livingstone E , Sucker A , et al\nDifferential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma . Annals of oncology: official journal of the European Society for Medical Oncology / ESMO . 2014 ;25 (3 ):747 –53 . Epub 2014/02/08. 10.1093/annonc/mdt587 PubMed .24504444 \n20 \nYu DT , Clements PJ , Paulus HE , Peter JB , Levy J , Barnett EV . Human lymphocyte subpopulations. Effect of corticosteroids . The Journal of clinical investigation . 1974 ;53 (2 ):565 –71 . Epub 1974/02/01. 10.1172/JCI107591 PubMed 11344571 \n21 \nFauci AS . Mechanisms of corticosteroid action on lymphocyte subpopulations. I. Redistribution of circulating T and b lymphocytes to the bone marrow . Immunology . 1975 ;28 (4 ):669 –80 . Epub 1975/04/01. PubMed 1080130 \n22 \nYamane H , Ochi N , Yamagishi T , Takigawa N . Guidelines for long-term steroid therapy in end-of-life palliative care . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2014 ;32 (6 ):607 –8 . Epub 2014/01/15. 10.1200/JCO.2013.53.2226 PubMed .24419116 \n23 \nDeichmann M , Benner A , Waldmann V , Bock M , Jackel A , Naher H . Interleukin-6 and its surrogate C-reactive protein are useful serum markers for monitoring metastasized malignant melanoma . Journal of experimental & clinical cancer research: CR . 2000 ;19 (3 ):301 –7 . Epub 2001/01/06. PubMed .11144523\n\n",
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"pubdate": "2015",
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"title": "Corticosteroids augment BRAF inhibitor vemurafenib induced lymphopenia and risk of infection.",
"title_normalized": "corticosteroids augment braf inhibitor vemurafenib induced lymphopenia and risk of infection"
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"abstract": "OBJECTIVE\nDrug-drug interactions can involve inhibition or induction of cell membrane transporters. Deinduction occurs after an inducing agent is stopped.\n\n\nMETHODS\nThis case describes suspected P-glycoprotein (P-gp) deinduction by carbamazepine resulting in a slow viral response during treatment of chronic hepatitis C virus (HCV) infection. Evidence of deinduction occurred beyond clearance of carbamazepine and resulted in extension of HCV treatment.\nThe understanding of the role P-gp transport plays in drug elimination is relatively new and evidence of P-gp deinduction is variable.\n\n\nCONCLUSIONS\nClinicians should consider deinduction when starting and stopping medications involving strong inducers of P-gp transport proteins.",
"affiliations": "Department of Pharmacy, Veterans Health Care System of the Ozarks, Fayetteville, AR, USA.;Department of Pharmacy, Veterans Health Care System of the Ozarks, Fayetteville, AR, USA.",
"authors": "Stark|Jennifer E|JE|https://orcid.org/0000-0002-5957-782X;Cole|Jennifer L|JL|",
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"pages": "1465-1468",
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"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Deinduction of P-glycoprotein resulting in delayed viral response during hepatitis C treatment.",
"title_normalized": "deinduction of p glycoprotein resulting in delayed viral response during hepatitis c treatment"
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"abstract": "BACKGROUND\nPrimary cardiac lymphoma (PLC) is an extremely uncommon malignancy. PCL is more common in secondary immunodeficient patients. In this report, we describe a unique case of PLC who had been diagnosed as a STK4 deficient patient. This case is the first Primary immunodeficiency (PID) patient developing PCL in the world.\nAn eleven-year-old girl, a known case of PID, was referred to the pediatric cardiology department because of chest pain and dyspnea. Her CXR revealed cardiomegaly without mediastinal involvement and the echocardiography showed a mild pericardial effusion and cystic-shape echogenic masses.\nAfter a period of missed follow up, she presented with respiratory distress following with syncope at the clinic because of a pressure effect of a large mass on the right ventricular outflow tract (RVOT) .An emergency operation was done for debulking of the tumors and resolving of RVOT obstruction. Biopsy and immunohistochemical staining was revealing \"T-cell lymphoma\", non-Hodgkin's type.\n\n\nMETHODS\nChemotherapy was done with cyclophosphamide, methotrexate, adriamycine, vincristine, hydrocortisone and allopurinol.\n\n\nRESULTS\nThe tumors shrank after chemotherapy initiation and she stayed stable for almost one month. Finally, she developed sever thrombocytopenia during her chemotherapy and died because of lung hemorrhage two months after her operation.\n\n\nCONCLUSIONS\nAlthough PCL is very rare, it must be considered in the differential diagnosis of intracardiac mass or refractory pericardial effusions, especially in PIDs which are widely known for developing EBV-associated diseases such as lymphoma.",
"affiliations": "Acquired Immunodeficiency Research Center Pediatric Cardiovascular Research Center, Isfahan Cardiovascular Research Institute Department of Cardiovascular Surgery Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.",
"authors": "Sherkat|Roya|R|;Sabri|Mohammad Reza|MR|;Dehghan|Bahar|B|;Bigdelian|Hamid|H|;Reisi|Nahid|N|;Afsharmoghadam|Nooshin|N|;Rahimi|Hamid|H|;Rahmanian|Narges|N|;Klein|Cristoph|C|",
"chemical_list": "D047908:Intracellular Signaling Peptides and Proteins; C095566:STK4 protein, human; D017346:Protein Serine-Threonine Kinases",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-17-0400210.1097/MD.0000000000008852088523600Research ArticleClinical Case ReportEBV lymphoproliferative-associated disease and primary cardiac T-cell lymphoma in a STK4 deficient patient A case reportSherkat Roya MDaSabri Mohammad Reza MDbDehghan Bahar MDbBigdelian Hamid MDcReisi Nahid MDbAfsharmoghadam Nooshin MDdRahimi Hamid MDbRahmanian Narges MD, PhDa∗Klein Cristoph MD, PhDeNA. a Acquired Immunodeficiency Research Centerb Pediatric Cardiovascular Research Center, Isfahan Cardiovascular Research Institutec Department of Cardiovascular Surgeryd Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Irane Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.∗ Correspondence: Narges Rahmanian, Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan 8174675731, Iran (e-mail: nrg_rahmanian@yahoo.com)12 2017 01 12 2017 96 48 e885228 6 2017 27 10 2017 2 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0Abstract\nRationale:\nPrimary cardiac lymphoma (PLC) is an extremely uncommon malignancy. PCL is more common in secondary immunodeficient patients. In this report, we describe a unique case of PLC who had been diagnosed as a STK4 deficient patient. This case is the first Primary immunodeficiency (PID) patient developing PCL in the world.\n\nPatient concerns:\nAn eleven-year-old girl, a known case of PID, was referred to the pediatric cardiology department because of chest pain and dyspnea. Her CXR revealed cardiomegaly without mediastinal involvement and the echocardiography showed a mild pericardial effusion and cystic-shape echogenic masses.\n\nDiagnoses:\nAfter a period of missed follow up, she presented with respiratory distress following with syncope at the clinic because of a pressure effect of a large mass on the right ventricular outflow tract (RVOT) .An emergency operation was done for debulking of the tumors and resolving of RVOT obstruction. Biopsy and immunohistochemical staining was revealing “T-cell lymphoma”, non-Hodgkin's type.\n\nInterventions:\nChemotherapy was done with cyclophosphamide, methotrexate, adriamycine, vincristine, hydrocortisone and allopurinol.\n\nOutcomes:\nThe tumors shrank after chemotherapy initiation and she stayed stable for almost one month. Finally, she developed sever thrombocytopenia during her chemotherapy and died because of lung hemorrhage two months after her operation.\n\nLessons:\nAlthough PCL is very rare, it must be considered in the differential diagnosis of intracardiac mass or refractory pericardial effusions, especially in PIDs which are widely known for developing EBV-associated diseases such as lymphoma.\n\nKeywords\nprimary cardiac lymphomaprimary immunodeficiencySTK4 deficiencyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary immunodeficiency (PID) patients are at great risk of malignancy in comparison with the normal population. After infections, malignancy is the second cause of death in these patients.[1] The most widely recognized sorts of malignancies among PID patients are non-Hodgkin lymphoma (NHL), which represent 48.6% of tumors found in PID patients.[2] NHL developing is frequently associated with the Epstein-Barr virus (EBV). In fact EBV infection is a potentially premalignant incident in PID patients.[3] B-cells infected by EBV stimulate a notable activation of immunoregulatory T cells. Therefore, a restoration of immune homeostasis during convalescence is required. This homeostasis is not completely reached in a person with significant immune deficiency.[4] Consequently, immunodeficient patients infected by EBV with impairment of lymphocytic cytotoxic pathway, T-cell signaling, or T-B cell interaction are at great risk of developing immunoregulatory disturbances and lymphoproliferative diseases such as lymphoma.[5,6]\n\nPrimary cardiac lymphoma (PLC) is a very rare malignancy (under 200 cases), occurring more frequently in secondary immunocompromised patients.[7,8] PCL is typically of a non-Hodgkin type, and involves just the heart or pericardium without confirmation of extracardiac involvement. PLC represents around 1% of the primary cardiac tumors and 0.5% of the extranodal lymphomas. Most PCLs are of B-cell origin and PCLs with T-cell origin are extremely rare. Moreover, PCL is very rare in children.\n\nIn this report, we describe a unique case of primary cardiac T-cell lymphoma with PID who has been diagnosed as a novel PID syndrome, STK4 deficiency. STK4 protein is critical for maintenance of lymphocytes and control of unrestricted EBV-induced lymphoproliferation. Human STK4 deficiency afford a PID syndrome influencing T cells, B cells, and potentially neutrophil granulocytes.[9] To the best of our knowledge, this case is the first PID patient developing PCL and the first known little girl with primary cardiac T-cell lymphoma in the world.\n\n2 Case report\nAn 11-year-old girl from a consanguine family died because of primary cardiac T-cell lymphoma. She was a known case of PID. Her genetic background had been investigated in 2010 at Germany and for the first time a novel PID syndrome caused by a homozygous nonsense mutation in STK4 was found in this family (the patient, her aunt, and her uncle).[9] Human STK4 deficiency causes a PID syndrome affecting T cells, B cells, and possibly neutrophil granulocytes. She had history of recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, mouth ulcers, skin abscesses, recurrent sinusitis and rhinitis, and at least 2 episodes of staphylococcal pneumonia. Her hematological investigations revealed T- and B-cell lymphopenia and intermittent neutropenia. Her echocardiogram was revealed structural cardiac abnormalities, including atrial septal defect. At the age of 9, she developed generalized lymphadenopathy and chronic fever. Her cell count showed significant increase in CD8+ T-cells and NK cells, a relative increase in transitional B cells and evidence of hypergammaglobulinemia. The lymph node biopsy showed an EBV-associated B-lymphoproliferative disorder with plasmacytoid differentiation, κ-light chain restriction, monoclonal immunoglobulin gene rearrangement and positive EBV-DNA PCR of tissue biopsy. Epstein-Barr encoding region (EBER) in situ hybridization proved EBV infection. Three years after generalized lymphadenopathy she was referred to the pediatric cardiology department because of chest pain and dyspnea. Her CXR revealed cardiomegaly without mediastinal involvement and the echocardiography showed a mild pericardial effusion. During follow-up her echocardiograms showed 3 cystic-shape echogenic masses on the inter-atrial septum, RV free wall, and inter ventricular septum on and off. After a period of missed follow-up, she presented with respiratory distress followed with syncope at the clinic because of a pressure effect of a large mass on the right ventricular outflow tract (RVOT) (Fig. 1A). It is necessary to state that informed consent was obtained for all photographic documentation. An emergency operation was done for debulking of the tumors and resolving of RVOT obstruction. During the operation, there were at least 2 large masses in the RVOT and right atrium. It was not possible to remove the tumor masses, so a Glenn shunt was inserted for compensation of RVOT obstruction (Fig. 1B). Biopsy and immunohistochemical staining was positive for CD30, Ki67, EBV, and EMA and negative for CD20 revealing “T-cell lymphoma,” non-Hodgkin type (Fig. 2). Chemotherapy was done with cyclophosphamide, methotrexate, adriamycin, vincristine, hydrocortisone, and allopurinol. The tumors shrank after chemotherapy initiation and she stayed stable for almost 1 month.\n\nFigure 1 (A) Transthoracic echocardiography, 2 echogenic masses with lucent centers on RA free wall and RVOT. (B) Two large extra cardiac masses with pressure effect on RVOT.\n\nFigure 2 Biopsy and immunohistochemical staining of cardiac mass.\n\nNevertheless, her malignancy invaded to the lungs and the liver. She had pleural effusion with infiltrations of malignant cells and severe lung infection due to the neutropenia. She also developed attacks of generalized tonic-clonic seizures due to brain sinuses thrombosis. Finally, she developed sever thrombocytopenia during her chemotherapy and died because of lung hemorrhage 2 months after her operation\n\n3 Discussion\nIn this report, we describe a unique case of primary cardiac T-cell lymphoma with STK4 deficiency, a PID syndrome. PLC is defined as a typical non-Hodgkin type and involving just the heart or pericardium without confirmation of extracardiac involvement. PCL is a very rare malignancy occurring more frequently in secondary immunocompromised patients. PCL represents around 1% of the primary cardiac tumors and 0.5% of the extranodal lymphomas. Most PCLs are of B-cell origin, while PCLs with T-cell origin are extremely rare.[7,8] The male-to-female ratio is 1.94, with a median age of 63. Moreover, PCL is very rare in children. The most common symptoms and signs are dyspnea, chest pain, pericardial effusion, heart failure, and AV-block.[10] A careful work-up ought to incorporate transthoracic and transesophageal echocardiography, computed tomography, and magnetic resonance imaging. The ECG shows nonspecific change and is non-valuable. Chest radiography reveals nonspecific findings, such as a cardiomegaly or pleural effusion. PCL diagnosis is confirmed by histology/cytology.[11–13]\n\nThe clinical manifestations of PCL are all nonspecific making early diagnosis troublesome. Unlike the other cardiac tumors PCL is rapidly progressive and fatal though; a physician should always keep in mind PCL as a differential diagnosis in cardiac mass or refractory pericardial effusion especially in immunocompromised patients. These tumors often result in a clinical emergency requiring immediate diagnosis and instant treatment. PCL should be treated as soon as possible because of the possibility of sudden death caused by disturbance of hemodynamics, ventricular fibrillation, or massive pulmonary embolism. The diagnostic lag leads to a poor prognosis in PCL.[7,14,15] Chemotherapy is the main successful treatment for PCL and some patients display a clinical remission or cure (radiotherapy does not appear to enhance quiet survival rate, and a radical surgical methodology is not prescribed). In any case, PCL with T cell origin is resistant to chemotherapy, which makes it more aggressive with a shorter survival time.[16] The survival is usually <1 month without treatment but has been extended up to 5 years by palliative treatments in selected cases. Autologous stem cell transplantation is a promising treatment in resistant cases.\n\nAs we mentioned before, PCL is a NHL. NHL happens more frequently in immunocompromised patients and is frequently caused by EBV infection.[7,10] EBV infection is a potentially premalignant incident in PID patients.[3] Some kinds of primary immunodeficiencies (PIDs) are widely known for developing EBV-associated disease. The EBV can cause a self-limiting lymphoproliferative disorder, called infectious mononucleosis (IM). However, EBV infection rarely results in severe, often fatal conditions, including lethal IM, hemophagocytic syndrome, polyclonal lymphoproliferative disorders, and malignant lymphoma. PIDs with lymphocyte cytotoxic pathway impairment or T-cell dysfunction are at great risk for developing these fatal conditions.[17]\n\nHuman STK4 deficiency affords a PID syndrome influencing T cells, B cells, and potentially neutrophil granulocytes. Clinically, the patients shared intermittent neutropenia, T- and B-cell lymphopenia, atrial septal defect, recurrent viral and bacterial infection, mucocutaneous candidiasis, cutaneous warts, and skin abscesses.[9] In 50% of STK4 deficiency reported cases persistent EBV viremia and EBV-associated lymphoproliferative disease has been reported.[18]\n\nNatural killer (NK) cells and EBV-specific cytotoxic CD8+ T lymphocytes (CTLs) are essential for the elimination of virus-infected cells and surveillance against tumor cells. B-cells infected by EBV stimulate a notable activation of immunoregulatory T-cells. Therefore, a restoration of immune homeostasis during convalescence is required. STK4 protein is critical for maintenance of lymphocytes and control of unrestricted EBV-induced lymphoproliferation. Indeed STK4 is necessary for activation of FOXO1 and FOXO3, crucial transcription factors for powerful CTL response to chronic viral infection and T cell homeostasis. Though, this homeostasis is not completely reached in a person with STK4 deficiency.[9,19–21] Impairment of CTLs and NK cells cytotoxic activity impede efficient removal of infected cells leading to continuous antigenic stimulation. This condition precludes downregulation of the elicited immune response resulting in persistent hyperactivation and proliferation of these effector cells.[18] Consequently, immunodeficient patients with impairment of lymphocytic cytotoxic pathway, T cell signaling or T-B cell interaction which is infected by EBV are at great risk of developing immunoregulatory disturbances and lymphoproliferative diseases such as lymphoma.[5,6]\n\nThis patient had STK4 deficiency and was susceptible to develop EBV-associated disease but because of the rare incidence of PCL especially in children, her presentation was unexpected. Clinicians should always keep in mind EBV-associated lymphoproliferative disease in PID patient with EBV infection history especially those who have shown reduced number or function impairment of NK cells or CTLs.\n\n4 Conclusion\nMalignancy is the second most common cause of death in PID patients and the most common type of malignancy among these patients is NHL. PLC is a very rare malignancy, which is usually non-Hodgkin type. PLC has often poor prognosis, mainly because of delay in the diagnosis, owing to a lack of clinical suspicion of this rare cardiac malignancy. PCL may cause sudden death due to disturbance of hemodynamics, ventricular fibrillation, or massive pulmonary embolism. However, early diagnosis and initiation of appropriate chemotherapy may result in a remission of disease and survival increase. Although PCL is very rare, it must be considered in the differential diagnosis of intracardiac mass or refractory pericardial effusions, especially in PIDs which are widely known for developing EBV-associated diseases such as lymphoma.\n\nAbbreviations: EBV = Epstein-Barr virus, NHL = non-Hodgkin lymphoma, PID = primary immunodeficiency, PLC = primary cardiac lymphoma, RVOT = right ventricular outflow tract.\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n[1] Lederman HM \nCancer in children with primary or secondary immunodeficiencies . J Pediatr \n1995 ;127 :335 .7503894 \n[2] Kersey JH Shapiro RS Filipovich AH \nRelationship of immunodeficiency to lymphoid malignancy . Pediatr Infect Dis J \n1988 ;7 :S10 –2 .2840629 \n[3] Grulich AE Vajdic CM Cozen W \nAltered immunity as a risk factor for non-Hodgkin lymphoma . Cancer Epidemiol Biomarkers Prev \n2007 ;16 :405 –8 .17337643 \n[4] Purtilo D Sakamoto K \nImmunodeficiency as a factor in lymphomagenesis . Perspect Pediatr Pathol \n1984 ;8 :181 –91 .6330665 \n[5] Henle W Henle G \nEpstein-Barr Virus (EBV) and Immunodeficiencies . Viruses, Immunity, and Immunodeficiency . Boston, MA : Springer ; 1986 \n43 –8 .\n[6] Ghosh S Bienemann K Boztug K \nInterleukin-2-inducible T-cell kinase (ITK) deficiency—clinical and molecular aspects . J Clin Immunol \n2014 ;34 :892 –9 .25339095 \n[7] Gowda RM Khan IA \nClinical perspectives of primary cardiac lymphoma . Angiology \n2003 ;54 :599 –604 .14565636 \n[8] Petrich A Cho SI Billett H \nPrimary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns . Cancer \n2011 ;117 :581 –9 .20922788 \n[9] Abdollahpour H Appaswamy G Kotlarz D \nThe phenotype of human STK4 deficiency . Blood \n2012 ;119 :3450 –7 .22294732 \n[10] Miguel CE Bestetti RB \nPrimary cardiac lymphoma . Int J Cardiol \n2011 ;149 :358 –63 .20227122 \n[11] Araoz PA Mulvagh SL Tazelaar HD \nCT and MR imaging of benign primary cardiac neoplasms with echocardiographic correlation . Radiographics \n2000 ;20 :1303 –19 .10992020 \n[12] Ceresoli GL Ferreri AJ Bucci E \nPrimary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic management . Cancer \n1997 ;80 :1497 –506 .9338475 \n[13] Faganello G Belham M Thaman R \nA case of primary cardiac lymphoma: analysis of the role of echocardiography in early diagnosis . Echocardiography \n2007 ;24 :889 –92 .17767544 \n[14] Giunta R Cravero RG Granata G \nPrimary cardiac T-cell lymphoma . Ann Hematol \n2004 ;83 :450 –4 .14722737 \n[15] Patel J Melly L Sheppard M \nPrimary cardiac lymphoma: B-and T-cell cases at a specialist UK centre . Ann Oncol \n2010 ;21 :1041 –5 .19846467 \n[16] Cho SW Kang YJ Kim TH \nPrimary cardiac lymphoma presenting with atrioventricular block . Korean Circ J \n2010 ;40 :94 –8 .20182596 \n[17] Cai Q Chen K Young KH \nEpstein-Barr virus-positive T/NK-cell lymphoproliferative disorders . Exp Mol Med \n2015 ;47 :e133 .25613730 \n[18] Parvaneh N Filipovich AH Borkhardt A \nPrimary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases . Br J Haematol \n2013 ;162 :573 –86 .23758097 \n[19] Kerdiles YM Beisner DR Tinoco R \nFoxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor . Nat Immunol \n2009 ;10 :176 –84 .19136962 \n[20] Ouyang W Beckett O Flavell RA \nAn essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance . Immunity \n2009 ;30 :358 –71 .19285438 \n[21] Sullivan JA Kim EH Plisch EH \nFOXO3 regulates the CD8 T cell response to a chronic viral infection . J Virol \n2012 ;86 :9025 –34 .22675000\n\n",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003131:Combined Modality Therapy; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D006338:Heart Neoplasms; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016399:Lymphoma, T-Cell; D008232:Lymphoproliferative Disorders; D017346:Protein Serine-Threonine Kinases",
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"title": "EBV lymphoproliferative-associated disease and primary cardiac T-cell lymphoma in a STK4 deficient patient: A case report.",
"title_normalized": "ebv lymphoproliferative associated disease and primary cardiac t cell lymphoma in a stk4 deficient patient a case report"
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"abstract": "To determine whether older adults with the hepatitis C virus (HCV) achieve a sustained viral response (SVR) after treatment with direct-acting antiviral therapy.\n\n\n\nIndividuals aged 80 and older with chronic HCV infection (N = 253; n = 213 with cirrhosis, n = 40 with advanced fibrosis).\n\n\n\nWe investigated the efficacy, safety, and global clinical effect of treatment with different combinations of direct antiviral agents (DAAs). Participants with cirrhosis were staged according to Child-Pugh-Turcotte class, Model for End-Stage Liver Disease score, and the D'Amico staging system. The type and number of comorbidities at baseline and hepatic and nonhepatic events during follow-up were registered.\n\n\n\nNinety-five percent of participants with cirrhosis and 95% of those with advanced fibrosis attained SVR. The rate was independent of sex, HCV genotype, and treatment schedule. During a mean follow-up of 14 ± 4 months (range 5-23 months), 34 events occurred in 27 participants: 10 hepatocellular carcinomas, 12 hepatic decompensations, 9 nonhepatic events, 3 deaths. Multivariate analysis of risk factors for experiencing adverse events during follow up showed that participants in D'Amico Stages 4 and 5, with a baseline serum albumin level of 3.5 mg/dL or less, and 3 or more comorbidities were the most at risk.\n\n\n\nIn a real-world setting, DAAs are safe and effective in older adults with HCV-related advanced fibrosis or cirrhosis. Individuals with preserved albumin synthesis and fewer than 3 comorbidities at baseline have the most to gain from long-term DAA therapy.",
"affiliations": "Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.;Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.;Clinics of Infectious Diseases, University of Bari, Bari, Italy.;Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Infectious and Tropical Diseases Unit, S. Anna and S. Sebastiano Hospital, Caserta, Italy.;Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.;Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.;Division of Gastroenterology, Department of Clinical Medicine and Surgery, Federico II University of Napoli, Naples, Italy.;Section of Gastroenterology, Department of Emergency and Organ Transplantation, Azienda Ospedaliero Universitaria Policlinico, University of Bari, Bari, Italy.;Liver Unit, Hospital of Castellaneta, Castellaneta, Italy.;Clinics of Infectious Diseases, Federico II University of Napoli, Naples, Italy.;Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.",
"authors": "Ippolito|Antonio Massimo|AM|0000-0003-2135-5209;Iacobellis|Angelo|A|;Milella|Michele|M|;Conti|Fabio|F|;Messina|Vincenzo|V|;Valvano|Maria Rosa|MR|;Niro|Grazia Anna|GA|;Morisco|Filomena|F|;Barone|Michele|M|;Termite|Antonio Patrizio|AP|;Brancaccio|Giuseppina|G|;Andriulli|Angelo|A|",
"chemical_list": "D000998:Antiviral Agents",
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"issue": "66(1)",
"journal": "Journal of the American Geriatrics Society",
"keywords": "\nHCV\n; chronic hepatitis; direct-acting antivirals; octogenarians",
"medline_ta": "J Am Geriatr Soc",
"mesh_terms": "D000369:Aged, 80 and over; D000998:Antiviral Agents; D058625:End Stage Liver Disease; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007558:Italy; D008103:Liver Cirrhosis; D008297:Male; D000072230:Sustained Virologic Response",
"nlm_unique_id": "7503062",
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"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
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"title": "Hepatitis C Virus Clearance in Older Adults.",
"title_normalized": "hepatitis c virus clearance in older adults"
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"abstract": "Chronic obstructive pulmonary disease (COPD) exacerbations are most commonly triggered by infections, but up to 25% of those that require hospitalization are thought to be triggered by acute pulmonary embolism. We present the case of a 71-year-old patient with a history of unprovoked pulmonary embolisms on anticoagulation therapy hospitalized for a COPD exacerbation. The exacerbation was triggered by an acute pulmonary embolism, representing anticoagulation failure.\nPulmonary embolism (PE) is an important trigger of COPD exacerbations and should be considered, especially when there is an unexplained abrupt or recurrent increase in the frequency or severity of exacerbations.Therapeutic anticoagulation does not preclude the presence of PE.Clinical risk stratification is a crucial component of medical decision-making.",
"affiliations": "Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.;Medicine Services, VA North Texas Health Care System, Dallas, TX, USA.",
"authors": "Saleh|Sameh N|SN|;Mansi|Ishak A|IA|",
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"doi": "10.12890/2020_001884",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n10.12890/2020_001884\n1884-1-16498-1-10-20200922\nArticles\nThe Clot Thickens: Diagnosing Acute Pulmonary Embolism as a Trigger for Chronic Obstructive Pulmonary Disease Exacerbation in the Setting of Anticoagulation Failure\nSaleh Sameh N 12 Mansi Ishak A 23 \n1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA\n\n2 Medicine Services, VA North Texas Health Care System, Dallas, TX, USA\n\n3 Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA\n2020 \n23 9 2020 \n7 12 00188412 7 2020 04 8 2020 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseChronic obstructive pulmonary disease (COPD) exacerbations are most commonly triggered by infections, but up to 25% of those that require hospitalization are thought to be triggered by acute pulmonary embolism. We present the case of a 71-year-old patient with a history of unprovoked pulmonary embolisms on anticoagulation therapy hospitalized for a COPD exacerbation. The exacerbation was triggered by an acute pulmonary embolism, representing anticoagulation failure.\n\nLEARNING POINTS\nPulmonary embolism (PE) is an important trigger of COPD exacerbations and should be considered, especially when there is an unexplained abrupt or recurrent increase in the frequency or severity of exacerbations.\n\nTherapeutic anticoagulation does not preclude the presence of PE.\n\nClinical risk stratification is a crucial component of medical decision-making.\n\nCOPD exacerbationpulmonary embolismanticoagulationanticoagulation failureenoxaparin\n==== Body\nCASE DESCRIPTION\nA 71-year-old man with severe chronic obstructive pulmonary disease (COPD) on 3 litres per minute (l/min) of home oxygen and a distant history of unprovoked pulmonary embolisms (PEs) currently on warfarin presented to the emergency room with an overnight history of increased dyspnoea with blood-streaked sputum production and oxygen desaturation. He denied fevers, chills or sputum purulence. Over the previous few months, he had an increase in the frequency of COPD exacerbations resulting in 5 admissions, all thought to be triggered by viral respiratory infection.\n\nOn examination, he had tachycardia of 130 beats per minute, tachypnoea of 25 breaths per minute and oxygen saturation of 90% at rest and 80% with conversation on 4 l/min of oxygen. He was afebrile and normotensive. Pulmonary examination revealed diffuse wheezing and bronchial breath sounds in the right upper lobe.\n\nHe had a white blood cell count of 10.5 K/μl, stable haemoglobin around 10 g/dl, creatinine of 0.89 mg/dl and an INR of 2.11. A week earlier, his INR was 3.27. Arterial blood gas (ABG) analysis showed a pH of 7.42, PCO2 of 41.8 mmHg and PO2 of 53.7 mmHg on 4 l/min of oxygen supplementation. A chest x-ray was unrevealing.\n\nMethods and Procedures\nThe patient was admitted to a step-down unit and started on oral corticosteroids, nebulized bronchodilators and antibiotics. Searching for an explanation for the recent increase in his COPD exacerbation readmissions, chest computed tomography (CT) angiography was pursued, which revealed an acute-on-chronic right upper lobe segmental PE. A Doppler ultrasound revealed an acute left popliteal deep venous thrombosis despite the lack of symptoms or signs. The patient was treated with enoxaparin with significant improvement. Given warfarin failure despite a therapeutic INR level, the patient was evaluated for causes of thrombophilia and was discharged on enoxaparin.\n\nDISCUSSION\nCOPD exacerbations are often reflexively managed with corticosteroids, bronchodilators, antimicrobials, oxygen and, if necessary, noninvasive mechanical ventilation. Although respiratory infections trigger approximately 50 to 70% of COPD exacerbation cases[1], it is imperative that alternative diagnoses and precipitants are considered. PE, which can often have similar symptoms of cough and dyspnoea, is an important trigger in nearly 25% of hospitalized COPD exacerbations[2]. Left untreated, a PE has a high case fatality rate and morbidity burden, especially in COPD patients where the risk of mortality nearly doubles[2]. It is important to have a high index of suspicion and to evaluate pre-test probability to guide testing.\n\nThe pre-test probability for our patient was relatively high. Risk factors in our patient that raised suspicion of PE included a sedentary lifestyle, a history of advanced COPD, a history of multiple PEs, repeated unexplained COPD readmissions and clinical presentation with dyspnoea, hypoxia and significant sinus tachycardia. Of note, his Geneva score was 11 points, which is high risk with greater than 60% incidence of PE[3]. While the fact that this patient was therapeutically anticoagulated on presentation decreased his pre-test probability of PE, it certainly did not rule out its possibility. Approximately 2% of patients on anticoagulation therapy (treated with direct oral anticoagulants; DOACs, or warfarin) experience a recurrence, which is a poor prognostic factor[4]. There was no significant difference in the recurrence of venous thromboembolism between treatment with DOACs and warfarin (relative risk; RR 0.90, 95% confidence interval; CI 0.77–1.06), but treatment with a DOAC was associated with a significantly reduced risk of major bleeding (RR 0.61, 95% CI 0.45–0.83)[4]. There is no clear evidence that allows evaluation of the effectiveness of DOACs when there is true warfarin anticoagulation failure and limited evidence guides the current standard of practice to switch to low molecular weight heparin[5].\n\nIn those patients with anticoagulation failure, it is important to consider the aetiology and distinguish between true failure and pseudo-failure due to subtherapeutic anticoagulation (that is, adherence, drug–drug interactions and malabsorption). Given our patient’s therapeutic INR on admission and 1 week prior, this coincides with true failure. Important considerations for true failure include underlying malignancies (specifically, myeloproliferative neoplasms), antiphospholipid syndrome, heparin-induced thrombocytopenia and inherited thrombotic disorders[5]. However, none of these conditions were identified in our patient.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Sethi S Murphy TF Infection in the pathogenesis and course of chronic obstructive pulmonary disease N Engl J Med 2008 359 22 2355 2365 19038881 \n2 Rizkallah J Man SFP Sin DD Prevalence of pulmonary embolism in acute exacerbations of COPD Chest 2009 135 3 786 793 18812453 \n3 Le Gal G Righini M Roy PM Sanchez O Aujesky D Bounameaux H Prediction of pulmonary embolism in the emergency department: the revised Geneva score Ann Intern Med 2006 144 3 165 16461960 \n4 van Es N Coppens M Schulman S Middeldorp S Büller HR Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials Blood 2014 124 12 1968 1975 24963045 \n5 Rodger MA Miranda S Delluc A Carrier M Management of suspected and confirmed recurrent venous thrombosis while on anticoagulant therapy. What next? Thromb Res 2019 180 105 109 31279158\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "7(12)",
"journal": "European journal of case reports in internal medicine",
"keywords": "COPD exacerbation; anticoagulation; anticoagulation failure; enoxaparin; pulmonary embolism",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001884",
"pmc": null,
"pmid": "33312998",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "18812453;16461960;31279158;19038881;24963045",
"title": "The Clot Thickens: Diagnosing Acute Pulmonary Embolism as a Trigger for Chronic Obstructive Pulmonary Disease Exacerbation in the Setting of Anticoagulation Failure.",
"title_normalized": "the clot thickens diagnosing acute pulmonary embolism as a trigger for chronic obstructive pulmonary disease exacerbation in the setting of anticoagulation failure"
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"companynumb": "US-TEVA-2021-US-1874808",
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"abstract": "Endocarditis and cardiac device infection due to Mycobacterium fortuitum is a rare entity in the hospital settings. We report a case of pacemaker infection and native valve endocarditis due to Mycobacterium fortuitum, which was associated with tricuspid valve vegetation. two days after admission with fever, chills, body aches and swelling around her pacemaker, the patient's pacing system was surgically removed. The patient was then discharged at day 16 after surgery and treated with a multidrug regimen of azithromycin, levofloxacin, imipenem/cilastatin, and amikacin for six weeks followed by trimethoprim/sulfamethoxazole plus doxycycline for a further three months.",
"affiliations": "Department of Infectious Disease, Mercyhealth, Rockford, IL, USA.;Department of Internal Medicine, Mercyhealth, Rockford, IL, USA.;Department of Internal Medicine, Mercyhealth, Rockford, IL, USA.;Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Infectious Disease, Mercyhealth, Rockford, IL, USA.",
"authors": "Al Zoubi|Moamen|M|;Cheng|Joyce|J|;Dontaraju|Venkate S|VS|;Evans|Colin E|CE|;Spier|Addie B|AB|",
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"doi": "10.1016/j.idcr.2021.e01200",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00156-6\n10.1016/j.idcr.2021.e01200\ne01200\nCase Report\nNative valve endocarditis and pacemaker infection with Mycobacterium fortuitum\nAl Zoubi Moamen Malzoubi@mhemail.org\nac⁎\nCheng Joyce c\nDontaraju Venkate S. c\nEvans Colin E. b\nSpier Addie B. ac\na Department of Infectious Disease, Mercyhealth, Rockford, IL, USA\nb Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA\nc Department of Internal Medicine, Mercyhealth, Rockford, IL, USA\n⁎ Corresponding author at: Mercyhealth Javon Bea Hospital, 8201 E Riverside Blvd, Rockford, IL, USA. Malzoubi@mhemail.org\n16 6 2021\n2021\n16 6 2021\n25 e0120013 1 2021\n14 6 2021\n14 6 2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nEndocarditis and cardiac device infection due to Mycobacterium fortuitum is a rare entity in the hospital settings. We report a case of pacemaker infection and native valve endocarditis due to Mycobacterium fortuitum, which was associated with tricuspid valve vegetation. two days after admission with fever, chills, body aches and swelling around her pacemaker, the patient’s pacing system was surgically removed. The patient was then discharged at day 16 after surgery and treated with a multidrug regimen of azithromycin, levofloxacin, imipenem/cilastatin, and amikacin for six weeks followed by trimethoprim/sulfamethoxazole plus doxycycline for a further three months.\n\nKeywords\n\nCardiac pacemaker\nDefibrillator\nMycobacterium fortuitum\nNontuberculous mycobacteria\n==== Body\nIntroduction\n\nMycobacterium fortuitum, a member of rapidly growing nontuberculous mycobacteria, is a well-known cause of skin and soft tissue infections and postsurgical wound infection. Here, we describe a case of native tricuspid valve endocarditis and pacemaker infection secondary to M. fortuitum. We also review the published literature of cardiac device–associated infections and native valve endocarditis caused by M. fortuitum.\n\nCase report\n\nA 26-year-old female presented to our hospital for evaluation of fever, chills, body aches and swelling around her pacemaker generator of 5 days duration. Four weeks prior, she had implantable cardioverter-defibrillator (ICD) placement for prevention of sudden cardiac death in the setting of ventricular arrhythmias. Vital signs revealed a temperature 38.9 F, pulse 90bpm, and blood pressure 117/76 mmHg. Her physical exam was unremarkable except for tenderness over the pacemaker site. No murmurs were appreciated. Laboratory evaluation showed the following values: white blood cells,7800 /μL; hemoglobin, 13.4 g/dL; and platelets, 151 × 109/L. Two sets of blood cultures revealed no growth at 5 days. Transthoracic echocardiography (TTE) showed 1.2 cm mobile mass attached to the ICD lead at the base of the posterior leaflet of the tricuspid valve suggestive of vegetation (Fig. 1A). At day 2 after admission, the patient was taken to the operating room where the entire pacing system was removed. The patient was found to have 25mLof purulent fluid which was. The acid-fast stain was positive (Fig. 1B, left panel), while the gram stain from the intraoperative culture showed beaded gram-positive bacilli (Fig. 1B, right panel). TEE showed hypoechoic mobile vegetation on the tricuspid valve measuring 0.87 cm without evidence of tricuspid regurgitation (Fig. 1C).Fig. 1 A case of native valve endocarditis and pacemaker infection with Mycobacterium fortuitum.\n\n(A) Two-dimensional transthoracic echocardiography showing 1.2 cm mobile mass attached to the pacemaker lead at the base of the posterior leaflet of the tricuspid valve. (B) Gram stain from OR cultures showing beady gram-positive bacilli (right panel); acid-fast stain showing positive Mycobacterium (bright pink, left panel). (C) Two-dimensional transesophageal echocardiography showing 0.872 mm vegetation on the tricuspid valve.\n\nFig. 1\n\nAt day 5 after admission, the patient was treated empirically with azithromycin (250 mg per mouth daily), imipenem/cilastatin (1 g intravenously every 8 h), amikacin (17 mg/kg intravenously three times per week) and tigecycline (250 g intravenously every 24 h). The surgical specimen was sent to Mayo Clinic (Rochester, Minnesota) for further testing and M. fortuitum was identified by DNA probe analysis. The patient developed significant nausea 5 days after tigecycline was started and this was switched to levofloxacin (750 mg per mouth daily). Drug resistance testing by broth microdilution of the M. fortuitum isolate indicated that this isolate was resistant to macrolides and tobramycin, intermediate to cefoxitin (MIC 32 μg/mL −1), and susceptible to amikacin (MIC <1 μg/mL− 1), imipenem (MIC 4 μg/mL− 1), tigecycline (MIC 0.12 μg/mL− 1), ciprofloxacin (MIC < 0.12 μg/mL− 1), moxifloxacin (MIC < 0.25 μg/mL− 1), linezolid (MIC 4 μg/mL− 1), doxycycline (MIC < 0.25 μg/mL− 1), and trimethoprim/sulfamethoxazole (MIC 2/38 μg/mL− 1). At days16 after admission, the patient was discharged. The patient completed the multidrug treatment regimen of azithromycin, levofloxacin, imipenem/cilastatin, and amikacin for 6 weeks and was subsequently switched to oral trimethoprim/sulfamethoxazole (800−160 mg twice daily) plus doxycycline (100 mg twice daily) for a further 12 weeks. At weeks 18 after the start of therapy, the patient discovered she was pregnant, and her oral antibiotics were stopped. The patient completed 4.5months of treatment in total. A follow up transeophageal echocardiography at 20 weeks after discharge showed no vegetation.\n\nDiscussion\n\nCardiovascular infection with M. fortuitum is rarely encountered in clinical practice. However, M. fortuitum infection of a pacemaker system with associated endocarditis has been described previously [1]. We searched the available literature using PubMed with no starting date restrictions through September 31, 2020 and identified only 12 previously reported cases of cardiovascular implantable electronic device (CIED) infections caused by M. fortuitum including our patient species (Table 1). We observed that 4 (33.3 %) of the 12 patients with M. fortuitum infection had associated mycobacteremia [3,[9], [10], [11]].Table 1 Pacemaker infections due to M. fortuitum.\n\nTable 1Year\n(Ref)\tAge/Sex\tTime from implant\tPresenting signs and symptoms\tBacteremia\tValve or lead vegetation\tTime to diagnosis\tMethod of diagnosis\tPacemaker removal\tAntibiotics treatment\tDuration of treatment\tOutcome\t\n1998 [2]\t74/F\t13 days\tFever, pain and purulent discharge\tNo\tNR\t2 days\tCulture of pus\tYes\tOfloxacin + gentamycin\t1 month\tCured\t\n2005 [3]\t62/F\t6 months\tFever, erythema\tYes\tYes (atrial lead)\t1 month\tCulture of aspirate\tYes\tCiprofloxacin/ clarithromycin\t6 months\tCured\t\n2005 [8]\t72/F\t2 weeks\tSubcutaneous nodules and chronic drainage\tNo\tNo\t1 week\tAbscess culture\tYes\tAmikacin/ ciprofloxacin\t6 months\tCured\t\n2006 [9]\t80/M\t18 days\tNR\tYes\tNo\tNR\tNR\tNo\tCiprofloxacin/ clarithromycin\t6 weeks\tCured\t\n2006 [1]\t78/F\t6 months\tSwelling and discomfort over the pacemaker pocket.\tYes\tYes (right atrial lead)\t2 weeks\t16S ribosomal RNA\tYes\tLinezolid + levofloxacin + clarithromycin\t6 months\tCured\t\n2007 [4]\t84/F\t2 months\tFever, pain, and erythema\tNo\tNo\t7 days\t16S rRNA PCR and culture of aspirate\tYes\tlevofloxacin\t3 months\tCured\t\n2009 [10]\t15/F\t7 weeks\tGreenish discharge and fever\tYes\tYes (endocardial and epicardial leads)\t3 days\tLead culture\tYes\tCiprofloxacin/ clarithromycin\t6 months\tCured\t\n2010 [12]\t78/M\tNR\tNot reported\tNR\tYes (non-specific pacemaker infection)\tNR\tNR\tNR\tCiprofloxacin/ Clarithromycin\t26 weeks\tCured\t\n2011 [8]\t61/M\t17 months\tCutaneous infection overlying the generator\tNo\tNo\t1 year\tLead culture\tYes\tLevofloxacin + amikacin\tNR\tCured\t\n2012 [11]\t43/M\t4 years\tFever, night sweats, and weight loss\tYes\tYes (right ventricular lead)\t157 days\tLead culture\tYes\tClarithromycin/ ciprofloxacin/ amikacin\t22 weeks\tDied\t\n2012 [5]\t56/M\t4 months\tPain and swelling at the BiV ICD pocket site\tNo\tYes (right atrial and ventricular leads)\t10 days\tOR culture\tYes\tMeropenem + linezolid + doxycycline\t\tCourse complicated by right middle cerebral artery (MCA) infarct and withdrawal of care with subsequent death\t\n2020\t27/F\t1 month\tFever, purulent discharge\tNo\tYes (tricuspid valve and ICD lead)\t1 month\tOR culture\tYes\tAzithromycin + Levofloxacin + imipenem then TMX/SMX + doxycycline\t4.5 months\tCured\t\n\nThis finding indicates that the infection had spread beyond the device pocket to the intravascular component of the CIED system, suggesting endovascular infection. In the 4 patients for which positive blood culture results were reported, 3 (31 %) had lead vegetation seen on echocardiographic images [3,9,11]. None of these three patients had evidence of valvular vegetation. The fourth patient had negative echocardiographic images, but she fulfilled pathologic criteria for infective endocarditis based on the isolation of the organism in an operative culture [10,13]. This patient was the only one with valvular endocarditis among all the reports in our review. We did not find any cases that described valvular vegetations on transthoracic echocardiogram (TTE) nor transesophageal echocardiogram (TEE). We believe that our case is the first case that described pacemaker and valvular and lead vegetations seen on echocardiogram images. The initial transthoracic echocardiogram (TTE) showed lead but no valvular vegetations. The transesophageal echocardiogram (TEE) confirmed a tricuspid valve vegetation. TTE has variable sensitivity for the detection of vegetations (<50 % to >90 % positive), indicating that a negative study does not exclude infective endocarditis (IE). TEE is also more sensitive than conventional TTE. In one report of 96 patients with IE [14], the sensitivity of TEE was 100 %, compared with 63 % for TTE, and the specificity values were identical (98 %).\n\nThe first documented case of pacemaker infection associated with M. fortuitum alone was reported in 2005, it was successfully treated with ciprofloxacin/clarithromycin for 6 months and removal of the entire pacing system [3].This patient had associated mycobacteremia and evidence of lead but not valvular vegetation. All other reported cases were cured with a combination of antimicrobials, except for in the case reported by Giannella et al., in which the patient was treated with quinolone monotherapy because the bacteria was resistant to the remaining agents [4], and in a report by Hu et al., in which the patients course was complicated by a stroke, withdrawal of care, and subsequent death [5]. All reported cases involved the removal of the pacemaker system, except for the case by Pastor et al., in which the patient was treated with ciprofloxacin and clarithromycin for 6 weeks total [9]. Other cases of native valve endocarditis (in patients who did not have any cardiac devices) caused by M. fortuitum have also been reported (Table 2). The first reported case of native valve endocarditis due to M. fortuitum with visible vegetations on echocardiography was reported in 2000 [7]. Spell et al. described a 47-year-old male with newly diagnosed HIV whose blood cultures grew M. fortuitum. Initial transthoracic echocardiography showed no evidence of vegetations, but the repeated transthoracic echocardiography at 3 weeks later displayed peduncular vegetations on the left coronary, noncoronary, and right coronary cusps of the aortic valve. The patient was treated with amikacin, cefoxitin, and ciprofloxacin for a total of 6 weeks then switched to oral ciprofloxacin and trimethoprim-sulfamethoxazole. The patient died 12 weeks after his initial clinical presentation.Table 2 Native valve endocarditis due to M. fortuitum.\n\nTable 2Year (Ref)\tAge/sex\tPresenting signs and symptoms\tBacteremia\tValve affected\tTime to diagnosis\tMethod of diagnosis\tSurgical therapy\tAntibiotics therapy\tDuration of treatment\tOutcome\t\n1992 [6]\t54/F\tFever, headache, productive cough, shortness of breath, fever\tYes\tMitral + aortic\t2 weeks\tBlood cultures\tNo\tAmoxycillin, TMP/SMX, ciprofloxacin, clofazimine, cefoxitin, amikacin\t6 weeks\tDied\t\n1999 [15]\t20/F\tNR\tNR\tMitral\tNR\tNR\tNo\tAmikacin, azithromycin, rifampin\tNR\tDied\t\n2000 [7]\t47/M\tDysphagia, odynophagia, fever, and chills\tYes\tAortic\t8 days\tBlood cultures\tNo, patient preferred medical management\tAmikacin, cefoxitin,ciprofloxacin,\t6 weeks\tPatient died 12 weeks after his initial clinical presentation\t\n2015 [17]\t64/F\tPulmonary edema and multifocal pneumonia\tYes\tPulmonic\tNR\tPCR of a tracheal aspirate\tNo\tAmikacin, imipenem, and clarithromycin\t16 days\tPatient decided to stop antibiotic therapy and entered hospice\t\n2006 [16]\t50/M\tNR\tNR\tMitral + aortic\tNR\tNR\tAVR + MVR\tClarithromycin, imipenem, moxifloxacin, amikacin\tNR\tDied\t\n2012 [18]\t49/F\tFever, malaise nausea\tYes\tAortic + tricuspid\t15 days\tBlood cultures\tNo\tLinezolid and ciprofloxacin, and oral TMP/SMX\t6−12 months\tNot reported\t\n2013 [19]\t12/F\tFever, fatigue\tYes\tTricuspid\tNR\tGenoType Mycobacterium CM assay\tNo\tAmikacin, ciprofloxacin, and imipenem\t6 weeks\tAlive at 12months after diagnosis\t\n2/F\tFever, fatigue\tYes\tTricuspid\tNR\tGenoType Mycobacterium CM assay\tNo\tAmikacin, ciprofloxacin, and imipenem\t6 weeks\t\n0.5/F\tFever, fatigue\tYes\tTricuspid\tNR\tGenoType Mycobacterium CM assay\tVSD patch removal\tAmikacin, ciprofloxacin, and imipenem\t6 weeks\t\nCurrent\t27/F\tFever\tNo\tTricuspid\t1 month\tOR culture, DNA Gene probe\tNo\tAzithromycin + Levofloxacin + imipenem then TMX/SMX + doxycycline\t4.5 months\tCured\t\n\nOwing to the rarity of non-tuberculous mycobacteria-related cardiac device-associated infective endocarditis, there are no clear management guidelines for the type and duration of therapy. Based on prior reports, a combination of two or three drugs for 6−12 months appears necessary. The choice of antibiotics depends on the results of susceptibility testing. M. fortuitum isolates are usually susceptible to multiple oral antimicrobial agents, including newer macrolides, quinolones, doxycycline, minocycline, and sulfonamides. Removal of the infected pacemaker device is of paramount importance given the high replapse rate despite prolonged antimicrobial therapy. In summary, we describe a rare case of pacemaker infection and native valve endocarditis with M. fortuitum, which highlights this mycobacterium as an important possible cause of cardiovascular infections.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of Competing Interest\n\nNone.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Siu Cw Cheng Lc Woo Pc Lau Cp Tse Hf. A patient with relapsing pacemaker infection due to \"Gram-positive bacilli\" Int J Cardiol 114 2 2007 E40 E41 10.1016/j.ijcard.2006.07.211 17070607\n2 Verghese S. Mullaseri A. Padmaja P. Subhadra A.C. Cherian K.M. Pacemaker implant site infection caused by atypical mycobacteria Indian Heart J 50 2 1998 201 202 9622990\n3 Sharma S. Tleyjeh I.M. Espinosa R.E. Costello B.A. Baddour L.M. Pacemaker infection due to Mycobacterium fortuitum Scand J Infect Dis 37 1 2005 66 67 15773026\n4 Giannella M. Valerio M. Franco J.A. Marin M. Bouza E. Muñoz P. Pacemaker infection due to Mycobacterium fortuitum: the role of universal 16S rRNA gene PCR and sequencing Diagn Microbiol Infect Dis 57 3 2007 337 339 10.1016/j.diagmicrobio.2006.08.010 17020794\n5 Hu Y.L. Bridge B. Wang J. Jovin I.S. Mycobacterium fortuitum causing infection of a biventricular pacemaker/implantable cardioverter defibrillator Int J Mycobacteriol 1 4 2012 221 223 10.1016/j.ijmyco.2012.10.001 26785629\n6 Singh M. Bofinger A. Cave G. Boyle P. Mycobacterium fortuitum endocarditis in a patient with chronic renal failure on hemodialysis Pathology 24 3 1992 197 200 10.3109/00313029209063173 1437294\n7 Spell D.W. Szurgot J.G. Greer R.W. Brown J.W. 3rd. Native valve endocarditis due to Mycobacterium fortuitum biovar fortuitum: case report and review Clin Infect Dis 30 3 2000 605 606 10.1086/313695 10722456\n8 Hemmersbach-Miller M. Cardenes-Santana M.A. Conde-Martel A. Bolanos-Guerra J.A. Campos-Herrero M.I. Cardiac device infections due to Mycobacterium fortuitum Can J Infect Dis Med Microbiol 16 3 2005 183 185 10.1155/2005/175132 18159541\n9 Pastor E. Luz Andreu A. Llombart M. Chiner E. Mycobacterium fortuitum: a rare cause of pacemaker infection [in Spanish] Enferm Infecc Microbiol Clin 24 2 2006 136 137 10.1157/13085023 16545324\n10 Al Soub H. Al Maslamani M. Al Khuwaiter J. El Deeb Y. Abu Khattab M. Myocardial abscess and bacteremia complicating Mycobacterium fortuitum pacemaker infection: case report and review of the literature Pediatr Infect Dis J 28 11 2009 1032 1034 10.1097/INF.0b013e3181aa6592 19859019\n11 Sharma H. Keshavan A. Little M.A. Cross J. Lipman M.C. Talukdar S. Fortuitous vasculitis Ren Fail 34 3 2012 378 382 10.3109/0886022X.2011.647337 22250755\n12 van Duin D. Goldfarb J. Schmitt S.K. Tomford J.W. Tuohy M.J. Hall G.S. Nontuberculous mycobacterial blood stream and cardiac infections in patients without HIV infection Diagn Microbiol Infect Dis 67 3 2010 286 290 10.1016/j.diagmicrobio.2010.02.006 20462726\n13 Li J.S. Sexton D.J. Mick N. Nettles R. Fowler V.G. Ryan T. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis Clin Infect Dis 30 4 2000 633 638 10.1086/313753 10770721\n14 Erbel R. Rohmann S. Drexler M. Mohr-Kahaly S. Gerharz C.D. Iversen S. Improved diagnostic value of echocardiography in patients with infective endocarditis by transesophageal approach: a prospective study Eur Heart J 9 1 1988 43 53\n15 Kuruvila M.T. Mathews P. Jesudason M. Ganesh A. Mycobacterium fortuitum endocarditis and meningitis after balloon mitral valvotomy J Assoc Physicians India 47 10 1999 1022 1023 10778701\n16 Collison S.P. Trehan N. Native double-valve endocarditis by Mycobacterium fortuitum following percutaneous coronary intervention J Heart Valve Dis 15 6 2006 836 838 17152794\n17 Mulhall A.M. Hebbeler-Clark R.S. Native pulmonic valve endocarditis due to Mycobacterium fortuitum: a case report and literature review Case Rep Infect Dis 2015 274819 10.1155/2015/274819 26167313\n18 Natsag J. Min Z. Hamad Y. Alkhalil B. Rahman A. Williams R. A mysterious gram-positive rods Case Rep Infect Dis 2012 841834 10.1155/2012/841834 22957282\n19 Vuković D. Parezanović V. Savić B. Dakić I. Laban-Nestorović S. Ilić S. Mycobacterium fortuitum endocarditis associated with cardiac surgery Serbia. Emerg Infect Dis 19 3 2013 517 519 10.3201/eid1903.120763 23750363\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "25()",
"journal": "IDCases",
"keywords": "Cardiac pacemaker; Defibrillator; Mycobacterium fortuitum; Nontuberculous mycobacteria",
"medline_ta": "IDCases",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "22957282;9622990;10770721;22250755;17152794;3345769;19859019;15773026;23750363;26167313;1437294;10722456;17070607;16545324;18159541;20462726;17020794;26785629;10778701",
"title": "Native valve endocarditis and pacemaker infection with Mycobacterium fortuitum.",
"title_normalized": "native valve endocarditis and pacemaker infection with mycobacterium fortuitum"
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"abstract": "Serotonin syndrome (SS) is an iatrogenic, drug-induced clinical syndrome caused by serotoninergic hyperstimulation. The diagnosis of SS is easily overlooked as most physicians (up to 85%) are unaware of this syndrome as a clinical entity. Diagnosis is also difficult due to its protean manifestations which can mimic a variety of medical conditions. Herein, we describe two cases of SS, who initially presented to the Surgical Department as surgical emergencies. The first case developed urinary retention after the administration of sertraline. The second case developed features mimicking acute intestinal obstruction. Both cases responded to the removal of offending agents and administration of cyproheptadine. There is a need to increase the awareness of SS among physicians because of the widespread use of serotonergic agents all around the world.",
"affiliations": "Department of Neurology, Smt B. K. Shah Medical Institute and Research Centre Medical College, Vadodara, Gujarat, India.;Department of Neurology, Smt B. K. Shah Medical Institute and Research Centre Medical College, Vadodara, Gujarat, India.",
"authors": "Prakash|Sanjay|S|;Rathore|Chaturbhuj|C|",
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"doi": "10.4103/0972-5229.175944",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-20-12010.4103/0972-5229.175944Case ReportSerotonin syndrome presenting as surgical emergency: A report of two cases Prakash Sanjay Rathore Chaturbhuj From: Department of Neurology, Smt B. K. Shah Medical Institute and Research Centre Medical College, Vadodara, Gujarat, IndiaCorrespondence: Dr. Sanjay Prakash, Department of Neurology, Smt B. K. Shah Medical Institute and Research Centre Medical College, Piperia, Waghodia, Vadodara - 391 760, Gujarat, India. E-mail: drprakashs@yahoo.co.in2 2016 20 2 120 122 Copyright: © Indian Journal of Critical Care Medicine2016This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.Serotonin syndrome (SS) is an iatrogenic, drug-induced clinical syndrome caused by serotoninergic hyperstimulation. The diagnosis of SS is easily overlooked as most physicians (up to 85%) are unaware of this syndrome as a clinical entity. Diagnosis is also difficult due to its protean manifestations which can mimic a variety of medical conditions. Herein, we describe two cases of SS, who initially presented to the Surgical Department as surgical emergencies. The first case developed urinary retention after the administration of sertraline. The second case developed features mimicking acute intestinal obstruction. Both cases responded to the removal of offending agents and administration of cyproheptadine. There is a need to increase the awareness of SS among physicians because of the widespread use of serotonergic agents all around the world.\n\nAutonomic dysfunctionclonuscyproheptadineserotonin syndrome\n==== Body\nIntroduction\nSerotonin syndrome (SS) is a drug-induced clinical syndrome characterized by a clinical triad of neuromuscular hyperactivity, altered mental status, and autonomic hyperactivity.[1] The clinical features range from mild nonspecific symptoms such as mild tremors to a life-threatening condition. The diagnosis of SS is easily overlooked as most physicians (up to 85%) are not aware of this syndrome as a clinical entity.[1] Diagnosis is also difficult due to its protean manifestations which can mimic a variety of medical conditions.[12] Herein, we describe two patients with SS, who initially presented to surgical departments.\n\nCase Reports\n\nCase 1\nA 62-year-old male attended Urology Department for voiding dysfunction which started as hesitancy for 2–3 days followed by acute retention of urine. Ultrasound examination and urinalysis were normal. Cystometric study demonstrated decreased detrusor pressure at maximum urinary flow rate. Biochemical parameters were normal. After the initial catheterization, he was put on the intermittent catheterization and a neurology opinion was sought. Neurological examinations revealed coarse postural tremors, hypertonia, hyperreflexia, and ankle and knee clonus. The patient had been receiving sertraline (50 mg/day) and clonazepam (0.5 mg/day) for the last 3–4 weeks for depression and insomnia.\n\nThe patient fulfilled the Hunter's criteria for SS.[1] Fluoxetine was discontinued. Cyproheptadine was administered in an initial dose of 12 mg, followed by 2 mg every 2-h for 24 h. Within 12 h of the administration of the first dose, the patient started to pass urine voluntarily. Other physical findings such as clonus, hyperreflexia, tremors, and hypertonia also disappeared in 48 h. The dosing schedule of cyproheptadine was changed after 24 h to 8 mg tds. Cyproheptadine was continued for another 7 days. In the next 6 months of follow-up, the patient has remained symptom-free.\n\nCase 2\nA 43-year-male had a long history of chronic back pain. Paroxetine (40 mg/day) and tramadol/acetaminophen combination (37.5/325 mg 3 times) were started for the recent exacerbation of back pain. Though backache improved, he developed abdominal pain, nausea and occasional vomiting on the 4th day of the administration of the drugs. Oral ondansetron (8 mg tds) was added for nausea and vomiting. His condition deteriorated with increasing abdominal pain, diffuse abdominal distension, and frequent vomiting. He was admitted in the surgery department with a possibility of acute intestinal obstruction. Abdominal examinations revealed tender, and distended abdomen with hyperactive bowel sound. Routine biochemical tests were normal. Plain abdominal X-ray showed dilated loops of small bowel. A diagnosis of intestinal obstruction was made. He was managed conservatively with nasogastric suctioning, intravenous fluids, and intravenous ondansetron. His condition further deteriorated, and he developed new symptoms such as agitation, irritability, restlessness, and tremors of both hands. At this point, a neurological consultation was sought.\n\nPhysical examinations revealed diaphoresis, mydriasis, postural-tremor, rigidity, hyperreflexia, and ankle and knee clonus. A diagnosis of SS was made. The patient had already stopped paroxetine and tramadol 2 days back. Ondansetron was discontinued. Cyproheptadine was administered at an initial dose of 12 mg, followed by 2 mg every 2 h for 24 h through a nasogastric tube. Diaphoresis, agitation, and irritability disappeared completely in 24-h. Gastrointestinal features (abdominal pain, distention, and vomiting) also subsided in next 24 h. After 48 h, the dosing schedule of cyproheptadine was changed to 8 mg tid and the patient was asked to continue for 7 days. In the next 2 months of follow-up, the patient was symptom-free.\n\nDiscussion\nBoth patients fulfilled the Hunter Serotonin Toxicity Criteria. Response to therapeutic doses of cyproheptadine further established the diagnosis of SS. Hunter criteria suggest that any person who had received serotonergic drug in the previous 5 weeks may develop SS.[1] In Case 1, the patient developed bladder symptoms after 3–4 weeks of the administration of sertraline. In Case 2, the patient was on two serotonergic agents, and he developed symptoms on the 4th day. Unfortunately, he received another serotonergic drugs (ondansetron) and his condition deteriorated further.\n\nDiagnosis of SS depends on the demonstration of a few specific physical signs (clonus, hyperreflexia, tremor, ocular clonus, hypertonia, etc.). Clonus is considered as the most important feature in establishing the diagnosis of the SS.[1] Autonomic manifestations in SS include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, diarrhea, dilated pupil, and hyperactive bowel sound.[13] Our both cases have prominent autonomic symptoms. In fact, symptoms related to autonomic features were the main reasons to seek initial medical consultation. In Case 1, symptoms started with voiding dysfunctions and, later on, other features were added. In Case 2, SS started with gastrointestinal symptoms (nausea, vomiting, abdominal pain, and abdominal distension) and, later on, other classical features of SS were added.\n\nSSRIs, including sertraline, can cause voiding dysfunctions.[4] However, these observations are silent regarding the presence of physical findings required for SS. Case 2 was on multiple serotonergic drugs. Each of these drugs may cause SS independently. Nausea, vomiting, and abdominal pain are reported in a few cases with SS. However, features suggestive of intestinal obstruction have not been reported previously.\n\nManagement of the SS comprises the removal of the offending drugs, providing supportive care, and the administration of 5-HT2a antagonists, especially cyproheptadine.[1] Urinary symptoms (Case 1) and gastrointestinal symptoms (Case 2) improved in parallel with the improvement of other features of SS with cyproheptadine. Therefore, we speculate that urinary symptoms and gastrointestinal symptoms were the part of SS.\n\nThere is just one case report where urinary retention was one of the accompanying features of SS.[3] However, to the best of our literature search, urinary retention as a presenting feature have not been reported. In the same way, nausea, vomiting, and abdominal pain are reported in a few cases with SS. However, features suggestive of intestinal obstruction have not been reported previously with SS.\n\n\nPathophysiology\nSerotonin toxicity results from an increase in the intrasynaptic concentration of serotonin (5-HT), especially in the brainstem and spinal cord. In parallel to central 5-HT effects, peripheral 5-HT receptors and other neurotransmitters also contribute to the pathophysiology of SS.[1] The different symptoms of SS are related to type of receptors or neurotransmitters involved.\n\nSerotonin is an important neurotransmitter involved in the voiding functions. 5-HT2 receptors are located in Onuf's nucleus and control micturition reflex and urinary continence.[5] In fact, in a study on rats, Duloxetine (norepinephrine and 5-HT reuptake inhibitor) prevented stress-induced incontinence by facilitating noradrenergic and serotoninergic systems.[5] Therefore, our Case 1 was in accordance with the known physiology of serotonin receptors and drugs acting on these receptors, and urinary problems were the part SS symptom complex.\n\nSerotonin is closely related to gastrointestinal motility and peristaltic reflex. Moreover, depending on various factors, it is related with both reduced gastrointestinal motility (constipation) and increased motility (diarrhea).[6] SS usually causes diarrhea, but it may cause constipation.[13] Case 2 was receiving combination therapy (paroxetine, tramadol, and ondansetron). Each of these drugs affects gastrointestinal motility. Therefore, multiple mechanisms could be speculated here.\n\nConclusion\nSS is a highly underdiagnosed condition. This is partly due to unawareness by a physician of SS and partly because of its protean manifestation. Any patient who is on any serotonergic agent if develops a new symptom, should be suspected for the presence of SS.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Boyer EW Shannon M The serotonin syndrome N Engl J Med 2005 352 1112 20 15784664 \n2 Prakash S Patel V Kakked S Patel I Yadav R Mild serotonin syndrome: A report of 12 cases Ann Indian Acad Neurol 2015 18 226 30 26019424 \n3 Radomski JW Dursun SM Reveley MA Kutcher SP An exploratory approach to the serotonin syndrome: An update of clinical phenomenology and revised diagnostic criteria Med Hypotheses 2000 55 218 24 10985912 \n4 Lowenstein L Mueller ER Sharma S FitzGerald MP Urinary hesitancy and retention during treatment with sertraline Int Urogynecol J Pelvic Floor Dysfunct 2007 18 827 9 17089079 \n5 Miyazato M Kaiho Y Kamo I Chancellor MB Sugaya K de Groat WC Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats Am J Physiol Renal Physiol 2008 295 F264 71 18480175 \n6 Sikander A Rana SV Prasad KK Role of serotonin in gastrointestinal motility and irritable bowel syndrome Clin Chim Acta 2009 403 47 55 19361459\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "20(2)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Autonomic dysfunction; clonus; cyproheptadine; serotonin syndrome",
"medline_ta": "Indian J Crit Care Med",
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"title": "Serotonin syndrome presenting as surgical emergency: A report of two cases.",
"title_normalized": "serotonin syndrome presenting as surgical emergency a report of two cases"
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"abstract": "BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.",
"affiliations": "Hospital Pablo Tobón Uribe, Department of Nephrology and Kidney Transplant, Medellín, Colombia.;University of Antioquia, Nephrology Section, Department of Internal Medicine, Medellin, Colombia.;Hospital Pablo Tobón Uribe, Department of Nephrology and Kidney Transplant, Medellín, Colombia.;University of Antioquia, Nephrology Section, Department of Internal Medicine, Medellin, Colombia.;University of Antioquia, Nephrology Section, Department of Internal Medicine, Medellin, Colombia.;Hospital Pablo Tobón Uribe, Department of Nephrology and Kidney Transplant, Medellín, Colombia.;Eberhard Karls University, Institute for Clinical Epidemiology and Applied Biometrics, Tuebingen, Germany.",
"authors": "Nieto-Ríos|John Fredy|JF|http://orcid.org/0000-0003-4781-3597;Benavides-Henao|Diego Armando|DA|http://orcid.org/0000-0003-2613-9230;Aristizabal-Alzate|Arbey|A|;Morales-Contreras|Carol|C|;Chacón-Jaimes|Diana Carolina|DC|http://orcid.org/0000-0001-5510-5764;Zuluaga-Valencia|Gustavo|G|http://orcid.org/0000-0002-9067-2710;Serna-Higuita|Lina María|LM|http://orcid.org/0000-0001-5182-8295",
"chemical_list": "D007166:Immunosuppressive Agents",
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"doi": "10.1590/2175-8239-JBN-2020-0049",
"fulltext": "\n==== Front\nJ Bras Nefrol\nJ Bras Nefrol\njbn\nJornal Brasileiro de Nefrologia\n0101-2800\n2175-8239\nSociedade Brasileira de Nefrologia\n\n33527977\n10.1590/2175-8239-JBN-2020-0049\nCase Report\nBK virus nephropathy in a heart transplant recipient\nNefropatia pelo vírus BK em um receptor de transplante cardíacohttp://orcid.org/0000-0003-4781-3597\nNieto-Ríos John Fredy 12\nhttp://orcid.org/0000-0003-2613-9230\nBenavides-Henao Diego Armando 2\nAristizabal-Alzate Arbey 1\nMorales-Contreras Carol 2\nhttp://orcid.org/0000-0001-5510-5764\nChacón-Jaimes Diana Carolina 2\nhttp://orcid.org/0000-0002-9067-2710\nZuluaga-Valencia Gustavo 1\nhttp://orcid.org/0000-0001-5182-8295\nSerna-Higuita Lina María 3\n1 Hospital Pablo Tobón Uribe, Department of Nephrology and Kidney Transplant, Medellín, Colombia.\n2 University of Antioquia, Nephrology Section, Department of Internal Medicine, Medellin, Colombia.\n3 Eberhard Karls University, Institute for Clinical Epidemiology and Applied Biometrics, Tuebingen, Germany.\nCorrespondence to: John Fredy Nieto-Ríos. E-mail: johnfredynieto@gmail.com\nAuthors' contribution\n\nWe hereby declare that all authors have contributed to the intellectual content of this manuscript and to the analysis of the data and have read and approved the final version of the article.\n\nConflict of interest\n\nThe authors declare no conflict of interest.\n\n22 1 2021\nJul-Sep 2021\n43 3 434439\n05 3 2020\n26 10 2020\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAbstract\n\nBK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.\n\nResumo\n\nA nefropatia pelo vírus BK no transplante renal é amplamente reconhecida como uma importante causa de disfunção e perda do enxerto. No caso de transplantes de órgãos que não sejam rins, a nefropatia pelo vírus BK em rins nativos tem sido reconhecida como uma causa de doença renal crônica, que está relacionada com imunossupressão; entretanto, o diagnóstico é geralmente tardio porque a disfunção renal é atribuída a outras causas, tais como toxicidade por drogas anticalcineurínicas, nefrite intersticial devido a medicamentos, alterações hemodinâmicas, diabetes, hipertensão, etc. Relatamos um caso de nefropatia pelo vírus BK em um paciente que foi submetido a transplante cardíaco devido à cardiomiopatia periparto. A biópsia renal relatou nefrite túbulo-intersticial crônica ativa associada à nefrite por poliomavírus em estágio avançado e a carga viral sanguínea para o vírus BK foi positiva (logaritmo 4,5). O tratamento imunossupressor foi reduzido, e após dois anos de acompanhamento, o paciente apresentava função renal estável com creatinina sérica de 2,5 mg/dL (TFG de 23,4 mL/min/1,73m2). Recomendamos que o vírus BK seja considerado como uma causa de disfunção renal em receptores de transplante cardíaco, com o objetivo de detectar sua replicação a tempo de reduzir a terapia imunossupressora antes que um comprometimento irreversível da função renal possa se manifestar.\n\nKeywords:\n\nPolyomavirus\nBK virus\nBK Virus Nephropathy\nOrgan Transplantation\nHeart Transplantation\nImmunosuppression.\nDescritores:\n\nPoliomavírus\nVírus BK\nNefropatias\nTransplante de Órgãos\nTransplante de Coração\nImunossupressão.\n==== Body\npmcIntroduction\n\nBK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.\n\nAt present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.\n\nIn recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.\n\nClinical case\n\nA 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.\n\nTable 1 Laboratory tests results\n\nUrine Tests\t\nDensity\t1.005\t\nProteinuria\tNegative\t\nGlycosuria\tNegative\t\nLeukocytes\t0-5\t\nErythrocytes\t0-2\t\nBacteria\tScarce\t\nTest for infectious diseases\t\nBk virus, viral load (blood)\t33800 copies/mL\t\nAgS Hepatitis B\tNegative\t\nAntibodies for hepatitis C\tNegative\t\nAntibodies for human immunodeficiency virus\tNegative\t\nImmunological Tests\t\nSerological test for syphilis\tNegative\t\nAntinuclear antibodies (ANAS)\tNegative\t\nAntibodies anti-DNA\tNegative\t\nComplement C3 y C4\tNormal\t\nBlood Tests\t\nSodium\t140 mmol/L\t\nChloride\t108 mmol/L\t\nPotassium\t3.68 mmol/L\t\nCalcium\t8.5 mg/dL\t\nPhosphorus\t3.3 mg/dL\t\nLactate dehydrogenase\t188 U/L\t\nParathormone\t81 pg/mL\t\nCPK total\t126 U/L\t\nAlbumin\t4 g/dL\t\nHemoglobin\t11.3 g/dL\t\nHematocrit\t26.80%\t\nLeukocytes\t4900 mm3\t\nPlatelets\t168000 mm3\t\nNeutrophils\t66%\t\nLymphocytes\t20%\t\nEchocardiography\t\nLeft ventricular ejection fraction: 60%\t\nAgS: surface antigen.\n\nThe kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.\n\nFigure 1 Laboratory values during follow up.\n\nFigure 2 BK viral load (number of copies).\n\nFigure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.\n\nDiscussion\n\nPolyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.\n\nIn the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.\n\nDetection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.\n\nKidney biopsy is considered the \"gold\" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.\n\nCurrently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.\n\nIn summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest.\n==== Refs\nReferences\n\n1 Ambalathingal GR Francis RS Smyth MJ Smith C Khanna R BK polyomavirus: clinical aspects, immune regulation, and emerging therapies Clin Microbiol Rev 2017 30 2 503 528 28298471\n2 Gardner SD Field AM Coleman DV Hulme B New human papovavirus (B. K.) isolated from urine after renal transplantation Lancet 1971 6 1 7712 1253 1257 4104714\n3 Ahsan N Shah KV Polyomaviruses and human diseases Adv Exp Med Biol 2006 577 1 18 16626024\n4 Chong S Antoni M MacDonald A Reeves M Harber M Magee CN BK vírus: current understanding of pathogenicity and clinical disease in transplantation Rev Med Virol 2019 7 29 4 e2044 30958614\n5 Parasuraman R Yee J Karthikeyan V del Busto R Infectious complications in renal transplant recipients Adv Chronic Kidney Dis 2006 7 13 3 280 294 16815233\n6 Helle F Brochot E Handala L Martin E Castelain S Francois C Biology of the BKPyV: an update Viruses 2017 11 9 11 327 327\n7 Lee W Langhoff E Polyomavirus in human cancer development Adv Exp Med Biol 2006 577 310 318 16626045\n8 Vigil D Konstantinov NK Barry M Harford AM Servilla KS Kim YH BK nephropathy in the native kidneys of patients with organ transplants: clinical spectrum of BK infection World J Transplant 2016 9 6 3 472 504 27683628\n9 Nickeleit V Mihatsch MJ Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat Transpl Int 2006 12 19 12 960 973 17081225\n10 Limaye AP Smith KD Cook L Groom DA Hunt NC Jerome KR Polyomavirus nephropathy in native kidneys of non-renal transplant recipients Am J Transplant 2005 3 5 3 614 620 15707418\n11 Saundh BK Tibble S Baker R Sasnauskas K Harris M Hale A Different patterns of BK and JC polyomavirus reactivation following renal transplantation J Clin Pathol 2010 8 63 8 714 718 20702473\n12 Sawinski D Goral S BK virus infection: an update on diagnosis and treatment Nephrol Dial Transplant 2015 2 30 2 209 217 24574543\n13 Kotla SK Kadambi PV Hendricks AR Rojas R BK polyomavirus-pathogen, paradigm and puzzle Nephrol Dial Transplant 2019 12 gfz273\n14 Park S Kim YW Lee YJ Park KM Park JH Kim BM Polyomavirus nephropathy in native kidneys of an immunocompetent individual Am J Case Rep 2017 18 498 501 28473689\n15 Aksenova M Tsetlina V Gutovskaya E Mitrofanova A Balashov D Maschan A BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation Pediatr Transplant 2015 2 19 1 E29 E32 25484248\n16 Pendse SS Vadivel N Ramos E Mudge GH Von Visger T Fang JC BK viral reactivation in cardiac transplant patients: evidence for a double-hit hypothesis J Heart Lung Transplant 2006 7 25 7 814 819 16818124\n17 Barten MJ Zuckermann A BK vírus: a cause for concern in thoracic transplantation? Ann Transplant 2018 23 310 321 29748530\n18 Viswesh V Yost SE Kaplan B The prevalence and implications of BK virus replication in non-renal solid organ transplant recipientes: a systematic review Transplant Rev (Orlando) 2015 7 29 3 175 180 25736693\n19 Jamboti JS BK virus nephropathy in renal transplant recipients Nephrology 2016 8 21 8 647 654 26780694\n20 Rodriguez-Benot A Suarez-Fernández ML Fernández-Tagarro E Cañas L Calvo-Romero N Amenábar JJ Nefropatía por poliomavirus BK. Diagnóstico y tratamiento Nefrologia 2018 10 9 Suppl 2 S50 S66\n21 Hara S Banff 2013 update: pearls and pitfalls in transplant renal pathology Nephrology 2015 7 20 Suppl 2 2 8\n22 Vu D Shah T Ansari J Naraghi R Min D Efficacy of intravenous immunoglobulin in the treatment of persistent BK viremia and BK virus nephropathy in renal transplant recipients Transplant Proc 2015 3 47 2 394 398 25769580\n23 Yoon SH Cho JH Jung HY Choi JY Park SH Kim YL Clinical impact of BK virus surveillance on outcomes in kidney transplant recipients Transplant Proc 2015 4 47 3 660 665 25891706\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0101-2800",
"issue": "43(3)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D001739:BK Virus; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D009395:Nephritis, Interstitial; D027601:Polyomavirus Infections; D014412:Tumor Virus Infections",
"nlm_unique_id": "9426946",
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"pages": "434-439",
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"pmid": "33527977",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "24574543;16626024;25484248;26031578;25769580;25736693;30958614;28298471;29099746;15707418;27683628;26780694;29748530;31891401;17081225;25891706;16815233;16818124;28473689;20702473;4104714;16626045",
"title": "BK virus nephropathy in a heart transplant recipient.",
"title_normalized": "bk virus nephropathy in a heart transplant recipient"
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"abstract": "A 70-year-old woman with rheumatoid arthritis undergoing methotrexate (MTX) treatment presented with dyspnea and a subfever. Computed tomography (CT) revealed a diffuse minimal ground-glass appearance in both lungs and splenomegaly. The gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen. The lung biopsy specimen revealed the presence of CD20-positive atypical lymphocytes in the small pulmonary vessels. The patient was diagnosed with pulmonary intravascular diffuse large B-cell lymphoma (IVLBCL) and exhibited spontaneous regression after MTX was discontinued. This report describes a rare case of MTX-associated lymphoproliferative disorder expressing pulmonary IVLBCL.",
"affiliations": "Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Japan.;Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan.",
"authors": "Iwami|Eri|E|;Ito|Fumimaro|F|;Sasahara|Kotaro|K|;Kuroda|Aoi|A|;Matsuzaki|Tatsu|T|;Nakajima|Takahiro|T|;Abe|Daichi|D|;Matsumoto|Kimihiro|K|;Sasaki|Aya|A|;Eguchi|Keisuke|K|;Terashima|Takeshi|T|",
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"doi": "10.2169/internalmedicine.3216-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3161959710.2169/internalmedicine.3216-19Case ReportPulmonary Intravascular Large B-cell Lymphoma in a Patient Administered Methotrexate for Rheumatoid Arthritis Iwami Eri 1Ito Fumimaro 1Sasahara Kotaro 1Kuroda Aoi 1Matsuzaki Tatsu 1Nakajima Takahiro 1Abe Daichi 2Matsumoto Kimihiro 2Sasaki Aya 3Eguchi Keisuke 4Terashima Takeshi 1\n1 Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan\n2 Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Japan\n3 Department of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Japan\n4 Department of Surgery, Tokyo Dental College Ichikawa General Hospital, JapanCorrespondence to Dr. Takeshi Terashima, terasima@tdc.ac.jp\n\n17 10 2019 1 2 2020 59 3 429 433 18 4 2019 9 9 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 70-year-old woman with rheumatoid arthritis undergoing methotrexate (MTX) treatment presented with dyspnea and a subfever. Computed tomography (CT) revealed a diffuse minimal ground-glass appearance in both lungs and splenomegaly. The gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen. The lung biopsy specimen revealed the presence of CD20-positive atypical lymphocytes in the small pulmonary vessels. The patient was diagnosed with pulmonary intravascular diffuse large B-cell lymphoma (IVLBCL) and exhibited spontaneous regression after MTX was discontinued. This report describes a rare case of MTX-associated lymphoproliferative disorder expressing pulmonary IVLBCL. \n\ndiffuse large B-cell lymphomahypoxiaintravascular lymphomamethotrexaterheumatoid arthritis\n==== Body\nIntroduction\nMethotrexate (MTX) is a key drug for the treatment of rheumatoid arthritis (RA). The differential diagnosis of pulmonary diseases presenting as diffuse infiltration and hypoxia during treatment with MTX includes infection, interstitial pneumonia associated with RA, and MTX-associated interstitial pneumonia (1,2). MTX is also known to induce lymphoproliferative disorders (MTX-LPDs), and diffuse large B-cell lymphoma (DLBCL) is the most common type (3-9).\n\nIntravascular LBCL (IVLBCL) is a rare type of DLBCL, and tumor cells are seen only in the blood vessel lumina (10). There are some clinical challenges associated with IVLBCL, including the difficulty of making a diagnosis due to the non-specificity of the symptoms, such as a persistent fever, as well as the aggressive and potentially fatal disease progression. Only three cases of MTX-associated IVLBCL have been reported (11-13).\n\nWe herein report an extremely rare case of pulmonary IVLBCL with hypoxia and dyspnea in a patient with RA receiving MTX. The diagnosis was confirmed using a lung specimen obtained by video-associated thoracic surgery (VATS).\n\nCase Report \nA 70-year-old woman with RA who had been treated with MTX (12-16 mg/week) for 7 years was referred to our hospital with complaints of progressive dyspnea on exertion and an intermittent subfever. The patient had a smoking history of 25 packs a year. Her body temperature was 37.3℃, respiratory rate was 16 breaths/min, and oxygen saturation was 90% on room air. There were no pain spots, skin eruptions, or lymphadenopathy. Physical and neurological examinations showed no abnormal findings.\n\nAn initial laboratory examination showed a white blood cell (WBC) count of 8,600 cells/μL (66.5% neutrophils, 17.1% lymphocytes), lactate dehydrogenase (LDH) level of 947 U/L, and C-reactive protein (CRP) level of 3.28 mg/dL. The serum levels of soluble interleukin-2 receptor (sIL-2R), KL-6, and matrix metalloproteinase (MMP)-3 were 5,280 U/mL (normal range, 121-613 U/mL), 308 U/mL (normal range <500 U/mL), and 42.9 ng/mL (normal range, 17.3-59.7 ng/mL), respectively. The beta-D-glucan level was 12 pg/mL (normal range <20 pg/mL). There was no marked increase in the level of antibody against Trichosporon asahii. The T-SPOT test for TB, which measures the number of interferon-gamma-secreting spot-forming T cells obtained from a patient stimulated by Mycobacterium tuberculosis-specific antigens, was negative. The chest radiograph findings were normal, whereas computed tomography (CT) revealed diffuse minimal nonspecific ground-glass appearance in the both lungs (Fig. 1) and splenomegaly. Bone marrow aspiration revealed no malignancy. Bronchoscopy was nondiagnostic with normal findings in the bronchoalveolar lavage fluid (BALF), showing alveolar macrophages, 98.5%; neutrophils, 0.5%; and lymphocytes, 1%. A transbronchial lung biopsy was not performed. Pathogenic bacteria, mycobacteria, and fungi were not observed in the BALF culture. Staining of the BALF specimen did not show evidence of Pneumocystis jirovecii or cytomegalovirus infection. P. jirovecii DNA was also not detected in the BALF on a polymerase chain reaction (PCR) analysis.\n\nFigure 1. Computed tomography (CT) showed a diffuse, minimal, nonspecific ground-glass appearance in both lungs.\n\nAlthough MTX was discontinued on day 2 after hospitalization, the patient's respiratory failure gradually worsened. The clinical course of the patient is shown in Fig. 2. She needed supplemental oxygen therapy (1-4 L/min via a nasal cannula). A gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen (Fig. 3). On day 17, a lung biopsy using VATS was performed, and a specimen was collected from S6 and S8 of the right lower lobe. A microscopic examination revealed the presence of moderate to large atypical lymphocytes in small pulmonary vessels (Fig. 4a). The neoplastic cells had large nuclei and moderate amounts of cytoplasm. Immunochemical staining showed that the tumor cells were positive for CD20 (Fig. 4b) and CD79a but negative for CD3, CD10, and Epstein-Barr virus (EBV)-encoded small RNA (EBER) using in situ hybridization. Based on these findings, the patient was diagnosed with pulmonary IVLBCL. A few weeks after discontinuation of MTX, her respiratory condition gradually improved, and oxygen therapy was withdrawn. The numbers of peripheral lymphocytes just before and 2 weeks after the cessation of MTX were 1,153 and 2,655 cells/μL, respectively.\n\nFigure 2. The clinical course of the patient. LDH: lactate dehydrogenase, sIL-2R: soluble interleukin-2 receptor, VATS: video-associated thoracic surgery\n\nFigure 3. A gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen.\n\nFigure 4. (a) A microscopic examination revealed the presence of atypical moderate to large lymphocytes in small pulmonary vessels. (b) Immunochemical staining showed that these cells were positive for CD20.\n\nShe was discharged on day 35. She became afebrile, and her serum LDH, CRP, and sIL-2R values decreased to normal levels. On CT, the diffuse ground-glass opacities and splenomegaly were found to have disappeared. Because the patient showed spontaneous regression after the cessation of MTX and her symptoms completely disappeared, chemotherapy was not administered, and she was only observed. 18-fluorodeoxyglucose positron-emission tomography (PET)/CT performed after discharge revealed no specific fluorodeoxyglucose uptake in the lungs, spleen, or lymphoid or extra-lymphoid organs. The patient is currently under careful observation and shows no signs of recurrence.\n\nDiscussion\nThis report describes a case of MTX-LPD in a patient expressed as pulmonary IVLBCL. The pulmonary IVLBCL regressed spontaneously after simple cessation of MTX, and there has been no recurrence.\n\nAccording to the revised 4th edition of the World Health Organization (WHO) guidelines, LPDs that develop in a patient under treatment with an immunosuppressive drug are classified as “other iatrogenic immunodeficiency-associated LPDs” (14). Among them, cases of LPD in patients with RA who are treated with MTX have been called MTX-LPD. DLBCL is the common histologic type of MTX-LPD, and its typical clinical features have been reported to be lymphadenopathy or a mass lesion in an extranodal location (3-9), including the skin, liver, spleen, lung, gastrointestinal tract, and bone marrow (3-8,14). The patterns observed most frequently in the lungs of patients with DLBCL are consolidation, nodules and mass lesions (15-17). However, diffuse ground-glass opacity has been very rarely reported (17). This is a rare case of MTX-associated pulmonary DLBCL showing ground-glass opacity on CT with histopathological confirmation of the lesion as IVLBCL.\n\nThe initial differential diagnosis in our patient was opportunistic infections, interstitial pneumonia associated with RA, and MTX-induced pneumonitis. Hypersensitivity pneumonitis and sarcoidosis were also included as the differential diagnosis based on the symptoms, clinical course, and CT findings. No abnormalities were noted in the BALF, suggesting that the possibility of MTX-associated interstitial pneumonia, hypersensitivity pneumonitis, or sarcoidosis was low. Negative pathological findings and normal values of beta-D-glucan and serum KL-6 suggested that opportunistic infections, such as tuberculosis and pneumocystis pneumonia, were unlikely to be the cause of the pulmonary disease. According to a database search of papers published from 1990 to 2015, pulmonary complications seen in patients with RA under MTX treatment included LPD (42%), interstitial fibrosis (33%), and infections (25%) (2). In the cases of MTX-LPD, the median treatment period and cumulative dose of MTX were reported to be 4-10 years and 940-1,400 mg, respectively (3-8). The duration of 7 years and cumulative dose of 4,200 mg in our case suggested the possibility of MTX-LPD, which was further indicated by the findings of the gallium scintigram and elevated levels of sIL-2R. VATS was performed to identify the cause of pulmonary disease, confirm the pulmonary IVLBCL, and examine the contribution of interstitial pneumonia associated with RA. The findings of the VATS specimen confirmed the diagnosis of pulmonary IVLBCL.\n\nThe main sites of involvement in patients with IVLBCL are the central nervous system, skin, bone marrow, and lymph nodes, and involvement of the lungs has also been reported (10,18,19). Clinical manifestations of IVLBCL in the lungs have included a fever, cough, hypoxemia, and progressive dyspnea (18-23). The common patterns of parenchymal abnormality seen on CT images include bilateral diffuse ground-glass opacity, and in a few cases, peribronchovascular and interlobular septal thickening, nodules, and consolidation (19-23). These CT features have been reported to correlate with thickened alveolar septa owing to the distension of small vessels filled with neoplastic lymphoid cells (19). The clinical, radiological, and pathological findings seen in our case were consistent with those described in previous reports (19-22).\n\nIVLBCL usually shows an aggressive clinical course with a poor prognosis (10). Chemotherapy has given a survival advantage to patients with IVLBCL (24). However, spontaneous regression has been reported to occur in 23-77% of patients with MTX-LPD after cessation of MTX (3-8). Previous studies showed that patients with spontaneous regression had a higher rate of EBV positivity than those without regression (3,4). Another study reported that spontaneous regression occurred in 18 of 20 cases following MTX cessation alone and that the rate of lymphocyte recovery 2 weeks after MTX cessation was higher in cases with regression than in those without regression (5). This observation was confirmed by a study showing that an increase in the lymphocyte count of >220 cells/μL at 2 weeks after MTX cessation may predict a favorable prognosis for spontaneous regression of LPD (25). Although EBER was negative in our case, the lymphocyte count rapidly recovered from 1,153 cells/μL to 2,655 cells/μL by 2 weeks after the cessation of MTX. Indeed, in our case, the patient demonstrated spontaneous regression of MTX-associated IVLBCL after the cessation of MTX. Close observation must be applied, as relapse is known to occur in a moderate number of patients whose LPD initially regresses after cessation of MTX (14).\n\nThis case report is important because pulmonary IVLBCL should be considered as a differential diagnosis in patients undergoing MTX treatment complicated with dyspnea and hypoxia.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nConway R , Low C , Coughlan RJ , O'Donnell MJ , Carey JJ \nMethotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials . Arthritis Rheum \n66 : 803 -812 , 2014 .\n2. \nThaniyan A , Ayman FFA , Mirghani HO , Al-Sayed BA , Merghani TH \nHistopathological features of methotrexate induced pulmonary lesions in rheumatoid arthritis patients: a systematic review of case reports . Open Access Maced J Med Sci \n5 : 266 -270 , 2017 .28507640 \n3. \nHoshida Y , Xu J-X , Fujita S , et al \nLymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication . J Rheumatol \n34 : 322 -331 , 2007 .17117491 \n4. \nIchikawa A , Arakawa F , Kiyasu J , et al \nMethotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression . Eur J Haematol \n91 : 20 -28 , 2013 .23560463 \n5. \nInui Y , Matsuoka H , Yakushijin K , et al \nMethotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal . Leuk Lymphoma \n56 : 3045 -3051 , 2015 .25721751 \n6. \nHarigai M \nLymphoproliferative disorders in patients with rheumatoid arthritis in the era of widespread use of methotrexate: a review of the literature and current perspective . Mod Rheumatol \n28 : 1 -8 , 2018 .28758827 \n7. \nTokuhira M , Saito S , Okuyama A , et al \nClinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression . Leuk Lymphoma \n59 : 1143 -1152 , 2018 .28877615 \n8. \nGion Y , Iwaki N , Takata K , et al \nClinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types . Cancer Sci \n108 : 1271 -1280 , 2017 .28380678 \n9. \nKurita D , Miyoshi H , Ichikawa A , et al \nMethotrexate-associated lymphoproliferative disorders in patients with rheumatoid arthritis: clinicopathologic features and prognostic factors . Am J Surg Pathol \n43 : 869 -884 , 2019 .31116708 \n10. \nPonzoni M , Ferreri AJM , Campo E , et al \nDefinition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting . J Clin Oncol \n25 : 3168 -3173 , 2007 .17577023 \n11. \nKikuchi J , Kaneko Y , Kasahara H , et al \nMethotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis . Intern Med \n55 : 1661 -1665 , 2016 .27301524 \n12. \nKida T , Kohno M , Chinen Y , et al \nIntravascular lymphoma in a rheumatoid arthritis patient following short-term methotrexate treatment . Rheumatology \n56 : 318 -320 , 2017 .27818387 \n13. \nHagihara M , Mese T , Ohara S , Hua J , Ide S , Inoue M \nMethotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis: a very rare case . Intern Med \n57 : 3001 -3005 , 2018 .29780139 \n14. \nGaulard P , Swerdlow SH , Harris NL , Sundstrom C , Jaffe ES \nOther iatrogenic immunodeficiency-associated lymphoproliferative disorders . In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . 4th ed. \nSwerdlow SH , Campo E , Harris NL et al , Eds. IARC , Lyon, France , 2017 : 462 -464 .\n15. \nHare SS , Souza CA , Bain G , Seely JM , Gomes MM , Quigley M \nThe radiological spectrum of pulmonary lymphoproliferative disease . Br J Radiol \n85 : 848 -864 , 2012 .22745203 \n16. \nZhang M-C , Zhou M , Song Q , et al \nClinical features and outcomes of pulmonary lymphoma: a single center experience of 180 cases . Lung Cancer \n132 : 39 -44 , 2019 .31097092 \n17. \nChen Y , Chen A , Jiang H , et al \nHRCT in primary pulmonary lymphoma: can CT imaging phenotypes differentiate histological subtypes between mucosa-associated lymphoid tissue (MALT) lymphoma and non-MALT lymphoma? \nJ Thorac Dis \n10 : 6040 -6049 , 2018 .30622775 \n18. \nShimada K , Kinoshita T , Naoe T , Nakamura S \nPresentation and management of intravascular large B-cell lymphoma . Lancet Oncol \n10 : 895 -902 , 2009 .19717091 \n19. \nCha MJ , Lee KS , Hwang HS , et al \nPulmonary intravascular lymphomatosis: clinical, CT, and PET findings, correlation of CT and pathologic results, and survival outcome . Radiology \n280 : 602 -610 , 2016 .26943231 \n20. \nZhang Y , Bi L , Qiu Y , et al \nPrimary pulmonary intravascular large B-cell lymphoma: a report of three cases and literature review . Oncol Lett \n15 : 3610 -3613 , 2018 .29467882 \n21. \nMartusewicz-Boros M , Wiatr E , Radzikowska E , Roszkowski-Sliz K , Langfort R \nPulmonary intravascular large B-cell lymphoma as a cause of severe hypoxemia . J Clin Oncol \n25 : 2137 -2139 , 2007 .17513823 \n22. \nChoi EJ , Jin GY , Chung MJ \nSerial chest CT findings of intravascular large B-cell lymphoma of the lungs . J Thorac Dis \n10 : E218 -E220 , 2018 .29707378 \n23. \nSouza CA , Quan K , Seely J , Kravcik S , Burns B \nPulmonary intravascular lymphoma . J Thorac Imaging \n24 : 231 -233 , 2009 .19704329 \n24. \nRajyaguru DJ , Bhaskar C , Borgert AJ , Smith A , Parsons B \nIntravascular large B-cell lymphoma in the United states (US): a population-based study using surveillance, epidemiology, and end results program and national cancer database . Leuk Lymphoma \n58 : 2080 -2088 , 2017 .\n25. \nSaito S , Kaneko Y , Yamaoka K , Tokuhira M , Takeuchi T \nDistinct patterns of lymphocyte count transition in lymphoproliferative disorder in patients with rheumatoid arthritis treated with methotrexate . Rheumatology \n56 : 940 -946 , 2017 .28165538\n\n",
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"issn_linking": "0918-2918",
"issue": "59(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "diffuse large B-cell lymphoma; hypoxia; intravascular lymphoma; methotrexate; rheumatoid arthritis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D016403:Lymphoma, Large B-Cell, Diffuse; D008727:Methotrexate; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
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"title": "Pulmonary Intravascular Large B-cell Lymphoma in a Patient Administered Methotrexate for Rheumatoid Arthritis.",
"title_normalized": "pulmonary intravascular large b cell lymphoma in a patient administered methotrexate for rheumatoid arthritis"
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"abstract": "A 67-year-old man presented for an evaluation after experiencing right hypochondrial pain lasting for two months. Abdominal ultrasonography showed a hepatic tumor in the right liver and extremely mild hepatic steatosis. The imaging findings indicated that the tumor (43 mm in size) was ischemic, and the lesion was surgically resected and examined. The histopathological findings demonstrated 95% necrosis with moderately differentiated hepatocellular carcinoma (HCC). The diagnosis was HCC with spontaneous regression. There was also pathological evidence of thrombus formation in the peripheral arteries and portal veins. In addition, the non-cancerous regions of the liver were diagnosed as exhibiting non-alcoholic steatohepatitis. The pathological findings obtained after resection of the HCC lesion showed spontaneous regression.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Japan.",
"authors": "Matsuoka|Shunichi|S|;Tamura|Akinori|A|;Moriyama|Mitsuhiko|M|;Fujikawa|Hirotoshi|H|;Mimatsu|Kenji|K|;Oida|Takatsugu|T|;Sugitani|Masahiko|M|",
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"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009365:Neoplasm Regression, Spontaneous; D065626:Non-alcoholic Fatty Liver Disease; D011169:Portal Vein; D013927:Thrombosis; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "9204241",
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"title": "Pathological evidence of the cause of spontaneous regression in a case of resected hepatocellular carcinoma.",
"title_normalized": "pathological evidence of the cause of spontaneous regression in a case of resected hepatocellular carcinoma"
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"companynumb": "JP-PFIZER INC-2015074540",
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"abstract": "BACKGROUND\nChronic spontaneous urticaria (CSU) is characterized by the repeated occurrence of persistent hives and/or angioedema for ≥6 weeks, without specific external stimuli. H1 -antihistamines have long been the standard of care of CSU, but many patients remain uncontrolled even at 4× the approved dose. Add-on therapy with omalizumab has proven effective in clinical trials, but little is known about omalizumab treatment in Belgium.\n\n\nOBJECTIVE\nTo collect real-world clinical data on omalizumab treatment in adults with CSU in Belgium.\n\n\nMETHODS\nThis was an observational, retrospective chart review of adults with CSU, who initiated omalizumab treatment between August 2014 and December 2016 (maximum 28 months follow-up).\n\n\nRESULTS\nIn total, 235 patients were included (median time from symptom onset to diagnosis, 5.4 months; median time from diagnosis to commencing omalizumab, 6.7 months). Treatments used before/after commencing omalizumab did not always adhere to guidelines; many patients (26.4%/11.1%) received first-generation H1 -antihistamines, while 20.4% used omalizumab monotherapy after initiating treatment. The mean interval between omalizumab administrations was 4.8 (SD 1.7) weeks; 67.8% of patients had ≥1 interval prolongation and/or shortening. Mean baseline 7-day Urticaria Activity Score (UAS7) was 32.0 (SD 6.05); this improved to 12.6 (SD 11.2) after 1 month of omalizumab. About 67.2% of patients reached UAS7 ≤ 6 (well controlled) during the study. A total of 87 patients stopped omalizumab and never restarted before the end of the observation period; the most prevalent reason was remission of symptoms (49.4% of patients), followed by lack of effect (12.6%), lost to follow-up (6.9%) and adverse events (3.4%). Headache was the most common adverse event (n = 8/82). No anaphylaxis was reported.\n\n\nCONCLUSIONS\nThis study revealed that patients initiated on omalizumab in Belgium had severe CSU at baseline, and showed substantial improvements after 1 month of treatment. Greater adherence to the prescription of guideline-recommended medications is needed for the treatment of CSU.",
"affiliations": "Department of Dermatology, Ghent University Hospital, Gent, Belgium.;Department of Dermatology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Department of Dermatology, AZ Delta Campus Rembert Torhout, Torhout, Belgium.;Department of Immunology-Allergology-Rheumatology, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.;Department of Dermatology, Universitair Ziekenhuis Brussel, Brussels, Belgium.;Service Infectious Diseases and General Internal Medicine, CHU Liège, Liège, Belgium.;Department of Dermatology University Hospital Antwerp, University of Antwerp, Antwerp, Belgium.;Groepspraktijk Dermatologie Roeselare, Roeselare, Belgium.;Department of Dermatology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;N.V. Novartis Pharma S.A., Vilvoorde, Belgium.;N.V. Novartis Pharma S.A., Vilvoorde, Belgium.;Laboratory of Clinical Immunology, KU Leuven Department of Microbiology and Immunology, Leuven, Belgium.",
"authors": "Lapeere|H|H|;Baeck|M|M|;Stockman|A|A|;Sabato|V|V|;Grosber|M|M|;Moutschen|M|M|;Lambert|J|J|;Vandebuerie|L|L|;de Montjoye|L|L|https://orcid.org/0000-0003-0673-0728;Rabijns|H|H|;Allewaert|K|K|;Schrijvers|R|R|",
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"doi": "10.1111/jdv.15684",
"fulltext": "\n==== Front\nJ Eur Acad Dermatol VenereolJ Eur Acad Dermatol Venereol10.1111/(ISSN)1468-3083JDVJournal of the European Academy of Dermatology and Venereology0926-99591468-3083John Wiley and Sons Inc. Hoboken 10.1111/jdv.15684JDV15684Original ArticleAllergy and EczemaA retrospective analysis omalizumab treatment patterns in patients with chronic spontaneous urticaria: a real‐world study in Belgium Omalizumab treatment patterns in BelgiumLapeere et al.Lapeere H. \n1\nHilde.Lapeere@uzgent.be Baeck M. \n2\nStockman A. \n3\nSabato V. \n4\nGrosber M. \n5\n\n6\nMoutschen M. \n7\nLambert J. \n8\nVandebuerie L. \n9\nde Montjoye L. https://orcid.org/0000-0003-0673-0728\n2\nRabijns H. \n10\nAllewaert K. \n10\nSchrijvers R. \n11\n\n1 \nDepartment of Dermatology\nGhent University Hospital\nGent\nBelgium\n\n2 \nDepartment of Dermatology, Cliniques Universitaires Saint‐Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n3 \nDepartment of Dermatology\nAZ Delta Campus Rembert Torhout\nTorhout\nBelgium\n\n4 \nDepartment of Immunology‐Allergology‐Rheumatology\nUniversity of Antwerp and Antwerp University Hospital\nAntwerp\nBelgium\n\n5 \nDepartment of Dermatology\nUniversitair Ziekenhuis Brussel\nBrussels\nBelgium\n\n6 \nVrije Universiteit Brussel\n Brussels\nBelgium\n\n7 \nService Infectious Diseases and General Internal Medicine\nCHU Liège\nLiège\nBelgium\n\n8 \nDepartment of Dermatology University Hospital Antwerp\nUniversity of Antwerp\nAntwerp\nBelgium\n\n9 \nGroepspraktijk Dermatologie Roeselare\nRoeselare\nBelgium\n\n10 \nN.V. Novartis Pharma S.A.\nVilvoorde\nBelgium\n\n11 \nLaboratory of Clinical Immunology\nKU Leuven Department of Microbiology and Immunology\nLeuven\nBelgium\n* \nCorrespondence: H. Lapeere. E‐mail: Hilde.Lapeere@uzgent.be\n19 8 2019 1 2020 34 1 10.1111/jdv.v34.1127 134 16 1 2019 23 4 2019 © 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and VenereologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nBackground\nChronic spontaneous urticaria (CSU) is characterized by the repeated occurrence of persistent hives and/or angioedema for ≥6 weeks, without specific external stimuli. H1‐antihistamines have long been the standard of care of CSU, but many patients remain uncontrolled even at 4× the approved dose. Add‐on therapy with omalizumab has proven effective in clinical trials, but little is known about omalizumab treatment in Belgium.\n\nObjective\nTo collect real‐world clinical data on omalizumab treatment in adults with CSU in Belgium.\n\nMethods\nThis was an observational, retrospective chart review of adults with CSU, who initiated omalizumab treatment between August 2014 and December 2016 (maximum 28 months follow‐up).\n\nResults\nIn total, 235 patients were included (median time from symptom onset to diagnosis, 5.4 months; median time from diagnosis to commencing omalizumab, 6.7 months). Treatments used before/after commencing omalizumab did not always adhere to guidelines; many patients (26.4%/11.1%) received first‐generation H1‐antihistamines, while 20.4% used omalizumab monotherapy after initiating treatment. The mean interval between omalizumab administrations was 4.8 (SD 1.7) weeks; 67.8% of patients had ≥1 interval prolongation and/or shortening. Mean baseline 7‐day Urticaria Activity Score (UAS7) was 32.0 (SD 6.05); this improved to 12.6 (SD 11.2) after 1 month of omalizumab. About 67.2% of patients reached UAS7 ≤ 6 (well controlled) during the study. A total of 87 patients stopped omalizumab and never restarted before the end of the observation period; the most prevalent reason was remission of symptoms (49.4% of patients), followed by lack of effect (12.6%), lost to follow‐up (6.9%) and adverse events (3.4%). Headache was the most common adverse event (n = 8/82). No anaphylaxis was reported.\n\nConclusions\nThis study revealed that patients initiated on omalizumab in Belgium had severe CSU at baseline, and showed substantial improvements after 1 month of treatment. Greater adherence to the prescription of guideline‐recommended medications is needed for the treatment of CSU.\n\nN.V. Novartis Pharma S.A. source-schema-version-number2.0cover-dateJanuary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:06.02.2020Conflicts of interest: HL has received honoraria for lectures and consulting, and funding to support work on this study from Novartis. AS has received honoraria for lectures from Novartis, and funding to support work on this study. VS has received honoraria for lectures and congress support, and funding to support work on this study from Novartis. MG has received honoraria for consulting and congress support, and funding to support work on this study from Novartis. JL has received honoraria for consulting, and funding to support work on this study from Novartis. MB, LD and MM have received funding to support work on this study. RS has received congress support from CSL Behring and Shire. HR and KA are employees of Novartis.\n\nFunding source: N.V. Novartis Pharma S.A. funded this study.\n==== Body\nIntroduction\nChronic urticaria (CU) is a common skin disorder characterized by the repeated occurrence of hives and/or angioedema for more than 6 weeks.1, 2 CU is divided into two types: chronic spontaneous urticaria (CSU), in which symptoms occur in the absence of specific external triggers, and chronic inducible urticaria (CIndU), in which symptoms occur in response to specific stimuli, such as exposure to cold, heat or pressure.1\n\n\nPrevious reports suggest that many patients are undertreated and not receiving the recommended therapy.3, 4, 5 CSU can be debilitating and unpredictable, and has a significant negative impact on quality of life (QoL);2 it can result in work productivity loss and absenteeism,6 interference with sleep and daily activities,5 and high levels of anxiety and psychological distress.7 Thus, the EAACI/GA2LEN/EDF/WAO guidelines recommended treatment using a specific algorithm that allows for stepping up or down of medications until achieving complete symptom control.1\n\n\nFor many years, H1‐antihistamines have been recommended as the standard of care in CSU,1, 8, 9, 10 but up to 60% of patients remain uncontrolled at the licensed dose.11 For these patients, the guidelines recommend uptitrating H1‐antihistamines up to four times the licensed dose, followed by add‐on therapy with omalizumab.1 Omalizumab is very effective in the treatment of CSU; it reduces the numbers of urticarial weals and pruritus, prevents angioedema, improves QoL and has a favourable safety profile.12, 13, 14, 15, 16, 17, 18, 19 Ciclosporin A, also off label for urticaria, is only recommended for patients with severe disease refractory to the combination of antihistamines and omalizumab.\n\nA systematic review of 84 observational studies indicated that findings from clinical trials underscore the real‐world effectiveness of omalizumab in the management of CSU;20 however, there was no data for Belgium in the systematic review, and there is little published information on the use of omalizumab in daily clinical practice in this country. This study was designed to describe omalizumab treatment patterns since becoming available in Belgium for CSU to better understand omalizumab dosing, treatment outcomes, patients’ characteristics and healthcare burden in the real‐world setting.\n\nMethods\nStudy design\nThis was a non‐interventional, observational, multi‐centre, retrospective, descriptive chart review performed in 16 centres in Belgium, where omalizumab is known to be used to treat patients with CSU. Omalizumab was funded via a medical need program from August 2014 based on a diagnosis of CSU for ≥6 months and 7‐day urticaria activity score (UAS7)≥16 and via the public healthcare system from 1 June 2015 onwards based on a diagnosis of CSU for ≥6 months and UAS7 ≥ 28. Funding of omalizumab treatment via the medical need program or national reimbursement was not mandatory for inclusion.\n\nThe data for this study were retrieved retrospectively from patients’ medical records at the participating dermatology and internal medicine centres. The study was designed, implemented and reported in accordance with the Guidelines for Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology,21 and the STROBE guidelines.22\n\n\nPatients\nPatients (≥18 years old) were included who had a diagnosis of CSU and had received ≥1 treatment with omalizumab and ≥1 follow‐up visit between August 2014 and December 2016. Patients were excluded if they participated in any randomized trial in CU during the observation period or if they were treated with omalizumab for any off‐label indication.\n\nDemographics and baseline characteristics\nDemographic data collected included age and gender. Baseline characteristics included date of CSU symptom onset and diagnosis; severity of CSU disease by means of Dermatology Life Quality Index (DLQI; range 0–30) and UAS7 (range 0–42);23 CSU relevant medical history; and work/school attendance. UAS7 scores/ranges are defined as: urticaria‐free (0); well‐controlled (1–6); mild (7–15); moderate (16–27); and severe (28–42).24 Change in UAS7 after starting omalizumab was determined.\n\nOmalizumab treatment exposure and outcome\nOmalizumab dosing, frequency of administration, duration and treatment intervals, as well as reasons for treatment delay or interruption were analysed. Treatments used before commencing and in combination with omalizumab were examined.\n\nCSU‐related healthcare resource use\nThe number and nature of urticaria tests, the number of CSU‐related emergency room admissions and length of stay, patient referrals and the number of CSU consultations were analysed.\n\nAdverse events\nThe type, severity and clinician’s assessment of causality of adverse events during omalizumab treatment were recorded.\n\nResults\nPatient characteristics\nIn total, 235 patients were included in this chart review, the majority of whom were female (67.7%), and the mean age was 46.2 years (Table 1). The mean observation period was 15.7 (SD 7.8) months. Of these, 70.2% of patients were treated in university hospitals (39.6% dermatology; 30.6% internal medicine), 9.8% in peripheral hospitals (all dermatology) and 20.0% in private dermatology practices. Patients treated in private practices had a mean of 11.9 CSU‐related consultations compared with 9.2 and 8.6 for university hospital dermatology and internal medicine specialties, respectively, and 8.7 for peripheral hospitals. Patients were mainly referred by their general practitioner (n = 98; 41.7%) or by other dermatologists (n = 58; 24.7%).\n\nTable 1 Demographics and baseline characteristics\n\nCategory\tTotal population (N = 235)\t\n\nDemographics\n\t\nAge in years\t46.2 ± 15.4\t\nFemale, n (%)\t159 (67.7)\t\nMale, n (%)\t76 (32.3)\t\n\nDisease characteristics, n (%)\n\t\n\nComorbid CIndU\n\n\nSymptomatic dermographism\n\n\n\t\n113 (49.3)\n\n\n71 (31.0)\n\n\n\t\nAngioedema\t93 (40.6)\t\nNo medical history\t36 (15.7)\t\nAtopy\t32 (14.0)\t\n\nOnset of symptoms, diagnosis and start of omalizumab treatment, median (range)\n\t\nTime from onset of symptoms to diagnosis of CSU, months\t5.4 (0.0–456.0)†\n\t\nTime from onset of CSU symptoms to omalizumab start, months\t23.5 (0.3–503.0)†\n\t\nTime from diagnosis of CSU to omalizumab start, months\t6.7 (0.0–425.5)†\n\t\n\nOther CSU medications\n\t\nNumber of combined medications before commencing omalizumab\t2.0 ± 1.7\t\nNumber of concomitant medications after commencing (in combination with) omalizumab\t0.6 ± 0.9\t\nData are mean ± standard deviation unless otherwise stated.\n\n† For three patients, the date of onset of CSU symptoms was unknown and arbitrarily encoded as being similar to the date of diagnosis.\n\nJohn Wiley & Sons, LtdIn the total population, 27 patients (11.5%) did not attend school or work for a mean duration of 1.2 (SD 5.3) days per month because of CSU‐related problems before omalizumab treatment. In contrast, 16 patients (6.8%) did not attend school or work for mean duration of 0.5 (SD 3.3) days per month since omalizumab initiation. Before omalizumab treatment, 13 (5.5% of total population) patients had a prior CSU‐related emergency room admission for angiooedema (n = 6), rash (n = 5), anxiety (n = 2) and infection (n = 1); one patient was admitted for two reasons. During the observation period, two patients had a CSU‐related emergency room admission while on omalizumab, one for angioedema and one for rash.\n\nIt should be noted that although omalizumab reimbursement became available during the course of this study (June 2015), the median time from symptom onset to omalizumab start was similar between those who were enrolled before and after reimbursement (Table 1); the median time from CSU diagnosis to omalizumab start was shorter for those enrolled after reimbursement (5.5 months) compared with those enrolled before (9.1 months). It should also be noted that 81 patients received omalizumab funding via the Medical Need Program, 208 received national reimbursement (71 of whom were previously funded via the Medical Need program), eight patients had their treatment paid for by other funding, and 19 patients had no funding information.\n\nThe mean number of diagnostic tests per patient was 2.7, the most common of which were differential blood count in 75.3% of patients (n = 177/235), immunoglobulin (Ig) E levels in 41.3% (n = 97/235) and CIndU provocations tests in 29.4% (n = 69/235); 13.6% of patients had no diagnostic test for CU (Fig. 1). The mean IgE level was 257.7 IU/mL, with a large distribution (range 2.0–2914.0 IU/mL, median 106.0 IU/mL). Angioedema was reported in 40.6% of patients and 49.3% suffered from comorbid CIndU, of which symptomatic dermographism was the most common (31.0%); all other CIndUs occurred in less than 10% of patients. Other comorbidities of interest included atopy (14.0% of patients) and allergic asthma (7.4%).\n\nFigure 1 Summary of diagnostic tests. ANA, antinuclear antibody; ASST, autologous serum skin test; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; HRT, histamine release test; IgE, immunoglobulin E; TPO, thyroid peroxidase.\n\nTreatment patterns before and after commencing omalizumab\nBefore commencing omalizumab, 87.7% of patients received second‐generation H1‐antihistamines (Table 2); of these, 42.7% (n = 88/206) were receiving them at the approved dose, while 15.5% (n = 32/206), 6.3% (n = 13/206) and 35.4% (n = 73/206) were updosed to 2×, 3× and 4× the approved dose, respectively. Of the 26.4% of patients who received first‐generation H1‐antihistamines before commencing omalizumab, 87.1% (n = 54/62) received them at the approved dose, while 8.1% (n = 5/62), 1.6% (n = 1/62) and 3.2% (n = 2/62) were updosed to 2×, 3× and 4× the approved dose, respectively. In total, 95.3% (n = 224/235) of patients received a first‐ or second‐generation H1‐antihistamine before omalizumab.\n\nTable 2 Proportion of the total population (N = 235) using selected treatments (in order of guideline recommendations) before and after initiating omalizumab treatment\n\nCategory\tBefore omalizumab\tCombined with omalizumab\t\n\nSecond‐generation\n\n\nH1‐antihistamine (any dose)\n\n\n\t87.7% (n = 206)\t74.5%† (n = 175)\t\nCiclosporin\t16.6% (n = 39)\t7.2%† (n = 17)\t\nMontelukast\t40.9% (n = 96)\t25.5%† (n = 60)\t\nCorticosteroids\t42.6% (n = 100)\t13.6%† (n = 32)\t\n\nFirst‐generation\n\n\nH1‐antihistamine (any dose)\n\n\n\t26.4% (n = 62)\t11.1%† (n = 26)\t\nNo medication\t0.0% (n = 0)\t20.4%‡ (n = 48)\t\n† Medications were used at least once since initiating omalizumab treatment.\n\n‡ Monotherapy (never any concomitant medication in addition to omalizumab during the treatment period).\n\nJohn Wiley & Sons, LtdAfter initiating omalizumab, 74.5% of patients received concomitant second‐generation H1‐antihistamines at least once; of these, 65.7% (n = 115/175) received them at the approved dose, 40.0% (n = 70/175) were updosed to 4× the approved dose. Of the 11.1% of patients who received first‐generation H1‐antihistamines after commencing omalizumab, 84.6% (n = 22/26) were receiving them at the approved dose, while 11.5% (n = 3/26) were updosed to 2–4× the approved dose. One‐hundred‐seventy‐nine patients (76.2%) received first‐ or second‐generation H1‐antihistamines in combination with omalizumab. Patients received first‐ or second‐generation H1‐antihistamines in combination with omalizumab for 48.9% and 74.9% of the time while on omalizumab, respectively. Before omalizumab treatment, corticosteroids were used by 42.6% (n = 100/235) of patients at least once, while 13.6% (n = 32/235) used them in combination after commencing omalizumab.\n\nBefore commencing omalizumab, 31.1% (n = 73/235) of patients were treated with monotherapy, 32.2% (n = 76/235) with dual therapy and 20.0% (n = 47/235) with triple therapy. After commencing omalizumab, it was used as monotherapy in 20.4% (n = 48/235) of patients, 34.4% (n = 81/235) of patients had one other CSU medication in combination (dual therapy), and 27.7% (n = 65/235) had two CSU medications added (triple therapy) as the maximum number of CSU treatments combined during the observation period.\n\nThe mean duration of omalizumab treatment within the observation period was 11.9 (SD 7.6) months; 54.0% of patients were treated for 1 year; 20.4% were treated for 1.5 years; and the remaining 25.5% were treated more than 1.5 years. The majority of patients (93.6%) received omalizumab 300 mg; however, 4.3% (n = 10/235) received 450 mg, 0.9% (n = 2/235) 600 mg, 13.2% (n = 31/235) 150 mg and 0.4% (n = 1/235) 75 mg at least once during the observation period. Most patients (84.3%) had no dose change during the omalizumab treatment period.\n\nThe mean interval between omalizumab administrations was 4.8 weeks; 32.2% of patients received omalizumab at a consistent 4‐week interval. At least once during the observation period, 61.7% had a prolonged (≥5 weeks) treatment interval, while 19.6% had a shortened (<3 weeks) interval; some patients (13.5%) had both a prolongation and shortening. In total, 10.6% of patients had ≥1 treatment interruption. Practical reasons were the most common cause of treatment interval prolongation (56.1%) or treatment interval shortening (57.5%). Other reasons for interval prolongation were temporary interruption of treatment (18.2%), tapering (40.2%) and other reasons (3.8%). Other reasons for interval shortening were lack of efficacy (32.5%). In most patients, the 4‐week interval was at least once prolonged/shortened, but in general by pooling all interval data only 15.4% were prolonged and 3.2% shortened.\n\nFor the 43 patients who stopped omalizumab treatment and did not restart during the observation period for remission of symptoms, nine patients (20.9%) were treated with omalizumab for less than 6 months and 34 patients (79.1%) were treated longer than 6 months. The interval between treatment stop and the end of the observation period was <1 month for 14 of these patients (32.6%), 1–2 months for nine patients (20.9%), 2–3 months for one patient (2.3%) and longer than 3 months for 19 patients (44.2%).\n\nEvolution of UAS7 score\nThe mean baseline UAS7 was 32.0 (SD 6.1); this improved to 12.6 (SD 11.2) after one month of omalizumab treatment (Fig. 2a). The number of patients for whom a UAS7 score was reported differs per month; 15.3% had no UAS score available during the observation period. During the observation period, 67.2% (n = 158/235) of patients reached UAS7 ≤ 6 (well controlled; Fig. 2b); 9.8%, 3.8% and 3.8% reached UAS7 of 7–15, 16–27 and 28–42, respectively; five patients (2.5%) remained at UAS7 > 28 during the omalizumab treatment period. During the observation period, 42.6% of patients (n = 106/235) became urticaria‐free (UAS7 = 0) after a mean of 4.0 ± 4.6 months treatment with omalizumab. The 52 patients who reached a minimum UAS7 ≤ 6, but not 0, needed a mean of 6.8 (SD 6.1) months treatment with omalizumab to achieve a well‐controlled state (Fig. 3).\n\nFigure 2 (a) UAS7 characteristics over time. (b) Evolution over time of patients with at least one UAS score of 0 and ≤6 since omalizumab treatment initiation. M, month; UAS7, 7‐day urticaria activity score. *One patient had a UAS7 score of 0 recorded at an unknown timepoint. This result is not included in the graph.\n\nFigure 3 Number of Patients reaching different UAS7 during the observation period as their lowest score (unique scores, not cumulative). *Patients with no UAS score determined since omalizumab treatment.\n\nWork/school absenteeism before and after commencing omalizumab\nIn total, 27 patients (11.5%) reported an absenteeism from work or school before omalizumab treatment, with an average of 1.2 days absent per month. After commencing omalizumab, 16 patients (6.8%) reported an absenteeism, with an average of 0.5 days per month.\n\nAdverse events\nIn total, 82 adverse events (AEs) were reported (0.35 AEs per patient) in 52 patients (22.1% of the total population) during the observation period. Of these, 29 AEs in 26 patients were possibly related to omalizumab (Table 3). Six severe AEs (SAEs; 7.3%) were reported in five patients (2.1%). Of these SAEs, one case of headache and one combined case of flu, nausea, dizziness, fatigue and constipation were possibly related to omalizumab; while one case of arthralgia with hospitalization, one case of extreme somnolence (not significant), one case of urticaria worsening with hospitalization and one case of stress (not significant) had unknown association with omalizumab. There were no reports of anaphylaxis. Causality was unknown for 31 cases in 21 patients.\n\nTable 3 Severity, seriousness and causality of adverse events\n\nCategory\tTotal population (N = 235)\t\n\nPatients with any adverse event, n (%)\n\t52 (22.1)\t\n\nSeverity, n (%)\n\t\nMild\t28 (11.9)\t\nModerate\t22 (9.4)\t\nSevere\t5 (2.1)\t\n\nSeriousness, n (%)\n\t\nFatal\t0 (0.0)\t\nLife‐threatening\t0 (0.0)\t\nHospitalization\t1 (0.4)\t\nDisability–Incapacity\t3 (1.3)\t\nBirth defect\t0 (0.0)\t\nNot significant\t49 (20.9)\t\n\nCausality, n (%)\n\t\nPossibly related to omalizumab\t26 (11.1)\t\nUnrelated to omalizumab\t13 (5.5)\t\nUnknown\t21 (8.9)\t\nJohn Wiley & Sons, LtdDiscussion\nThis patient chart review provides good insight into omalizumab treatment in Belgium, with a large patient cohort and more than 2 years of data. The findings revealed that patients initiated on omalizumab in Belgium had severe CSU at baseline (mean UAS7 = 32.0), and most had been treated with H1‐antihistamines for a relative long time prior to starting omalizumab. Patient demographics and clinical characteristics in this study are representative of the general population of patients with CSU.5 The difficult journey to diagnosis and treatment of patients with CSU was confirmed by the long periods of time between symptom onset to diagnosis, and from diagnosis to omalizumab treatment initiation. After reimbursement of omalizumab in Belgium, the median time from CSU diagnosis to omalizumab start was shortened by 3.6–5.5 months; however, better care is still needed to shorten the long period from symptom onset to diagnosis.\n\nAvailable data suggest that adherence to guideline recommendations is poor, leading to an unmet need within the CU population.5, 25, 26, 27, 28, 29 Furthermore, the majority of data on CU inadequately controlled with H1‐antihistamines is limited to patient populations derived from specialized urticaria centres, which may not represent the general CU population due to limited numbers.30, 31 Results from this study confirmed these findings in Belgium, where treatments used prior to commencing and in combination with omalizumab did not always adhere to guidelines. Many patients received first‐generation H1‐antihistamines, despite widespread agreement that these should no longer be prescribed owing to their pronounced anticholinergic effects and sedative actions, as well as their interactions with alcohol and CNS‐acting drugs, interference with rapid eye movement sleep and impact on learning and performance.1, 2, 32 Indeed, guidelines recommend that modern second‐generation H1‐antihistamines, which are minimally or non‐sedating and free of anticholinergic effects, should be prescribed as standard of care.1 However, the data in this study are in contrast to these guidelines, since H1‐antihistamines were updosed to 4× the approved dose in only 35.4% of patients; however, this could be associated with the requirement of patients to only be resistant to H1‐antihistamines at the approved dose for reimbursement in Belgium. Corticosteroid use was also high both before and after initiation of omalizumab. Recent evidence has shown that short‐term use of corticosteroids is associated with a 2‐ to 5‐fold increase in the incidence of acute adverse events, including sepsis, venous thromboembolism and fracture, compared with background rates.33, 34\n\n\nMontelukast and ciclosporin were both used as add‐on therapies before and after commencing omalizumab. Both of these treatments were previously recommended as third‐line add‐on therapies to H1‐antihistamines during this study; however, montelukast is no longer recommended owing to the poor level of evidence for its efficacy, and ciclosporin is only recommended as standard therapy owing to not being licensed and its inferior safety profile compared with omalizumab.1 It should be noted that the previous guidelines were the relevant guidelines during this study, which accounts for the relatively high use of montelukast (40.9%) and ciclosporin (16.6%) prior to initiating omalizumab.8 In the updated guidelines, ciclosporin is recommended to only be prescribed for patients with severe disease that is refractory to combined treatment with H1‐antihistamines (at any dose) and omalizumab.1\n\n\nThe updated guidelines provide strong recommendation for the use of omalizumab as third‐line therapy in patients who are unresponsive to high doses of H1‐antihistamines.1 This recommendation is based on numerous studies confirming the effectiveness of omalizumab in the treatment of CSU and its favourable safety profile.12, 13, 14, 15, 16, 17, 18, 19 Indeed, the results of this chart review support this recommendation, through the rapid and substantial decrease in disease activity from severe at baseline (mean UAS7 = 32.0) to mild after one month of omalizumab (mean UAS7 = 12.6). These benefits continued to improve with time, with the lowest mean UAS7 of 3.5 (i.e. well‐controlled urticaria) after 28 months of omalizumab treatment. Although the data are limited, improvements were noted in work/school absenteeism and CSU‐related ER admissions following omalizumab treatment initiation. These findings support the need for earlier diagnosis and treatment initiation in CSU, with a further need for escalation of treatment to add‐on omalizumab in patients who are inadequately treated with H1‐antihistamines.\n\nRecent studies suggest that dose interval adjustments may benefit some patients who respond early or late to omalizumab, requiring longer or shorter intervals between administrations, respectively.35, 36, 37, 38 As reimbursement of omalizumab in Belgium is only for a 4‐week dosing regimen, there is very little flexibility with treatment intervals. Still, in this study, many patients had a prolongation (≥5 weeks) or shortening (<3 weeks) of a treatment interval, with ‘practical reason’ being the most common reason for prolongation, and ‘lack of efficacy’ being the most common for interval shortening. The reported rate of discontinuations for remission of symptoms was high, but as only 44.2% of these patients were stopped for longer than 3 months, so these data should be interpreted with caution.\n\nPotential limitations of the present study are its non‐interventional character, and the likelihood of missing data and patients lost to follow‐up due to the long observation period. Indeed, few patients had data available on the effect of CSU on QoL, so this could not be assessed. However, non‐interventional studies are the preferred means of collecting real‐world data, which provides meaningful insight into patient treatment in clinical practice. The findings of this study are not only useful for physicians in Belgium, but for those worldwide who adhere to the EAACI/GA2LEN/EDF/WAO guidelines.\n\nThis chart review revealed that patients initiated on omalizumab in Belgium had severe CSU at baseline, and showed substantial improvements after one month of treatment and continued benefit for up to 28 months of treatment with omalizumab. Findings also identified a need for greater adherence to the prescription of guideline‐recommended medications before starting and in combination with omalizumab in Belgium.\n\nAcknowledgements\nMedical writing support was provided by Martin Wallace, PhD of Novartis Ireland, Ltd, which was funded by N.V. Novartis Pharma S.A., Belgium in accordance with Good Publication Practice (GPP3) guidelines (://www.ismpp.org/gpp3). The study was sponsored by N.V. Novartis Pharma S.A.\n==== Refs\nReferences\n1 \n\nZuberbier \nT \n, \nAberer \nW \n, \nAsero \nR \n, et al. The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2017 revision and update . Allergy \n2018 ; 73 : 1393 –1414 .29336054 \n2 \n\nMaurer \nM \n, \nWeller \nK \n, \nBindslev‐Jensen \nC \n, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report . Allergy \n2011 ; 66 : 317 –330 .21083565 \n3 \n\nMaurer \nM \n, \nStaubach \nP \n, \nRaap \nU \n, et al. H1‐antihistamine‐refractory chronic spontaneous urticaria: it's worse than we thought – first results of the multicenter real‐life AWARE study . Clin Exp Allergy. \n2017 ; 47 : 684 –692 .28160338 \n4 \n\nWeller \nK \n, \nViehmann \nK \n, \nBrautigam \nM \n, et al. Cost‐intensive, time‐consuming, problematical? How physicians in private practice experience the care of urticaria patients . 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The EAACI/GA(2) LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update . Allergy \n2014 ; 69 : 868 –887 .24785199 \n9 \n\nZuberbier \nT \n, \nAsero \nR \n, \nBindslev‐Jensen \nC \n, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria . Allergy \n2009 ; 64 : 1427 –1443 .19772513 \n10 \n\nZuberbier \nT \n, \nBindslev‐Jensen \nC \n, \nCanonica \nW \n, et al. EAACI/GA2LEN/EDF guideline: management of urticaria . Allergy \n2006 ; 61 : 321 –331 .16436141 \n11 \n\nGuillen‐Aguinaga \nS \n, \nJauregui Presa \nI \n, \nAguinaga‐Ontoso \nE \n, \nGuillen‐Grima \nF \n, \nFerrer \nM \n. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta‐analysis . Br J Dermatol. \n2016 ; 175 : 1153 –1165 .27237730 \n12 \n\nKaplan \nA \n, \nLedford \nD \n, \nAshby \nM \n, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy . J Allergy Clin Immunol. \n2013 ; 132 : 101 –109 .23810097 \n13 \n\nMaurer \nM \n, \nRosen \nK \n, \nHsieh \nHJ \n, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria . N Engl J Med. \n2013 ; 368 : 924 –935 .23432142 \n14 \n\nMaurer \nM \n, \nKaplan \nA \n, \nRosen \nK \n, et al. The XTEND‐CIU study: long‐term use of omalizumab in chronic idiopathic urticaria . J Allergy Clin Immunol. \n2017 ; 141 : 1138 –1139 .e7.29132956 \n15 \n\nStaubach \nP \n, \nMetz \nM \n, \nChapman‐Rothe \nN \n, et al. Effect of omalizumab on angioedema in H1‐antihistamine‐resistant chronic spontaneous urticaria patients: results from X‐ACT, a randomized controlled trial . Allergy \n2016 ; 71 : 1135 –1144 .27010957 \n16 \n\nStaubach \nP \n, \nMetz \nM \n, \nChapman‐Rothe \nN \n, et al. Omalizumab rapidly improves angioedema‐related quality of life in adult patients with chronic spontaneous urticaria: X‐ACT study data . Allergy \n2018 ; 73 : 576 –584 .29058822 \n17 \n\nZhao \nZT \n, \nJi \nCM \n, \nYu \nWJ \n, et al. Omalizumab for the treatment of chronic spontaneous urticaria: A meta‐analysis of randomized clinical trials . J Allergy Clin Immunol. \n2016 ; 137 : 1742 –1750 e4.27040372 \n18 \n\nMaurer \nM \n, \nAltrichter \nS \n, \nBieber \nT \n, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase . J Allergy Clin Immunol. \n2011 ; 128 : 202 –209.e5 .21636116 \n19 \n\nSaini \nSS \n, \nBindslev‐Jensen \nC \n, \nMaurer \nM \n, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo‐controlled study . J Invest Dermatol. \n2015 ; 135 : 67 –75 .25046337 \n20 \n\nWang \nL \n, \nKe \nX \n, \nKavati \nA \n, et al. Real‐world treatment patterns and outcomes of omalizumab use in patients with chronic idiopathic urticaria . Curr Med Res Opin. \n2018 ; 34 : 35 –39 .29064325 \n21 \nISPE \n. Guidelines for good pharmacoepidemiology practices (GPP) . Pharmacoepidemiol Drug Saf. \n2008 ; 17 : 200 –208 .17868186 \n22 \n\nVandenbroucke \nJP \n, \nvon Elm \nE \n, \nAltman \nDG \n, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration . Int J Surg. \n2014 ; 12 : 1500 –1524 .25046751 \n23 \n\nFinlay \nAY \n, \nKhan \nGK \n. Dermatology Life Quality Index (DLQI)–a simple practical measure for routine clinical use . Clin Exp Dermatol. \n1994 ; 19 : 210 –216 .8033378 \n24 \n\nKhalil \nS \n, \nMcBride \nD \n, \nGimenez‐Arnau \nA \n, \nGrattan \nC \n, \nBalp \nM \n, \nStull \nD \n. Weekly urticaria activity score (UAS7) and dermatology life quality index (DLQI) in validation of chronic spontaneous/idiopathic urticaria (CSU/CIU) health states . J Allergy Clin Immunol. \n2015 ; 135 : AB131 .\n25 \n\nCherrez \nA \n, \nMaurer \nM \n, \nWeller \nK \n, \nCalderon \nJC \n, \nSimancas‐Racines \nD \n, \nCherrez \nOjeda I \n. Knowledge and management of chronic spontaneous urticaria in Latin America: a cross‐sectional study in Ecuador . World Allergy Organ J \n2017 ; 10 : 21 .28546850 \n26 \n\nEgeberg \nA \n, \nKofoed \nK \n, \nGislason \nGH \n, \nVestergaard \nC \n, \nThyssen \nJP \n. Cardiovascular risk is not increased in patients with chronic urticaria: A retrospective population‐based cohort study . Acta Derm Venereol \n2017 ; 97 : 261 –262 .27535552 \n27 \n\nIrani \nC \n, \nHallit \nS \n, \nWeller \nK \n, \nMaurer \nM \n, \nEl Haber \nC \n, \nSalameh \nP \n. Chronic urticaria in most patients is poorly controlled. Results of the development, validation, and real life application of the Arabic urticaria control test . Saudi Med J. \n2017 ; 38 : 1230 –1236 .29209673 \n28 \n\nMaspero \nJF \n, \nStigliano \nI \n, \nBianculli \nP \n, \nMolinas \nJL \n, \nArdusso \n\n\nLRF \n. Translating chronic urticarial guidelines to clinical practice: a study assessing how allergists and dermatologists apply guidelines recommendations in Argentina . J Allergy Clin Immunol \n2017 ; 139 : AB248 .\n29 \n\nTanaka \nT \n, \nHiragun \nM \n, \nHide \nM \n, \nHiragun \nT \n. Analysis of primary treatment and prognosis of spontaneous urticaria . Allergol Int \n2017 ; 66 : 458 –462 .28094108 \n30 \n\nWeller \nK \n, \nSchoepke \nN \n, \nKrause \nK \n, \nArdelean \nE \n, \nBrautigam \nM \n, \nMaurer \nM \n. Selected urticaria patients benefit from a referral to tertiary care centres–results of an expert survey . J Eur Acad Dermatol Venereol \n2013 ; 27 : e8 –e16 .22176200 \n31 \n\nWeller \nK \n, \nViehmann \nK \n, \nBrautigam \nM \n, et al. Management of chronic spontaneous urticaria in real life–in accordance with the guidelines? A cross‐sectional physician‐based survey study . J Eur Acad Dermatol Venereol \n2013 ; 27 : 43 –50 .22150693 \n32 \n\nBousquet \nJ \n, \nKhaltaev \nN \n, \nCruz \nAA \n, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen) . Allergy \n2008 ; 63 (Suppl 86 ): 8 –160 .18331513 \n33 \n\nWaljee \nAK \n, \nRogers \nMA \n, \nLin \nP \n, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study . BMJ \n2017 ; 357 : j1415 .28404617 \n34 \n\nLedford \nD \n, \nBroder \nMS \n, \nAntonova \nE \n, \nOmachi \nTA \n, \nChang \nE \n, \nLuskin \nA \n. Corticosteroid‐related toxicity in patients with chronic idiopathic urticariachronic spontaneous urticaria . Allergy Asthma Proc \n2016 ; 37 : 458 –465 .27931301 \n35 \n\nTurk \nM \n, \nKocaturk \nE \n, \nCure \nK \n, \nYilmaz \nI \n. Two‐week intervals during omalizumab treatment may provide better symptom control in selected patients with chronic urticaria . J Allergy Clin Immunol Pract \n2018 ; 6 : 1389 –1390 .29410306 \n36 \n\nLarenas‐Linnemann \nDES \n, \nParisi \nCAS \n, \nRitchie \nC \n, et al. Update on omalizumab for urticaria: what's new in the literature from mechanisms to clinic . Curr Allergy Asthma Rep. \n2018 ; 18 : 33 .29744661 \n37 \n\nVadasz \nZ \n, \nTal \nY \n, \nRotem \nM \n, et al. Omalizumab for severe chronic spontaneous urticaria: real‐life experiences of 280 patients . J Allergy Clin Immunol Pract \n2017 ; 5 : 1743 –1745 .28988786 \n38 \n\nde Montjoye \nL \n, \nHerman \nA \n, \nDumoutier \nL \n, \nLambert \nM \n, \nTromme \nI \n, \nBaeck \nM \n. Omalizumab in chronic spontaneous urticaria: a real‐life experience of dose and intervals adjustments in Belgium . Ann Allergy Asthma Immunol \n2018 ; 121 : 620 –622 .30392532\n\n",
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"title": "A retrospective analysis omalizumab treatment patterns in patients with chronic spontaneous urticaria: a real-world study in Belgium.",
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"abstract": "A 67-year-old woman was diagnosed as having advanced gastric cancer(poorly differentiated adenocarcinoma)with multiple liver metastases. She had received combined S-1 plus cisplatin chemotherapy as first-line treatment and weekly paclitaxel chemotherapy as second-line treatment, however, both had eventually proved ineffective. Because the gastric cancer was HER2-positive, she was treated with trastuzumab plus capecitabine plus cisplatin(XP)chemotherapy as third-line treatment. The primary lesion and liver metastatic lesions were confirmed to show remarkable regression. The ToGA trial revealed increased efficacy of trastuzumab in first-line treatment of cancers showing high expression levels of the HER2- protein. This case suggested the increased efficacy of trastuzumab in third-line treatment. Neutropenia and hand foot syndrome of grade 2 were all reported adverse events. She could receive trastuzumab plus XP chemotherapy safely by dose reduction or dormancy temporarily of capecitabine.",
"affiliations": "Division of Gastroenterology, Chigasaki Municipal Hospital.",
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"title": "A case of HER2-positive gastric cancer successfully treated with trastuzumab plus capecitabine plus cisplatin chemotherapy as third-line treatment.",
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"abstract": "Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens-Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA). Hereby, we present the case of an 8-year-old boy who suffered from SJS and other complications two weeks after LTG was added to his VPA treatment in order to control his seizures. VPA is known to decrease LTG clearance via reduced glucuronidation. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of an arene oxide metabolite would be enhanced. As this reactive metabolite is detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans, arene oxide toxicity is increased when epoxide hydrolase or GSH-S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. VPA can cause inhibition of epoxide hydrolase enzymes and/or depletion of glutathione levels leading to adverse cutaneous reactions.",
"affiliations": "Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay.;Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay.;Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay.;Department of Neuropediatrics, Faculty of Medicine, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay.;Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay.;Genia-Genetics Molecular Laboratory, Bulevar General Artigas 922, 11300 Montevideo, Uruguay.;Genia-Genetics Molecular Laboratory, Bulevar General Artigas 922, 11300 Montevideo, Uruguay.",
"authors": "Vázquez|Marta|M|0000-0002-8459-4859;Maldonado|Cecilia|C|0000-0002-9452-2111;Guevara|Natalia|N|0000-0002-5541-6316;Rey|Andrea|A|;Fagiolino|Pietro|P|0000-0001-6756-1601;Carozzi|Antonella|A|;Azambuja|Carlos|C|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/5371854Case ReportLamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome http://orcid.org/0000-0002-8459-4859Vázquez Marta mvazquez@fq.edu.uy\n1\nhttp://orcid.org/0000-0002-9452-2111Maldonado Cecilia \n1\nhttp://orcid.org/0000-0002-5541-6316Guevara Natalia \n1\nRey Andrea \n2\nhttp://orcid.org/0000-0001-6756-1601Fagiolino Pietro \n1\nCarozzi Antonella \n3\nAzambuja Carlos \n3\n\n1Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay\n2Department of Neuropediatrics, Faculty of Medicine, Universidad de la República, Avenida General Flores 2125, 11800 Montevideo, Uruguay\n3Genia-Genetics Molecular Laboratory, Bulevar General Artigas 922, 11300 Montevideo, UruguayAcademic Editor: Bruno Megarbane\n\n2018 29 8 2018 2018 537185428 5 2018 5 8 2018 Copyright © 2018 Marta Vázquez et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens–Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA). Hereby, we present the case of an 8-year-old boy who suffered from SJS and other complications two weeks after LTG was added to his VPA treatment in order to control his seizures. VPA is known to decrease LTG clearance via reduced glucuronidation. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of an arene oxide metabolite would be enhanced. As this reactive metabolite is detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans, arene oxide toxicity is increased when epoxide hydrolase or GSH-S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. VPA can cause inhibition of epoxide hydrolase enzymes and/or depletion of glutathione levels leading to adverse cutaneous reactions.\n==== Body\n1. Introduction\nLamotrigine (LTG) is an important anticonvulsant with activity against both focal and generalized onset seizures [1]. It is also effective in the treatment of bipolar disorder [2, 3] and neuropathic pain [4]. However, its use is associated with a significant incidence of adverse cutaneous reactions, mainly when concomitant therapy is administered [5]. Rash is the most common adverse reaction of this antiepileptic agent and the most common reason for treatment discontinuation as it can be life-threatening. Children under polytherapy have a higher risk of this adverse event [6]. Such cutaneous reactions range from mild rashes to more serious conditions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis [7]. SJS is thought to be a hypersensitivity reaction involving skin and mucous membranes.\n\nLTG shows good absorption after oral administration, and 55% of LTG is bound to plasma proteins mostly to albumin. Its elimination half-life is 25–30 hours under monotherapy [8] and 60 hours approximately when combined with valproic acid (VPA) [9].\n\nLTG is mainly eliminated by UDP-glucuronosyltransferases leading to the formation of two major metabolites: LTG-N-2 glucuronide and LTG-N-5 glucuronide. A minor metabolism pathway is the formation of the N-2 methyl and the N-2-oxide-LTG [10]. The main route of LTG metabolism does not involve cytochrome P450 enzymes, so according to some authors, the possibility for drug interactions is generally low [11]. However, LTG does have some clinically relevant interactions. As glucuronidation is the main pathway for LTG elimination, anything that inhibits UDP-glucuronosyltransferase enzymes will affect LTG levels, leading LTG metabolism to the minor elimination route in which cytochrome P450 enzymes are involved. So in the absence of the major pathway such as N-glucuronidation, LTG can be bioactivated to an arene oxide [12, 13]. Figure 1 schematizes LTG metabolic pathways.\n\nArene oxides are of significant toxicological concern because these intermediates are chemically reactive. Arene oxides can be mainly detoxified by rearrangement to arenols, but enzymatic hydration to trans-dihydrodiols and/or enzymatic conjugations with GSH also play very important roles. If not effectively detoxified by the aforementioned pathways, an increase in arene oxide will take place, and this reactive metabolite will bind covalently with nucleophilic groups of proteins, DNA, and RNA, leading to cellular damage [14, 15].\n\nVPA is mainly metabolized by the liver, and it is a known inhibitor of UDP-glucuronosyltransferases [16]; according to some investigations [17], there was a significant increase in LTG serum concentrations from 4.67 ± 3.66 to 9.56 ± 5.27 µg/mL by concomitant administration of VPA, indicating a decrease in LTG clearance when VPA was added to the therapy. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of the arene oxide metabolite would be enhanced. As this epoxide appears to be detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase (EPHX) and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans [18], arene oxide toxicity is increased when EPHX or GSH S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. Inhibition of EPHX can occur when VPA is coadministered [19, 20]. High concentrations of VPA can deplete glutathione levels [21]. These two facts could lead to the frequent adverse effects, mainly rash and other cutaneous reactions, reported in the literature [22–24].\n\nHere, we present a case of SJS that occurred after addition of LTG to the VPA regimen.\n\n2. Case Report\nAn 8-year-old boy with chronic encephalopathy secondary to hypoxic ischemic syndrome, with cerebral palsy and symptomatic epilepsy, was admitted to the emergency department of the children's hospital. He had been seizure-free for the past year with an enteric-coated delayed release formulation of VPA (375 mg every 8 hours). Thirty days prior to hospital admission, he was started on LTG 25 mg/day along with VPA, since his seizures were no longer under control with VPA. Two weeks later, the dose was increased (50 mg/day). His morning trough plasma VPA level was measured before LTG was added to the therapy yielding a concentration of 85 mg/L. On admission, he presented macular lesions on the front of the thorax that extend to the back, followed by bilateral eyelid edema and ulcerated lesions at the level of lips, jugal mucosa, and pharynx. He developed erythematosus conjunctivitis with ulcers. He presented skin rash with high fever (39°C) and respiratory failure type I. History revealed that no such lesions occurred earlier and that was the first time such rashes have occurred. Other personal and family history was not relevant. From a dermatologic point of view and based on the history and clinical presentation, a diagnosis of SJS was made. Since the presumptive cause was LTG, the drug was discontinued immediately. Soon after the patient admission, periofocal and ocular involvement worsened. Intravenous immunoglobulin was administered for 48 hours. Mouth care (oral washes with sodium borate) and eye care (tobramycin ophthalmic drops) were also indicated.\n\nFrom a hemodynamic point of view, four hours after admission, his condition deteriorated and he developed septic shock with peripheral circulatory failure. The patient was admitted to the intensive care unit with intravenous fluids and antibacterial therapy due to skin infection by Staphylococcus aureus. In addition to fluid resuscitation, dopamine was administered. Despite the inotropic treatment, the patient's condition did not improve, indicating a septic shock refractory to conventional vasopressor therapy but during treatment with milrinone and norepinephrine for six days (apart from the antibiotics), the septic shock was reversed.\n\nHis clinical state steadily improved over the following days. He made an excellent recovery under control seizure and was discharged after twelve days on admission with VPA (375 mg every 8 hours) and oral L-carnitine (2 g/day).\n\n2.1. Genotyping Procedure of EPHX\nA blood sample (2 mL) of the patient was collected by venipuncture and was refrigerated (4–8°C) until analysis. The Wizard® genomic DNA purification kit was used to isolate the genomic DNA from whole blood. Then, it was quantified by spectrophotometry (260/280 nm) on a NanoQuant-Tecan instrument. EPHX genotype was determined by a real-time polymerase chain reaction using a TaqMan Drug Metabolism Genotyping Assay for rs1051740 and rs2234922.\n\nTwo polymorphisms, Tyr113His in exon 3 (SNP rs1051740 T > C) and His139Arg in exon 4 (SNP rs2234922 A > G), have been associated with a decrease or increase in enzyme activity, respectively [18, 25]. 113His/113His or 113His heterozygosity (mutated allele in exon 3) combined with His139/His139 (wild-type allele in exon 4) indicates a decrease in enzyme activity. An increase in activity occurs with 139Arg/139Arg or 139Arg heterozygosity (mutated allele in exon 4) combined with Tyr113/Tyr113 (wild-type allele in exon 3).\n\nThe genetic study revealed an increase in EPHX activity (wild-type allele in homozygosity for SNP rs1051740 and heterozygosity for SNP rs2234922).\n\nThis study was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki and was approved by the Ethics Review Committee of the Faculty of Chemistry (Uruguay). Written informed consent of the mother was obtained for the purpose of reporting this case.\n\n3. Discussion\nSeveral antiepileptic drugs (AEDs) are used in combination when seizures are poorly controlled. This fact leads to more potential pharmacokinetic and pharmacodynamic interactions in comparison with monotherapy.\n\nWhen LTG was started, the patient was also receiving VPA for several years, and no adverse effects were recorded during this therapy. However, VPA even at low concentrations [26] is known to decrease LTG clearance leading to higher serum concentrations of LTG which in turn increases the risk of serious rash. This is due, as it was mentioned in Introduction, to VPA's inhibition of glucuronidation pathway [16, 17, 27]. Therefore, concomitant administration of these drugs needs a much slower titration, 25 mg of LTG for the first two weeks and an increase of 25 mg/day for the next two weeks. The starting dosage of LTG in our case was 25 mg/day, and dosage had been increased slowly to 50 mg/day.\n\nPrevious work has suggested that the predisposition to such skin reactions evidenced with the use of AEDs is based on a genetic abnormality in the detoxification of reactive metabolites of the drugs [28]. Our research group has been working on this topic with phenytoin; in this case, EPHX is involved in arene oxide detoxification, so we started to investigate EPHX polymorphisms in patients with AED therapy [29, 30]. However, in the case of LTG, both Maggs et al. [12] and Chen et al. [13] research groups conclude that an arene oxide is formed and mainly an enzymatic conjugation with GSH takes place as the glutathione adduct was recovered in the bile. They also showed that human epidermal keratinocytes were capable of forming the GSH conjugate, evidencing that LTG could be bioactivated in skin cells giving a possible explanation for the cutaneous reactions observed with LTG therapy. So in view of their results, LTG can undergo hepatic and nonhepatic bioactivation. Genotyping of GSH S-transferases was not carried out in this patient, so a defective activity of this enzyme cannot be concluded. Nevertheless, VPA and its metabolites (i.e., 4-en-VPA) are likely to produce glutathione depletion or according to some authors, glutathione-S-transferases inhibition mainly at high VPA concentrations so detoxification of arene oxide could be impaired, as stated before [31, 32]. VPA is metabolized by three main routes: glucuronidation (50%), β-oxidation in the mitochondria using L-carnitine (40%), and ω-oxidation (10%); the latter leads to formation of a toxic metabolite, 4-en-VPA [33]. VPA chronic therapy or VPA overdose produces L-carnitine (LCAR) depletion, and this could impair β-oxidation leading to the ω-oxidation pathway and the formation of toxic metabolites. In our case, predose VPA level was high (85 mg/L). The enteric-coated preparation of VPA administered to our patient would yield important peak-trough fluctuations, so a predose of 85 mg/L could result in a much higher peak concentration. This could have resulted in β-oxidation impairment and higher concentrations of toxic metabolites [34–36].\n\nOur patient was discharged with the same dose initially administered of VPA, and LCAR was added. LCAR supplementation restores VPA metabolism to normal routes, increasing β-oxidation and thus decreasing ω-oxidation and therefore 4-en-VPA formation. Moreover, β-oxidation impairment produced perhaps by the initial high concentrations of VPA could have been the cause of hyperammonemia [36, 37], and thus of the occurrence of seizures. That was the reason why LTG was added to the therapy, not taking into consideration that perhaps seizures were the consequence of high levels of ammonia. The introduction of LCAR to VPA therapy would reverse such condition.\n\nEven though there is no current evidence of microsomal EPHX involvement in arene oxide detoxification in the case of LTG and no formation of dihydrodiol was reported in the literature, EPHX participation is chemically possible and cannot be disregarded. Only EPHX polymorphism was studied in this patient, and genetic study yielded an increased activity of the EPHX. On the one hand, the higher catalytic efficiency of EPHX increases the formation of trans‐dihydrodiol, but on the other hand, VPA, as it was stated in Introduction, inhibits the EPHX so perhaps an increase of arene oxide intermediate could have also occurred due to VPA inhibition.\n\nSeveral studies [38, 39] have determined the association of increased risk of LTG-induced cutaneous reactions with human leukocyte antigen (HLA) genotypes. However, the researchers concluded that further investigation was needed to confirm this association. No HLA genotyping was carried out in this patient in order to infer its implication.\n\nThe main limitation of this study is that LCAR, ammonia, and LTG levels were not measured prior admission, and even though no seizures were recorded in the follow-up, once again no VPA, ammonia, and LCAR levels were monitored.\n\nIn conclusion, the present case report supports the clinical evidence that a combination of LTG and VPA increases the frequency and severity of skin reactions. VPA not only decreases LTG clearance by competing with the glucuronidation pathway leading LTG metabolism to arene oxide formation, but also inhibits either epoxide hydrolase or GSH-S-transferases or depletes glutathione avoiding arene oxide detoxification regardless the polymorphisms of these enzymes. This case also supports the recommendation that antiepileptic levels as well as ammonia levels in patients undergoing chronic VPA treatment should be monitored.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 Metabolism pathways of lamotrigine. UDPGT: uridine diphosphate glucuronosyltransferase; EPHX: epoxide hydrolase; GSH: glutathione.\n==== Refs\n1 Warshavsky A. Eilam A. Gilad R. Lamotrigine as monotherapy in clinical practice: efficacy of various dosages in epilepsy Brain and Behaviour 2016 6 3 e00419 10.1002/brb3.419 2-s2.0-84958631178 \n2 Reid J. G. Gitlin M. J. Altshuler L. L. Lamotrigine in psychiatric disorders Journal of Clinical Psychiatry 2013 74 7 675 684 10.4088/jcp.12r08046 2-s2.0-84881014605 23945444 \n3 Clark C. T. Klein A. M. Perel J. M. Helsel J. Wisner K. L. Lamotrigine dosing for pregnant patients with bipolar disorder American Journal of Psychiatry 2013 170 11 1240 1247 10.1176/appi.ajp.2013.13010006 2-s2.0-84887420147 24185239 \n4 Finnerup N. B. Sindrup S. H. Jensen T. S. Management of painful neuropathies Handbook of Clinical Neurology 2013 115 279 290 10.1016/b978-0-444-52902-2.00017-5 2-s2.0-84881494945 23931787 \n5 Calabrese J. R. Sullivan J. R. Bowden C. L. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management Journal of Clinical Psychiatry 2002 63 11 1012 1019 10.4088/jcp.v63n1110 12444815 \n6 Egunsola O. Choonara I. Sammons H. M. Safety of lamotrigine in paediatrics: a systematic review BMJ Open 2015 5 6 e007711 10.1136/bmjopen-2015-007711 2-s2.0-84937249974 \n7 Fricke-Galindo I. Jung-Cook H. LLerena A. López-López M. Pharmacogenetics of adverse reactions to antiepileptic drugs Neurología 2018 33 3 165 176 10.1016/j.nrl.2015.03.005 2-s2.0-85043720784 25976948 \n8 Ramesh Yasam V. Jakki S. L. Senthil V. A pharmacological overview of lamotrigine for the treatment of epilepsy Expert Review of Clinical Pharmacology 2016 9 12 1533 1546 10.1080/17512433.2016.1254041 2-s2.0-84996432109 27825017 \n9 Zaccara G. Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs Epileptic Disorders 2014 16 4 409 432 25515681 \n10 Doig M. V. Clare R. A. Use of thermospray liquid chromatography-mass spectrometry to aid in the identification of urinary metabolites of a novel antiepileptic drug, lamotrigine Journal of Chromatography 1991 554 1-2 181 189 10.1016/s0021-9673(01)88448-x 2-s2.0-0025879343 1795036 \n11 Italiano D. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update Clinical Pharmacokinetics 2013 52 8 627 645 10.1007/s40262-013-0067-4 2-s2.0-84880787487 23640503 \n12 Maggs J. L. Naisbitt D. J. Tettey J. N. A. Pirmohamed M. Park B. K. Metabolism of lamotrigine to a reactive arene oxide intermediate Chemical Research in Toxicology 2000 13 11 1075 1081 10.1021/tx0000825 2-s2.0-0033725544 11087428 \n13 Chen H. Grover S. Yu L. Walker G. Mutlib A. Bioactivation of lamotrigine in vivo in rat and in vitro in human liver microsomes, hepatocytes, and epidermal keratinocytes: characterization of thioether conjugates by liquid chromatography/mass spectrometry and high field nuclear magnetic resonance spectroscopy Chemical Research in Toxicology 2010 23 1 159 170 10.1021/tx9003243 2-s2.0-75149197657 19961160 \n14 Naisbitt D. J. Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests Toxicology 2004 194 3 179 196 10.1016/j.tox.2003.09.004 2-s2.0-0348110315 14687965 \n15 Jerina D. M. Daly J. W. Arene oxides: a new aspect of drug metabolism Science 1974 185 4151 573 582 10.1126/science.185.4151.573 4841570 \n16 Lu W. Uetrecht J. P. Possible bioactivation pathways of lamotrigine Drug Metabolism and Disposition 2007 35 7 1050 1056 10.1124/dmd.107.015271 2-s2.0-34250728560 17409271 \n17 Lalic M. Cvejic J. Popovic J. Lamotrigine and valproate pharmacokinetics interactions in epileptic patients European Journal of Drug Metabolism and Pharmacokinetics 2009 34 2 93 99 10.1007/bf03191157 2-s2.0-68949110440 19645218 \n18 Wormhoudt L. W. Commandeur J. N. Vermeulen N. P. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity Critical Reviews in Toxicology 1999 29 1 59 124 10.1080/10408449991349186 2-s2.0-0032934961 10066160 \n19 Spiegelstein O. Kroetz D. L. Levy R. H. Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid Pharmaceutical Research 2000 17 2 216 221 10.1023/a:1007577600088 2-s2.0-0034059186 10751038 \n20 Rosa M. Bonnaillie P. Chanteux H. Prediction of drug–drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition Xenobiotica 2016 46 12 1076 1084 10.3109/00498254.2016.1151088 2-s2.0-84961211250 26936324 \n21 Dikić D. Jutrić D. Dominko K. The dual nature of the antiepileptic drug valproic acid, with possible beneficial effects in Alzheimer’s disease SEEMEDJ 2017 1 1 74 89 \n22 Wang X. Iv B. Wang H. Lamotrigine-induced severe cutaneous adverse reaction: update data from 1999–2014 Journal of Clinical Neuroscience 2015 22 6 1005 1011 10.1016/j.jocn.2015.01.016 2-s2.0-84928938525 25913750 \n23 Yalcin B. Karaduman A. Stevens–Johnson syndrome associated with concomitant use of lamotrigine and valproic acid Journal of the American Academy of Dermatology 2012 43 5 703 706 10.1067/mjd.2000.100544 \n24 Maduemem K. Vatca A. O’Neill T. Buckley D. Stevens– Johnson syndrome induced by combination of lamotrigine and valproic acid in a 9-year-old boy Irish Medical Journal 2017 110 6 p. 586 \n25 Pinarbasi H. Silig Y. Pinarbasi E. Microsomal epoxide hydrolase polymorphisms Molecular Medicine Reports 2010 3 4 723 727 10.3892/mmr_00000324 21472306 \n26 Kanner A. M. When thinking of lamotrigine and valproic acid, think “pharmacokinetically”! Epilepsy Currents 2004 4 5 206 207 10.1111/j.1535-7597.2004.04515.x 16059503 \n27 Rowland A. Elliot D. J. Williams J. A. Mackenzie P. I. Dickinson R. G. Miners J. O. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction Drug Metabolism and Disposition 2006 34 6 1055 1062 10.1124/dmd.106.009340 2-s2.0-33646784394 16565174 \n28 Chung W. H. Chang W. C. Lee Y. S. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions JAMA 2014 312 5 525 534 10.1001/jama.2014.7859 2-s2.0-84905901610 25096692 \n29 Vázquez M. Fagiolino P. Alvariza S. Skin reactions associated to phenytoin administration: multifactorial cause Clinical Pharmacology & Biopharmaceutics 2014 3 2 10.4172/2167-065x.1000125 \n30 Guevara N. Maldonado C. Uría M. Role of CYP2C9, CYP2C19 and EPHX polymorphism in the pharmacokinetic of phenytoin: a study on Uruguayan Caucasian subject Pharmaceuticals 2017 10 4 p. 73 10.3390/ph10030073 2-s2.0-85028571696 \n31 Nanau R. M. Neuman M. G. Adverse drug reactions induced by valproic acid Clinical Biochemistry 2013 46 15 1323 1338 10.1016/j.clinbiochem.2013.06.012 2-s2.0-84884355674 23792104 \n32 Fukushima Y. Seo T. Hashimoto N. Higa Y. Ishitsu T. Nakagawa K. Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gamma-glutamyltransferase in valproic acid-treated patients Clinica Chimica Acta 2008 389 1-2 98 102 10.1016/j.cca.2007.11.035 2-s2.0-38649130645 \n33 Klee S. Johanssen S. Ungemach F. R. Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity Pharmacology and Toxicology 2000 87 2 89 95 10.1034/j.1600-0773.2000.d01-50.x 10989947 \n34 Maldonado C. Guevara N. Queijo C. González R. Fagiolino P. Vázquez M. Carnitine and/or acetylcarnitine deficiency as a cause of higher levels of ammonia BioMed Research International 2016 2016 p. 8 2920108 10.1155/2016/2920108 2-s2.0-84960984461 \n35 Perrott J. Murphy N. G. Zed P. J. L-carnitine for acute valproic acid overdose: a systematic review of published cases Annals of Pharmacotherapy 2010 44 7-8 1287 1293 10.1345/aph.1p135 2-s2.0-77954584445 20587742 \n36 Vázquez M. Fagiolino P. Maldonado C. Hyperammonemia associated with valproic acid concentrations BioMed Research International 2014 2014 p. 7 217269 10.1155/2014/217269 2-s2.0-84901253057 \n37 Maldonado C. Guevara N. Silveira A. Fagiolino P. Vázquez M. L-carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: a case report Journal of International Medical Research 2017 45 3 1268 1272 10.1177/0300060517703278 2-s2.0-85021268045 28425821 \n38 Kim E. Y. Ji K. H. Kim H. J. Jung H. E. Cha E. Y. Shin J. G. HLA-A∗24:02/B∗51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans Translational and Clinical Pharmacology 2016 24 3 143 146 10.12793/tcp.2016.24.3.143 2-s2.0-85003601605 \n39 Koomdee N. Pratoomwun J. Jantararoungtong T. Association of HLA-A and HLA-B alleles with lamotrigine-induced cutaneous adverse drug reactions in the Thai population Frontiers in Pharmacology 2017 8 p. 879 10.3389/fphar.2017.00879 2-s2.0-85036656081 29238301\n\n",
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"references": "16059503;28952676;26904382;19961160;26936324;23945444;25913750;10066160;27825017;26998483;1795036;24185239;26070796;11087428;28425821;21472306;24868521;14687965;4841570;29238301;25096692;23931787;23792104;28820457;19645218;10989947;18155166;25515681;17409271;20587742;23640503;11044815;25976948;10751038;12444815;16565174",
"title": "Lamotrigine-Valproic Acid Interaction Leading to Stevens-Johnson Syndrome.",
"title_normalized": "lamotrigine valproic acid interaction leading to stevens johnson syndrome"
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"abstract": "We describe a case of immune reconstitution inflammatory syndrome (IRIS) secondary to reactivation of Mycobacterium tuberculosis in an HIV-infected patient with a high CD4+ cell count, who presented with a generalized seizure 6 weeks after starting antiretroviral therapy (ART). In our patient, the inflammatory response resulted in radiological features of neurological, pulmonary, and lymph node (LN) tuberculosis- (TB) IRIS, without the typical symptoms. Diagnosis was confirmed by LN biopsy and acid-fast bacilli (AFB) culture of LN and sputum. Treatment with isoniazid, rifabutin, ethambutol, and pyrazinamide was started in addition to continuation of ART. To our knowledge, we describe the first case of an atypical clinical presentation of an unmasking reaction of disseminated TB-IRIS in an HIV infected patient without acquired immune deficiency syndrome (AIDS), with restoring immunity during ART. Clinical and radiological predictors of TB-IRIS in co-infected patients starting ART are therefore essential in anticipating complications and facilitating expeditious management and prompt therapy.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States.;Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States.;Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States.;Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States.;Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States.",
"authors": "Shuker|Orel|O|;Villamil|Jose|J|;Ghitan|Monica|M|;Chapnick|Edward K|EK|;Lin|Yu Shia|YS|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00519",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30218-X10.1016/j.idcr.2019.e00519e00519ArticleTuberculosis-immune reconstitution inflammatory syndrome in HIV-infected patient: A case report Shuker Orel oshuker@maimonidesmed.org⁎Villamil Jose Ghitan Monica Chapnick Edward K. Lin Yu Shia Division of Infectious Diseases, Department of Medicine, Maimonides Medical Center, New York, United States⁎ Corresponding author. oshuker@maimonidesmed.org12 3 2019 2019 12 3 2019 15 e0051930 11 2018 13 1 2019 6 3 2019 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We describe a case of immune reconstitution inflammatory syndrome (IRIS) secondary to reactivation of Mycobacterium tuberculosis in an HIV-infected patient with a high CD4+ cell count, who presented with a generalized seizure 6 weeks after starting antiretroviral therapy (ART). In our patient, the inflammatory response resulted in radiological features of neurological, pulmonary, and lymph node (LN) tuberculosis- (TB) IRIS, without the typical symptoms. Diagnosis was confirmed by LN biopsy and acid-fast bacilli (AFB) culture of LN and sputum. Treatment with isoniazid, rifabutin, ethambutol, and pyrazinamide was started in addition to continuation of ART.\n\nTo our knowledge, we describe the first case of an atypical clinical presentation of an unmasking reaction of disseminated TB-IRIS in an HIV infected patient without acquired immune deficiency syndrome (AIDS), with restoring immunity during ART. Clinical and radiological predictors of TB-IRIS in co-infected patients starting ART are therefore essential in anticipating complications and facilitating expeditious management and prompt therapy.\n\nKeywords\nTuberculosisUnmaskingImmune reconstitution inflammatory syndromeHIVAntiretroviral therapy\n==== Body\nIntroduction\nTuberculosis- (TB) associated immune reconstitution inflammatory syndrome (IRIS) refers to an abnormally exaggerated immune response against alive or dead Mycobacterium tuberculosis infection [1]. This phenomenon occurs mostly in HIV-infected patients, most often within two months of the initiation of ART [1]. Risk factors for TB-IRIS include advanced HIV, rapid rise in CD4+ cell count or rapid drop in HIV RNA following initiation of ART, and high pathogen or antigen burden [1].\n\nThere are two distinct temporal versions of TB-IRIS: paradoxical and unmasking. Paradoxical refers to clinical deterioration after initiation of ART in a patient previously diagnosed with TB who has responded to antituberculosis treatment. Unmasking refers to a patient with asymptomatic TB disease prior to starting ART, which presents after initiating ART, as in our patient [2]. Lymph nodes (68%) and lungs (16%) are the principal sites involved in TB-IRIS. Typically, patients present with fever, abdominal pain, cough and lymphadenopathy [1]. Neurological involvement occurs in 12–31% of TB-IRIS patients [3]. Most reported cases were paradoxical TB-IRIS, which is the best studied of the two forms [2].\n\nThere is no specific diagnostic test that can establish or rule out the diagnosis of TB-IRIS [1]. Although there is no standard optimal treatment for TB-IRIS, antituberculosis therapy should be initiated as soon as possible [1].\n\nIn this unique case report, we describe a patient who presents with an atypical presentation of disseminated TB-IRIS, which is rarely seen in non-advanced HIV patients with restoring immunity during ART. Given this entity, it is important to ensure timely initiation of treatment.\n\nCase report\nA 42-year-old Chinese man was admitted to the hospital with a generalized seizure, which was witnessed. He recalled feeling twitching of his eyes and mouth prior to a brief period of loss of consciousness. The patient felt well after the episode, with the exception of fatigue. There was no fever, chills, headache, or visual disturbances.\n\nThe patient is from China, and has resided in the United States for 8 years. He has used intravenous heroin and alcohol but stopped 10 years previously. He smoked 1 package of cigarettes daily for 20 years.\n\nPast medical history is significant for HIV, hepatitis B and C (HCV), all diagnosed 3 months prior to this admission when he presented with progressive swelling of the lower extremities and elevated blood pressure. A renal biopsy showed membranoproliferative glomerulonephritis. The initial CD4+ cell count was 389/mm3, quantitative HIV RNA 58,254 copies/ml and HCV viral load 202,489 IU/mL.\n\nTreatment with dolutegravir and emtricitabine/tenofovir alafenamide was started 6 weeks previously, followed by sofosbuvir/velpatasvir.\n\nOn admission, the oral temperature was 99.30F, pulse 100 beats/minute, respiratory rate 16 breaths/min, blood pressure 155/104 mmHg and oxygen saturation 99% on room air.\n\nPhysical examination showed a laceration on the lateral aspect of the tongue and bilateral axillary lymphadenopathy. Neurological assessment revealed an alert and oriented patient with normal speech. No motor deficits were noted, and sensation was intact bilaterally. There was no facial weakness, and the tongue was midline. Cranial nerves were intact, with normal visual fields. Deep tendon reflexes were normal and symmetrical. No gait abnormalities were appreciated, and cerebellar function was intact.\n\nThe leukocyte count was 7900/UL, hemoglobin 10.2 g/dL, and platelet count 177,000/UL. Blood urea nitrogen was 16 mg/dL, and creatinine was 1.2 mg/dL. The erythrocyte sedimentation rate was greater than 145 mm/h. Cerebrospinal fluid (CSF) analysis showed 10 leukocytes/mm3, glucose of 45 mg/dL (serum glucose 90 mg/dL) and protein of 48 mg/dL. CSF cryptococcal antigen, VDRL and bacterial cultures were negative. Absolute CD4+ count was 343/mm3 and HIV RNA was undetectable. Hepatitis B viral DNA and hepatitis C RNA were undetectable.\n\nBlood cultures, urine culture, urine toxicology and an echocardiogram were normal. Chest radiograph (CXR) was also normal. Parasitological investigation of stool samples did not reveal pathogens. The initial brain computed tomography (CT) showed numerous areas of white matter edema at the gray-white junction within the bilateral hemispheres, as well as in the left cerebellum (Fig. 1). Gadolinium-enhanced magnetic resonance imaging (MRI) revealed numerous small ring-enhancing masses with targetoid appearance and moderate surrounding vasogenic edema (Fig. 2). Serum cysticercus IgG and toxoplasma IgM and IgG antibodies were negative. Although the CXR was normal, the CT of the chest (Fig. 3) showed extensive lymphadenopathy, with bilateral apical airspace disease with tree-in-bud like appearance. Initial sputum acid-fast smears were negative.Fig. 1 Initial brain computed tomography (pre-treatment) showing numerous areas of white matter edema at the gray-white junction within the bilateral hemispheres, as well as in the left cerebellum.\n\nFig. 1Fig. 2 Magnetic resonance imaging scan with gadolinium of the brain (pre-treatment) revealing numerous small ring-enhancing masses with targetoid appearance and moderate surrounding vasogenic edema.\n\nFig. 2Fig. 3 Pre-treatment computed tomography of the chest showing extensive lymphadenopathy, with bilateral apical airspace disease with tree-in-bud like appearance.\n\nFig. 3\n\nAn axillary lymph node biopsy showed granulomatous inflammation with necrosis. Acid fast and fungal stains were negative.\n\nTreatment with isoniazid, rifabutin, ethambutol, and pyrazinamide was started. In addition, dexamethasone 0.3 mg/kg/day was given together with anti-tuberculous medication and gradually tapered over six weeks. The patient was discharged on hospital day 23. Three weeks later, the axillary lymph node and sputum cultures grew Mycobacterium tuberculosis.\n\nFollow-up brain MRI with gadolinium five months later showed that nearly all of the previously demonstrated ring enhancing masses had decreased in size and markedly decreased surrounding vasogenic edema (Fig. 4). In addition, follow-up CT of the chest 2 weeks after initiation of treatment revealed partial resolution of the previously seen bronchial and bronchiolar inspissation in both upper lobes (Fig. 5).Fig. 4 Post-treatment brain magnetic resonance imaging showing that nearly all of the ring enhancing masses (blue arrows) had decreased in size and markedly decreased surrounding vasogenic edema.\n\nFig. 4Fig. 5 Post-treatment computed tomography of the chest revealing partial resolution of the previously seen bronchial and bronchiolar inspissation in both upper lobes.\n\nFig. 5\n\nDiscussion\nOur patient, who is a former injecting drug user, presented with a generalized seizure six weeks after starting ART.\n\nThe differential diagnosis of brain lesions in HIV infected patients includes cryptococcosis, neurocysticercosis, toxoplasmosis, progressive multifocal leukoencephalopathy-IRIS, syphilitic gummata, septic emboli and malignant lymphoma [3]. Because our patient had a CD4+ cell count over 300, opportunistic pathogens were less likely. We made a presumptive diagnosis of unmasking disseminated TB-IRIS based on the following: ART was initiated six weeks earlier; the presence of multiple small intracerebral space-occupying lesions; coexistent bilateral upper lung infiltrates; extensive lymphadenopathy throughout the chest, abdomen and pelvis; and granulomatous inflammation with necrosis in a lymph node.\n\nInterestingly, our patient did not present with any systemic or pulmonary manifestations.\n\nIn contrast to existing reports and case series, our patient presented with an unmasking pattern of disseminated TB-IRIS six weeks after initiation of ART. In addition, our patient’s nadir CD4+ cell count was 389 cells/mm3 and viral load was not high.\n\nThere is no specific diagnostic test that can establish or rule out the diagnosis of TB-IRIS [1]. It is difficult to differentiate this syndrome from the development of new occult opportunistic bacterial infections or malignancy. These diagnostic challenges often delay diagnosis and treatment. Clinicians should take into consideration a combination of clinical presentation and timing of initiation of antiretroviral therapy in making the correct diagnosis [1]. Although there is no standard optimal treatment for TB-IRIS, antituberculosis therapy should be initiated as soon as possible [1]. Furthermore, ART should be continued during the management of IRIS unless the disease is life threatening [2]. In severe forms of TB, use of anti-inflammatory medications such as corticosteroids improved symptoms, and reduced hospital days and morbidity [4].\n\nTo conclude, unmasking TB-IRIS should be included in the differential diagnosis in an HIV-infected patient with a high CD4+ cell count, even with an atypical presentation, to ensure timely initiation of treatment.\n\nConflict of interest\nOn behalf of all authors the corresponding author states that there is no conflict of interest.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of this written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAcknowledgments\nWe thank Dr. Evan Stein and Dr. Jack Twersky from the Department of Radiology of Maimonides Medical Center in Brooklyn, New York, for providing the radiological imaging figures.\n==== Refs\nReferences\n1 Friedland Gerald Tuberculosis immune reconstitution inflammatory syndrome: drug resistance and the critical need for better diagnostics Clin Infect Dis 48 March (5) 2009 677 679 19191656 \n2 Sharma Surendra K. Soneja Manish HIV & immune reconstitution inflammatory syndrome (IRIS) Indian J Med Res 134 January (6) 2011 866 877 22310819 \n3 Nathan Bahr David Boulware R. Suzaan Marais James Scriven Robert Wilkinson J. Graeme Meintjes Central nervous system immune reconstitution inflammatory syndrome Curr Infect Dis Rep 15 January (6) 2013 \n4 Lanzafame Massimiliano Vento Sandro Tuberculosis-immune reconstitution inflammatory syndrome J Clin Tuberc Other Myscobacterial Dis 3 2016 6 9\n\n",
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"keywords": "Antiretroviral therapy; HIV; Immune reconstitution inflammatory syndrome; Tuberculosis; Unmasking",
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"title": "Tuberculosis-immune reconstitution inflammatory syndrome in HIV-infected patient: A case report.",
"title_normalized": "tuberculosis immune reconstitution inflammatory syndrome in hiv infected patient a case report"
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"abstract": "BACKGROUND\nVaricella Zoster Virus (VZV) is associated with many disorders of the central and peripheral nervous systems including neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay-Hunt syndrome, and polyneuritis cranialis. Cranial nerves V, VI, VII, VIII, IX, X, XI, and/or XII may be affected. The neurological disorders caused by VZV usually present with rash, but may rarely present without rash.\n\n\nMETHODS\nWe herein present a case of polyneuritis cranialis without rash caused by VZV affecting cranial nerves VII, VIII, IX, and X. After excluding other causes of the condition, we diagnosed VZV infection based on VZV DNA in the CSF and an elevated anti-VZV IgG level in serum. The patient responded well to antiviral therapy.\n\n\nCONCLUSIONS\nVZV infection should be kept in mind during the differential diagnosis of polyneuritis cranialis; it is important to note that VZV re-activation may occur without rash.",
"affiliations": "Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey.;Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey.;Inonu university, Turgut Ozal medicine center, Radiology department, Malatya, Turkey.;Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey.;Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey.",
"authors": "Tecellioglu|Mehmet|M|;Kamisli|Suat|S|;Erbay|Mehmet Fatih|MF|;Kamisli|Ozden|O|;Ozcan|Cemal|C|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
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"doi": "10.5455/medarh.2017.71.293-295",
"fulltext": "\n==== Front\nMed ArchMed ArchMedical Archives0350-199X1986-5961AVICENA, d.o.o., Sarajevo Bosnia and Herzegovina MA-71-29310.5455/medarh.2017.71.293-295Case ReportA Rare Presentation of Cranial Polyneuropathy Without Rash Caused by Varicella Zoster Virus Tecellioglu Mehmet 1Kamisli Suat 1Erbay Mehmet Fatih 2Kamisli Ozden 1Ozcan Cemal 11 Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey2 Inonu university, Turgut Ozal medicine center, Radiology department, Malatya, TurkeyCorresponding author: Mehmet Tecellioglu, Inonu university, Turgut Ozal medicine center, Neurology department, Malatya, Turkey. E-mail: mehmettecelli@hotmail.com8 2017 71 4 293 295 10 6 2017 27 7 2017 Copyright: © 2017 Mehmet Tecellioglu, Suat Kamisli, Mehmet Fatih Erbay, Ozden Kamisli, Cemal Ozcan2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction:\nVaricella Zoster Virus (VZV) is associated with many disorders of the central and peripheral nervous systems including neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay-Hunt syndrome, and polyneuritis cranialis. Cranial nerves V, VI, VII, VIII, IX, X, XI, and/or XII may be affected. The neurological disorders caused by VZV usually present with rash, but may rarely present without rash.\n\nCase report:\nWe herein present a case of polyneuritis cranialis without rash caused by VZV affecting cranial nerves VII, VIII, IX, and X. After excluding other causes of the condition, we diagnosed VZV infection based on VZV DNA in the CSF and an elevated anti-VZV IgG level in serum. The patient responded well to antiviral therapy.\n\nConclusion:\nVZV infection should be kept in mind during the differential diagnosis of polyneuritis cranialis; it is important to note that VZV re-activation may occur without rash.\n\nVaricella Zoster VirusCranial Polyneuropathy\n==== Body\n1. INTRODUCTION\nVaricella Zoster Virus (VZV) is a neurotropic DNA virus as a member of the family Herpesviridae. It is the cause of varicella as primary infection and zoster as recurrence. (1). VZV produces a lot of disorders involving central and peripheral nervous system such as neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay Hunt syndrome and polyneuritis cranialis (2). Pathological mechanism is thought to be usually related to microinfarction of cranial nerves due to occlusion of vasa nervorum (3). These neurological disorders caused by VZV are usually seen with rash but rarely may present without rash. (4). In the literature some cases of polyneuritis cranialis caused by VZV have been reported. We herein present a case of polyneuritis cranialis without rash.\n\n2. CASE REPORT\nA 63 year-old man was admitted to our hospital with complaints of headake, dysphagia, hearing loss and left sided facial asymmetry continuing for 10 days. He was hospitalized to our clinic for further assesment. Detailed anamnesis revealed coronary artery disease with family history and smoking habit of one-pack-per day for 15 years. He had been using acetylsalicylic acid and propranolol. In the physical examination, his vital signs were normal, and there were no eruptions on his face, ears, mouth or pharynx. Neurological examination revealed hoarse voice, left sided peripheral facial asymmetry, hypoesthesia on the left side of the face and decreased gag reflex (Figure 1). The other neurological examinations were found normal. Blood cell counts, erythrocyte sedimentation rate, C-reactive protein, electrolytes, creatinine, hepatic enyzmes, thyroid tests, tumor markers, vitamins A, B1, B6 and E were in normal range. Magnetic resonance imaging (MRI) of brain demonstrated nonspecific ischemic gliotic focis. MRI venography, temporal MRI, neck computed tomography (CT), thorax CT were normal. Electromyography (EMG) demonstrated findings of axonal neuropathy on the left facial nerve (Figure 2). In the audiometry test pure tone averages of air and bone conduction were 44-36 dB in left and 41-35 dB in right, respectively (bilateral mild sensorineural hearing loss). Laryngeal fiberoscopy demonstrated left vocal cord paralysis (Abduction defect) (Figure 3). Lomber puncture revealed normal CSF pressure and levels of protein and chlorine while glucose level increased slightly. Cytological analysis of the CSF revealed lymphoid cell elevation (130/µl). Polymerase chain reaction (PCR) test for BK virus, Adenovirus, EBV, TBC, CMV, HSV1/2, JC virus, Brucella, atypical pneumonia agents in CSF were negative but only VZV-DNA was positive (+2/5 copy). Serum VZV IgG was elevated (749 mIU/ml) (Table 1).\n\nFigure 1 Left facial weakness\n\nFigure 2 Brain MRI. A contrast-enhanced T1-weighted image (a) and T2-weighted non-contrast image (b) disclosed normal cranial nerves\n\nFigure 3 Laryngeal fiberoscopy; left vocal cord paralysis\n\nWe initiated intravenous acylovir in dose 3x750 mg./day. In the 6 th day of the teraphy the patient’s creatinin and urea levels were increased (respectively 2.31 mg/dl and 38 mg/dl.) After nephrological consultation, no primary kidney problem was detected, therefore we supposed that this situation was related to acylovir terapy. So we decreased the dose of acylovir to 2x750 mg/day and within 3 days the kidney functions turned back to normal. In follow-up evaluation after 10 days of antiviral therapy, his facial weakness declined but dysphagia remained same. The antiviral teraphy was maintained 21 days. He was fed by orogastric probe for 3 weeks. After 3 week his gag reflex came back poorly and he started oral feeding. In second month of the illness, his gag reflex was normal. His control laryngeal fiberoscopy was normal (Figure 4). Control audiometry was performed and pure tone averages of air and bone conduction showed a slight improvement on the left and remained nearly same on the right (36-34 dB and 41-39 dB, respectively). But clinically his hearing complaints declined. The neurological examination showed mild left peripheral facial neuropathy as sequela. In third month of the illness control CSF analyses revealed normal cell count. PCR test for all agents including VZV-DNA were negative. Serum VZV IgG showed significant decrease (9.9 mIU/ml).\n\nFigure 4 Laryngeal fiberoscopy control; normal vocal cord functions\n\nThe patient was fully informed and gave written consent prior to this report.\n\n3. DISCUSSION\nThere have been various examples of polyneuritis cranialis caused by VZV (5). Cranial nerves V, VI, VII, VIII, IX, X, XI and XII may be affected. While especially, the involvement of cranial nerves V, VII and VIII with VZV is more prevalent, the other cranial nerves are affected lesser, relatively. In our case cranial nerves VII, VIII, IX and X were affected. Causes of polyneuritis cranialis include vascular diseases, infections, tumors, trauma, bone diseases, toxic causes, chemotherapy, surgery, vasculitis, inflammatory diseases and diabetes (2). Our patient did not have any story of malignancy, trauma, vasculitis, inflammatory diseases, diabetes and surgery. Some MRI findings have been reported in some cases related to involvement of multipl cranial nerves by VZV such as enlargement of cranial nerves with enhancement in the localization of auditory canal or swelling of nerves complex (6, 7). In a case report of VZV polyneuropathy which the IX and X. cranial nerves were involved, the MRI findings mimicked a small tumor (7). MRI findings of VZV polyneuritis cranialis have been suggested to be a temporary phenomenon in some case reports (8). Conversely, our patient did not display any similar MRI findings (Figure 2). Thus, it is important to take into consideration that polyneuropathy cranialis caused by VSV may present without MRI findings. Multiple cranial nerve involvement with rash by VZV is more prevalent and easily diagnosed. The main point of VZV reactivation is that it may present without rash. Infection of VZV without rash may cause various neurological disorders including chronic radicular pain, polyneuritis cranialis, cerebellitis, meningitis, vasculopathy (intracerebral and extracerebral arteries that causes ischemic or hemorrhagic stroke, dissection, arterial ectasia), myelopathy (myelitis and spinal cord infarction) (5, 9). Since the control CSF analysis revealed negative VZV-PCR and also no rash was detected in this period, we confirmed the diagnosis of VZV infection without rash. Antiviral and corticosteroid treatment has been recommended in some cases of polyneuritis cranialis by VZV (8, 10). Particularly, in a recent case report, urgent combined treatment with antiviral and agents was proposed (10). We initiated antiviral teraphy in our patient as soon as VZV infection was diagnosed. Since the disease was diagnosed on subacute period, the corticosteroid treatment was not applied. In the clinical follow up the pathological signs resolved by antiviral teraphy\n\n4. CONLUSION\nWe herein presented a case of polyneuritis cranialis caused by VZV without rash of which the cranial nerves VII, VIII, IX and X were affected. Excluding the other causes of polyneuritis cranialis, we diagnosed VZV infection showing VZV-DNA in the CSF and elevated VZV IgG in the serum. This clinical situation responded well to antiviral teraphy. VZV infection should be kept in mind in the differential diagnosis of polyneuritis cranialis causes and the other important consideration is that VZV reactivation may ocur without rash.\n\nCompliance with Ethical Standards:\n\n• This article does not contain any studies with human participants performed by any of the authors and no funding for this study.\n\n• All authors have no conflict of interest about this papers submission and to declare.\n\n• All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\n• Informed consent was obtained from all individual participants included in the case report.\n\n• Statement on consent for publication of this case report was obtained from the patient.\n\n• Approval of the case presentation was taken from the patient.\n==== Refs\nREFERENCES\n1 Sauerbrei A Diagnosis, antiviral therapy, and prophylaxis of varicella-zoster virus infections Eur J Clin Microbiol Infect Dis 2016 cited February 12, 2016 35 5 723 34 doi:10.1007/s10096-016-2605-0 26873382 \n2 Carroll CG Campbell WW Multiple cranial neuropathies Semin Neurol 2009 cited February 12, 2009 29 1 53 65 doi:10.1055/s-0028-1124023 19214933 \n3 Rhonda GK Straus SE Postherpetic neuralgia: pathogenesis, treatment and prevention N Engl J Med 1996 cited July 4, 1996 355 1 32 42 doi:10.1056/NEJM199607043350107 \n4 Gilden DH Dueland AN Devlin ME Mahalingam R Cohrs R Varicella-zoster virus reactivation without rash J Infect Dis 1992 cited August 1, 1992 166 1 S30 S34 doi:10.1093/infdis/166.Supplement 1.S30 1320648 \n5 Gilden D Cohrs RJ Mahalingam R Nagel MA Neurological Disease Produced by Varicella Zoster Virus Reactivation Without Rash Curr Top Microbiol Immunol 2010 cited April 14, 2011 342 243 53 doi:10.1007/82_2009_3 20186614 \n6 Yoshida T Fujisaki N Nakachi R Sueyoshi T Suwazono S Suehara M Persistent Hiccups and Vomiting with Multiple Cranial Nerve Palsy in a Case of Zoster Sine Herpete Intern Med 2014 cited October 15, 2014 53 20 2373 6 doi:10.2169/internalmedicine.53.1348 25318806 \n7 Adachi M A case of Varicella zoster virus polyneuropathy: involvement of the glossopharyngeal and vagus nerves mimicking a tumor AJNR Am J Neuroradiol 2008 cited June 19, 2008 29 9 1743 5 doi:10.3174/ajnr.A1141 18566008 \n8 Nisa L Landis BN Giger R Leuchter I Pharyngolaryngeal Involvement by Varicella-Zoster Virus Journal of Voice 2013 cited June 12, 2013 27 5 636 41 doi:10.1016/j.jvoice.2013.02.011 23769009 \n9 Gilden D Varicella-Zoster Virus Infections Continuum (Minneap Minn) 2015 cited December 21, 2015 21 6 1692 1703 doi:10.1212/CON.0000000000000246 26633783 \n10 Taniguchi D Nakahara PhDT Nakajima S Nakazato T Mikasa M Furukawa PhDY Successful treatment with acyclovir and a corticosteroid for lower cranial polyneuropathy in zoster sine herpete: a case report Rinsho Shinkeigaku 2015 cited October 28, 2015 55 12 932 5 doi:10.5692/clinicalneurol.cn-000781 26511031\n\n",
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"keywords": "Cranial Polyneuropathy; Varicella Zoster Virus",
"medline_ta": "Med Arch",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D003389:Cranial Nerve Diseases; D005155:Facial Nerve Diseases; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D051474:Neuralgia, Postherpetic; D011115:Polyneuropathies; D016896:Treatment Outcome",
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"title": "A Rare Presentation of Cranial Polyneuropathy Without Rash Caused by Varicella Zoster Virus.",
"title_normalized": "a rare presentation of cranial polyneuropathy without rash caused by varicella zoster virus"
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"abstract": "Aripiprazole is a second generation antipsychotic widely prescribed for the treatment of psychiatric diseases. It is generally known that antipsychotics have hypotensive effects. In this case report, however, we present the case of a medically healthy patient with schizophrenia who developed hypertension (HT) after the initiation of aripiprazole. The patient's blood pressure returned to normal after discontinuation of aripiprazole, suggesting that aripiprazole may have led to asymptomatic acute HT.",
"affiliations": "Drs. Seven, Giynaş Ayhan, Kürkçü, Özbek, Eren, MD, Konya Training and Research Hospital, Department of Psychiatry, Konya, Turkey.;Drs. Seven, Giynaş Ayhan, Kürkçü, Özbek, Eren, MD, Konya Training and Research Hospital, Department of Psychiatry, Konya, Turkey.;Drs. Seven, Giynaş Ayhan, Kürkçü, Özbek, Eren, MD, Konya Training and Research Hospital, Department of Psychiatry, Konya, Turkey.;Drs. Seven, Giynaş Ayhan, Kürkçü, Özbek, Eren, MD, Konya Training and Research Hospital, Department of Psychiatry, Konya, Turkey.;Drs. Seven, Giynaş Ayhan, Kürkçü, Özbek, Eren, MD, Konya Training and Research Hospital, Department of Psychiatry, Konya, Turkey.",
"authors": "Seven|Hilal|H|;Ayhan|Medine Giynaş|MG|;Kürkcü|Ayşe|A|;Özbek|Süleyman|S|;Eren|İbrahim|İ|",
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"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001794:Blood Pressure; D005260:Female; D006801:Humans; D006973:Hypertension; D008875:Middle Aged; D012559:Schizophrenia",
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"title": "Aripiprazole-induced Asymptomatic Hypertension: A Case Report.",
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"abstract": "Sodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier's gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS).\n\n\n\nWe mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR).\n\n\n\nWe retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.\n\n\n\nAlthough causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.",
"affiliations": "Department of Medicine, University of Padova, Padova, Italy.;Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;Department of Medicine, University of Padova, Padova, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.",
"authors": "Fadini|Gian Paolo|GP|0000-0002-6510-2097;Sarangdhar|Mayur|M|;De Ponti|Fabrizio|F|;Avogaro|Angelo|A|;Raschi|Emanuel|E|0000-0003-0487-7996",
"chemical_list": "D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin A; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C517652:hemoglobin A1c protein, human",
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"fulltext": "\n==== Front\nBMJ Open Diabetes Res CareBMJ Open Diabetes Res CarebmjdrcbmjdrcBMJ Open Diabetes Research & Care2052-4897BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjdrc-2019-00072510.1136/bmjdrc-2019-000725Clinical care education/Nutrition1506Pharmacovigilance assessment of the association between Fournier’s gangrene and other severe genital adverse events with SGLT-2 inhibitors http://orcid.org/0000-0002-6510-2097Fadini Gian Paolo 1Sarangdhar Mayur 2De Ponti Fabrizio 3Avogaro Angelo 1http://orcid.org/0000-0003-0487-7996Raschi Emanuel 31 Department of Medicine, University of Padova, Padova, Italy2 Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA3 Department of Medical and Surgical Sciences, University of Bologna, Bologna, ItalyCorrespondence to Professor Gian Paolo Fadini; gianpaolofadini@hotmail.com2019 4 10 2019 7 1 e00072506 7 2019 14 8 2019 12 9 2019 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Objective\nSodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier’s gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS).\n\nResearch design and methods\nWe mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR).\n\nResults\nWe retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.\n\nConclusions\nAlthough causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.\n\nsodium glucose cotransporterpharmacological therapytype 2 diabetesadverse drug reactionshttp://dx.doi.org/10.13039/501100003500Università degli Studi di Padovaspecial-featureunlocked\n==== Body\nSignificance of this study\nWhat is already known about this subject?\nSodium glucose cotransporter-2 inhibitors (SGLT2i) can protect from adverse cardiovascular and renal outcomes of diabetes.\n\nHowever, severe, although very rare, adverse events have been reported during therapy with SGLT2i, including Fournier’s gangrene (FG).\n\nWhat are the new findings?\nIn the U.S. Food and Drug Administration adverse event reporting system, we retrieved 47 cases of FG and 17 cases of other severe adverse events of the genital area reported with SGLT2i.\n\nIncreased reporting frequency of such events emerged for SGLT2i compared with other antidiabetic drugs, with disproportionality measures consistently ranging from 5 to 10.\n\nFG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.\n\nHow might these results change the focus of research or clinical practice?\nSince the use of SGLT2i is expected to increase significantly due to favourable cardiorenal effects, clinicians should be aware that they can rarely lead to severe adverse events of the genital area, including FG.\n\nIntroduction\nSodium glucose cotransporter-2 inhibitors (SGLT2i) are glucose-lowering medications (GLMs) provided with glycaemic and extraglycaemic effects.1 By inhibiting glucose and sodium resorption from the renal tubule, SGLT2i promote glycosuria and natriuresis, thereby reducing glycaemia, body weight and blood pressure. Cardiovascular outcome trials have demonstrated reduced risk of major adverse cardiovascular events and a consistent reduction in the incidence of hospitalisation for heart failure (HHF) in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) treated with SGLT2i.2 The reduction in HHF risk was also observed in patients with T2D without a history of CVD or prior HHF episodes,3 and solid data indicate that SGLT2i prevent future adverse renal outcomes of T2D.2 4 Based on these data, SGLT2i are being used by a progressively increasing number of patients worldwide.\n\nThe most common adverse events (AEs) during therapy with SGLT2i are genital infections,5 which are mild and resolve completely with or without treatment in most cases. Dehydration, hypovolemia and acute kidney injury are less common AEs.6 In addition, SGLT2i have been associated with an increased occurrence of rare but severe AEs, including bone fractures,7 diabetic ketoacidosis (DKA)8 and below-knee amputations.9 The risk for DKA is well documented and related to the drug’s mechanism of action,10 whereas the increased incidence of fractures and amputations has been reported inconsistently,11 and have no clear mechanistic explanation.\n\nIn August 2018, the U.S. Food and Drug Administration (FDA) issued a warning that SGLT2i may cause a severe form of perineal necrotising fasciitis (NF) known as Fournier’s gangrene (FG). This was based on the identification of 12 cases of FG occurred in patients taking SGLT2i and reported to the FDA from March 2013 to May 2018 or found in the medical literature.12 13 For comparison, the FDA safety announcement noted that only six cases of FG were identified in review of other GLM classes over a period of >30 years.14 A complete report up to January 2019 found a total of 55 cases of FG in patients taking SGLT2i and 19 in patients on other GLMs.15 To date, no formal quantification of the risk of FG associated with SGLT2i is available. We herein provide a comprehensive analysis of suspected FG reported in association with SGLT2i to the FDA AE reporting system (FAERS), along with other severe AEs of the genital area. For the first time, we performed a disproportionality analysis (DA) to size the dimension of this new SGLT2i-associated AE.\n\nResearch design and methods\nData sources and study design\nThe public FAERS database from 2004q1 to 2018q3 contains 11 525 276 reports of AEs and medication errors voluntarily submitted by healthcare professionals, consumers and drug companies from all over the world (serious reports from Europe and non-US countries are also collected). The report form contains data on suspect and concomitant drugs, drug dosage, duration and indications for use, patient demographics, outcomes, name and country of the reporting source. Not all fields are mandatory for submitting an AE report, and many reports are incomplete. FAERS data are publicly released on a quarterly basis as files that can be processed with methods for orthogonal database search.\n\nThe study was conceived as an observational, retrospective pharmacovigilance analysis, which combined descriptive case series with DA. Considering the expected rarity of FG, individual inspection of reports is useful to characterise patient-related and drug-related factors for causality, whereas DA is a recognised approach for rapid and timely detection of rare AEs and to preliminarily assess the magnitude of reporting as compared with other drugs with similar therapeutic indications.16\n\nRetrieval and characterisation of FG reports\nTo identify all possible reports for SGLT2i listing FG as an AE, we searched the FAERS using different methods. The search terms for data retrieval and disproportionality analysis are detailed in online supplementary material. ‘Necrotizing fasciitis’ was the preferred term in Medical Dictionary for Regulatory Activities (MedDRA) V.20.1 for ‘Fournier’s gangrene’, which has entered MedDRA 21.1 terms since September 2018. This implies that an automated search on databases using MedDRA terms up to 2018q3 could identify NF as FG only when the perineal site of NF was specified. We first searched the FAERS up to 2018q3 on the FDAble platform for AE reports listing SGLT2i among suspect or concomitant drugs, and the following MedDRA terms: ‘Fournier’s gangrene’ or ‘scrotal gangrene’ or ‘scrotal abscess’ or ‘perineal abscess’ or ‘perineal cellulitis’ or ‘perineal infection’ or ‘necrotising fasciitis’ or ‘necrotising fasciitis streptococcal’ or ‘necrotising fasciitis staphylococcal’ or ‘gangrenous balanitis’ or ‘vulval cellulitis’ or ‘cellulitis of male external genital organ’.\n\n10.1136/bmjdrc-2019-000725.supp1Supplementary data \n\n In parallel, we searched the public FAERS dashboard for all available AEs including ‘Fournier’s gangrene’ as a preferred term up to 2018q4. This allowed to definitely classify as FG cases initially retrieved as suspected FG based on MedDRA terms up to 2018q3. To further refine the search and increase specificity, on 4 March 2019 we asked the FDA for a freedom of information (FOI) in order to obtain structured and unstructured details on the retrieved events that could not be definitely classified as SGLT2i-associated FG. The FOI was released on 7 May 2019, when the FDA published details on 55 events of FG reported in patients taking SGLT2i up to 31 January 2019.15 Using narratives of single AE report, we could further classify as definite FG the remaining suspected cases or discharge them as non-genital AE or as severe AEs of the genital area, other than FG. Narratives criteria to define FG were the verbatim for ‘Fournier’s gangrene’ or the description of a necrotising infection of the perineum. Need for surgery was not a criterion to define FG because, like many other fields of many AE reports, diagnostic and therapeutic measures undertaken to treat the AE are often omitted.\n\nThe final list of SGLT2i-associated FG did not intentionally include cases reported in 2018q4 or later to limit the expected stimulated reporting after the FDA warning (the so-called notoriety bias).17\n\nDisproportionality analysis\nTo evaluate if and to what extent FG has been reported for SGLT2i more often than for other drugs, we performed a DA, a consolidated approach in pharmacovigilance to identify potential drug–event associations, especially in the diabetes area.18 Although pharmacovigilance evaluation cannot inform on causality, if a drug X causes the event Y, Y will be found more frequently in reports listing X than in reports listing non-X drugs as suspect or concomitant, thus generating disproportionality. Vice versa, if no link exists between X and Y, the event Y will have the same frequency in reports listing as in those not listing X as a suspect or concomitant drug.\n\nWe used the public web-based resource AERSmine, which allows customised analyses by filtering the AE search for drugs (suspected or concomitant) and their indications (MedDRA terms), AEs (MedDRA terms), outcomes, demographics and periods.19 The same definition of FG based on MedDRA terms was used as for the search in FDAble. Several search strategies were planned and performed, with different sensitivity and specificity: (a) FG among reports for SGLT2i versus reports for any other drug; (b) as in (a) but retaining only reports for drugs used for the treatment of diabetes (for definition of the indication filter, see the online supplementary material); (c) FG among reports for SGLT2i versus reports for other GLMs (ATC class plus insulin, for details see online supplementary material). For each search, a subanalysis was performed restricting to the time window from 2013q1 (when SGLT2i entered the market) to 2018q3 (at the end of which the FDA warning was published). The search strategy (c) from 2013q1 to 2018q3 was further refined using a restrictive definition of FG by MedDRA terms, obtained from the match between FDAble, the public FDA dashboard and the FOI (“necrotising fasciitis” OR “necrotising fasciitis streptococcal” OR “necrotising fasciitis staphylococcal” OR “scrotal abscess” OR “scrotal gangrene”). In addition, AEs for amputations (“amputation” OR “limb amputation” OR “leg amputation” OR “foot amputation” OR “finger amputation” OR “toe amputation” OR “arm amputation” OR “hand amputation”) were excluded because AEs listing NF of unknown site in association with an amputation were considered NF of the limbs and therefore unrelated to FG. For each search, we retrieved the number of FG cases over total reports and calculated frequencies of FG/1000 reports with 95% CI. Disproportionality was calculated using the proportional reporting ratio (PRR) and its 95% CI.\n\nResults\nAnalysis of retrieved cases\nOnline supplementary figure 1A shows the flowchart used to identify definite FG cases. Using a wide definition of FG based on MedDRA terms, we initially retrieved 84 cases of suspected FG reported in association with SGLT2i from 2004q1 to 2018q3. After removing two duplicates and excluding nine cases that were deemed unrelated to the genital area based on a review of the AE terms, 73 suspect FG cases were further evaluated against the public dashboard and narratives released by the FDA. Forty-seven of the 73 reports were confirmed as FG: 40 by the preferred term specified in the public dashboard (which is not limited to MedDRA terms) and seven that could be definitely classified as FG based on a review of the AE narratives. Aggregated characteristics of these cases are shown in table 1, whereas individual reports are shown in online supplementary table S1. Patients were on average 58.9 years old; 31 were men and 11 women (n=5 not reported).\n\nTable 1 Aggregate characteristics of reports for definite Fournier’s gangrene (FG) and severe genital adverse events (AEs), with SGLT2i as suspect or concomitant drugs\n\n\tDefinite FG\tSevere genital AEs\t\nTotal cases\t47\t17\t\nReporter country (US/non-US)\t29/18\t06/11/19\t\nAge, years (mean/range)*\t58.9/38–78\t50.7/35–70\t\nSex (M/F/)††\t31/11\t12/03/19\t\nType of SGLT2i\t\n Empagliflozin\t14\t3\t\n Dapagliflozin\t17\t7\t\n Canagliflozin\t16\t7†\t\nPrimary/secondary suspect\t47‡\t16†\t\nDiabetes type\t\t\n Type 1 diabetes\t0\t0\t\n Type 2 diabetes\t25\t10\t\n Not specified\t7\t1\t\n Not reported\t15\t6\t\nConcomitant medications‡‡\t\t\n Glucose-lowering agents\t21\t7\t\n Lipid-lowering agents\t7\t3\t\n Cardiovascular agents (including ASA)\t6\t3\t\n Systemic immunosuppressant drugs\t2§§\t1\t\n Systemic anti-infectives\t2\t0\t\n Levothyroxine\t2\t0\t\n Antiasthma\t1¶¶\t0\t\n Others\t11\t3\t\n None/not reported\t26\t11\t\nMean time to onset, days (range)§\t434 (0–2508)\t291 (0–965)\t\nOutcomes¶\t \t\t\n Hospitalisation\t36\t13\t\n Life-threatening\t19\t0\t\n Disability\t5\t2\t\n Requiring intervention\t5\t0\t\n Death**\t2\t0\t\n Other\t14\t6\t\n*Not reported in 20 cases.\n\n†In one case canagliflozin was reported as concomitant.\n\n‡In one case dapagliflozin was reported as secondary suspect.\n\n§Calculated for 27 reports with available data on ‘start date’ and ‘event date’. In case the specific day of start/event dates was not recorded, day 1 was imputed. Reports with incomplete data (both year and month of reporting) were excluded.\n\n¶A report may be coded with multiple outcomes.\n\n**One death was reported in the case narrative.\n\n††Not reported in seven cases.\n\n‡‡A report may contain multiple medications. If more than one drug of a given therapeutic class was reported (eg, glucose-lowering agents), the case counted only once.\n\n§§In one case, secukinumab was reported as primary suspect drug.\n\n¶¶Including a short-acting β2-adrenoreceptor agonist and a combination of inhaled corticosteroid and long-acting β2-adrenoreceptor agonist.\n\nASA, acetylsalicylic acid.\n\nAmong the cases that were not classified as FG, n=17 were severe inflammatory/infectious AEs involving the genital area: cellulitis of male (n=7) or female (n=1) external genital organ(s), scrotal or perineal abscess (n=5), other perineal infections (n=2) and NF of anatomical areas close to the perineum (pubis and pelvis, n=2). Aggregated characteristics of these cases are compared with those of FG cases (table 1). These patients were significantly younger than those with definite FG (50.7 vs 58.9 years; p=0.04), whereas gender distribution was similar (12 men, 3 women, 2 unknown).\n\nThe remaining nine cases were classified as NF of non-genital areas (n=4), NF of unknown site (n=4) or duplicate (n=1).\n\nWith the exception of ertugliflozin, all SGLT2i currently approved in the USA were represented and reported as primary/secondary suspect; in one case, the SGLT2i (canagliflozin) was reported as concomitant. The majority of cases were serious (ie, death, hospitalisation—initial or prolonged—life-threatening or disability were recorded), especially for definite FG (81% vs 75%), with hospitalisation recorded in 77% of reports. Only two deaths were recorded. Overall, information about concomitant medications and indications were scant. No concomitant drugs were recorded in 55% of definite FG cases. Of note, two reports listed SGLT2i concomitantly with drugs for the treatment of severe psoriasis (secukinumab and/or topical betamethasone), and another definite FG case listed prednisone.\n\nDisproportionality analysis\nAmong 11 525 276 AE reports filed to the FDA between 2004q1 and 2018q3, 45 927 listed SGLT2i as suspect or concomitant drugs, 91 of which satisfied the wide definition of FG, equal to a reporting frequency of 2.0/1000 (95% CI 1.6 to 2.4). Among the 11 479 349 reports filed for non-SGLT2i drugs, there were 2862 putative cases of FG, equal to a frequency of 0.2/1000 (95% CI 0.2 to 0.3). The resulting PRR was 7.95 (95% CI 6.45 to 9.79). Restricting this analysis to the period when SGLT2i were available in the market (2013q1–2018q3) but still excluding the quarters after the FDA warning, results did not change substantially because the rate of FG reports filed for non-SGLT2i drugs remained stable (table 2). The flowchart in online supplementary material 1 shows refinement of the DA.\n\nTable 2 Results of the disproportionality analysis\n\n\t2004q1–2018q3\t2013q1–2018q3\t\nNo indication filter\tSGLT2i\tAll others\tSGLT2i\tAll others\t\nReports, n\t45 927\t11 479 349\t45 835\t6 958 420\t\nFG cases, n\t91\t2862\t91\t1388\t\nFG/1000 (95% CI)\t2.0 (1.6 to 2.4)\t0.2 (0.2 to 0.3)\t2.0 (1.6 to 2.4)\t0.2 (0.2 to 0.2)\t\nPRR (95% CI)\t7.95 (6.45 to 9.79)\t9.95 (8.05 to 12.30)\t\nDiabetes indication\tSGLT2i\tAll others\tSGLT2i\tAll others\t\nReports, n\t29 808\t501 932\t29 716\t312 443\t\nFG cases, n\t65\t132\t65\t81\t\nFG/1000 (95% CI)\t2.2 (1.7 to 2.7)\t0.3 (0.2 to 0.3)\t2.2 (1.7 to 2.7)\t0.3 (0.2 to 0.3)\t\nPRR (95% CI)\t8.29 (6.16 to 11.16)\t8.44 (6.09 to 11.69)\t\nNo indication filter\tSGLT2i\tOther ATC10 class+insulin\tSGLT2i\tOther ATC10 class+insulin\t\nReports, n\t45 927\t945 918\t45 835\t555 472\t\nFG cases, n\t91\t268\t91\t134\t\nFG/1000 (95% CI)\t2.0 (1.6 to 2.4)\t0.3 (0.2 to 0.3)\t2.0 (1.6 to 2.4)\t0.2 (0.2 to 0.3)\t\nPRR (95% CI)\t6.99 (5.51 to 8.87)\t8.23 (6.31 to 10.74)\t\nStrict FG definition\tSGLT2i\tOther ATC10 class+insulin\tSGLT2i\tOther ATC10 class+insulin + diabetes indication\t\nReports, n\t45 927\t945 918\t29 716\t306 824\t\nFG cases, n\t62\t247\t46\t74\t\nFG/1000 (95% CI)\t1.3 (1.0 to 1.7)\t0.3 (0.2 to 0.3)\t1.5 (1.1 to 2.0)\t0.2 (0.2 to 0.3)\t\nPRR (95% CI)\t5.17 (3.91 to 6.83)\t6.42 (4.44 to 9.27)\t\nFG preferred term\tSGLT2i\tAll others\tSGLT2i\tOther ATC10 class+insulin+diabetes indication\t\nReports, n\t45 927\t945 918\t29 716\t306 824\t\nFG cases, n\t62\t247\t46\t74\t\nFG/1000 (95% CI)\t1.3 (1.0 to 1.7)\t0.3 (0.2 to 0.3)\t1.5 (1.1 to 2.0)\t0.2 (0.2 to 0.3)\t\nPRR (95% CI)\t5.17 (3.91 to 6.83)\t6.42 (4.44 to 9.27)\t\nFor each analysis, the table reports the number of total adverse event (AE) reports, the number of reports listing Fournier’s gangrene (FG) as an AE, the rate with 95% CI of FG and the proportional reporting ratio (PRR) with 95% CI.\n\nSince diabetes is a risk factor for FG,20 we wished to verify whether the disproportional association between FG reports and SGLT2i reflected diabetes-associated FG risk rather than SGLT2i-associated FG risk. First, we found that FG was reported disproportionally more for drugs having the diabetes indication, but the difference was small (PRR 1.48; 95% CI 1.28 to 1.71). In fact, when we restricted the search to reports for drugs with the diabetes indication, the rates of FG associated with SGLT2i and non-SGLT2i drugs did not change substantially and the PRR was 8.29 from the period 2004q1–2018q3 and 8.44 for the period 2013q1–2018q3.\n\nWe calculated that, in the FAERS, only 52% of the AE reports filed for GLM contain the diabetes indication. Although SGLT2i may be used off-label outside the diabetes indication (eg, for the treatment of obesity), this lack of diabetes indication is likely due to incomplete reporting. Thus, we compared SGLT2i with other GLMs (drugs of the ATC10 class and insulin): the number of retrieved events in the non-SGLT2i GLM control group was indeed higher than in reports with the diabetes indication, but reporting rates did not change substantially and the PRR was 6.99 for 2004q1–2018q3 and 8.23 for 2013q1–2018q3.\n\nFinally, we applied a more restrictive definition of FG, which included only MedDRA terms that were more likely to correspond to FG as determined by matching the various sources of information as described above and excluded terms related to amputations. With the refined definition, sensitivity against FG defined by preferred term and narratives remained high (from 100% to 95.7%) and specificity increased from 0% to 46.4%. Even with this definition, the PRR of FG for SGLT2i versus other GLMs was 5.17. When further restricted to 2013q1–2018q3 and limited to AE reporting the diabetes indication (figure 1), the number of retrieved cases was 46 for SGLT2i and 74 for other GLMs, with corresponding rates of 1.5/1000 versus 0.2/1000, equal to a PRR of FG for SGLT2i of 6.42 (95% CI 4.44 to 9.27).\n\nFigure 1 Results of the disproportionality analysis. Proportional reporting ratios (PRRs) are shown with bars indicating 95% CI. Different analyses are shown as reported in detail in table 2and described in the text. For each analysis, the PRR is shown for the entire FAERS but before stimulated reporting could take place (2004q1–2018q3) or starting from when SGLT2i entered the market (2013q1–2018q3). FG, Fournier’s gangrene; GLM, glucose-lowering medication (defined as ATC10 class and insulins); SGLT2i, sodium glucose contransporter-2 inhibitors. *This analysis was further filtered for the diabetes indication.\n\nFigure 2 shows that the rates of FG reports (using the strict definition) over time became significantly higher for SGLT2i versus other GLMs since 2015, increased for SGLT2i until 2018q3 and then showed a fourfold sudden increase in 2018q4, after the FDA warning. This likely reflects stimulated reporting and justifies the exclusion of such period from DA.\n\nFigure 2 Time trend in rates of Fournier’s gangrene (FG) reported to the FDA. The rates of FG reports per 1000 reports are shown for sodium glucose cotransporter-2 inhibitors (SGLT2i) and for other glucose-lowering medications (GLMs) over time. The dashed box illustrates the surge in FG cases among reports filed for SGLT2i during 2018q4, that is, after the warning issued by the U.S. Food and Drug Administration, indicating stimulated reporting.\n\nTo rule out that similar results could be obtained for other specific classes of GLMs, we performed a control analysis on DPP-4 inhibitors. The PRR of FG for DPP-4i was 1.36 (95% CI 0.96 to 1.91) versus any other drug and 0.52 (95% CI 0.30 to 0.91) versus other GLMs, suggesting that the association with FG was specific for SGLT2i.\n\nSince we detected that three patients with SGLT2i-associated FG or severe genital AEs received systemic immunosuppressant drugs, including agents to treat severe psoriasis such as secukinumab, we performed a DA for FG (strict definition) related to psoriasis. This analysis was extended to 2018q4 because it is unrelated to the warning for SGLT2i. We found a mild disproportionality of FG cases in reports for drugs with the psoriasis indication versus those with other indications (PRR 1.59; 95% CI 1.29 to 1.97). Furthermore, the rate of FG was 2.55 times as high (95% CI 1.36 to 4.78) as in reports for GLMs when a concomitant drug indicated for psoriasis was present. In reports concomitantly listing drugs with indication for diabetes and drugs with indication for psoriasis, the use of interleukin inhibitors was associated with a PRR for FG of 13.7 (95% CI 2.7 to 70.5). Finally, three cases of FG were identified in reports concomitantly listing SGLT2i and interleukin inhibitors (such as secukinumab), with a frequency of 16.0/1000, yielding a PRR of 6.79 (95% CI 2.12 to 21.17) versus the rate of FG associated with SGLT2i without concomitant interleukin inhibitors.\n\nConclusions\nFor their benefits on cardiorenal outcomes and according to international recommendations, SGLT2i should be prioritised over other GLMs in the treatment of T2D, especially in patients with heart failure and chronic kidney disease.21 Since it is expected that the number of SGLT2i users will increase substantially in the future, paying attention to severe AEs is very important even if they are extremely rare.\n\nIn this pharmacovigilance analysis, we show that, since 2015, FG has been reported significantly more often by patients taking SGLT2i than patients taking other medications. Our analysis yielded consistent and robust estimates of disproportionality even after accounting for reporting period, higher rates of FG associated with diabetes, and after refining the definition of FG.\n\nRemarkably, it appears that the rate of FG reports for SGLT2i, but not for other GLMs, was already increasing before the 2018 FDA warning. This trend should not be interpreted as a direct consequence of the increased use of SGLT2i worldwide, but may reflect that SGLT2i were being used in progressively less selected populations, with FG-predisposing factors such as impaired immune system.\n\nFG is an extremely dangerous NF of the perineum typically involving external genital organs. Its aggressive course can lead to sepsis and death if not promptly treated with antibiotics and surgery. Patients surviving from FG often have disfiguring or permanently disabling outcomes.20 Up to 2018q3, we found 47 cases of FG in patients taking SGLT2i and detected a sharp fourfold increase in the reporting frequency during 2018q4 (with 51 additional cases), which can be probably accounted for by the FDA warning issued at the end of August 2018. Although true FG may not resolve spontaneously without surgery, our definition of FG did not require the reports to specify that patients underwent surgery because under-reporting of diagnostic and therapeutic procedures for AEs is common. In contrast, a recent publication by the FDA reported 55 cases of SGLT2i-associated FG up to the end of January 2019.15 This report defined FG as a necrotising infection of the perineum that required surgery, but allowed extension beyond the perineum (eg, to the buttocks) and not necessarily reaching the fascial compartment, a criterion needed to define NF. Thus, the authors found a relatively small number of SGLT2i-associated FG cases despite they used a less rigorous definition than ours and captured 4 months of stimulated reporting because they excluded 41 cases for not having documented surgery.15 An underestimation of the number of FG events was also evident among reports for other GLMs (n=19), as compared with our analysis (n=247).\n\nWhile searching for FG, we found reports suggestive of other severe infections of the genital area occurred in SGLT2i recipients. Even though events of genital cellulitis, abscess and gangrene could not be referred to FG, they should not be overlooked and require as close monitoring as FG does. It is important to note that these AEs, somewhat less severe than FG, occurred in patients who were on average 10 years younger, in agreement with the notion that typical FG occurs more often in aged individuals.20 22\n\nThe analysis of individual cases identified no obvious hint of common precipitating factors that may highlight SGLT2i users at higher risk for FG, except that we found three patients taking immunosuppressive drugs, including drugs for the systemic treatment of psoriasis. Although this number is small, the finding might be more than a coincidence. Indeed, the combination of steroids and/or interleukin inhibitors (eg, to treat severe psoriasis) with SGLT2i can make the patients prone to infections.23 In determining the rates of FG reports, an interplay was noted among diabetes, psoriasis and the respective drugs. Psoriasis can affect genital organs24 and scratching can lead to skin lesions that allow bacteria to reach deeper planes. Psoriasis is relatively common among patients with T2D25 who would benefit from SGLT2i therapy. We therefore suggest that attention should be paid to patients with genital psoriasis receiving systemic immunosuppressants. However, this signal is based on a very small number of cases and needs to be confirmed. If any, it could identify a small minority of diabetic patients at risk for SGLT2i-associated FG.\n\nLack of the diabetes indication in individual reports listed in online supplementary table S1 should not be interpreted as if the patient was not diabetic because incomplete/missing reporting of drug indications is very common. Indeed, four cases listed SGLT2i along with other GLMs among suspect or concomitant, even when the diabetes indication was not reported.\n\n10.1136/bmjdrc-2019-000725.supp2Supplementary data \n\n Several caveats apply to the interpretation of pharmacovigilance analyses. First, a causal relationship cannot be inferred and indication of SGLT2i as suspect for FG was at discretion of the individuals who filed the reports. It is therefore impossible to judge whether SGLT2i caused FG or simply were the ongoing therapy in patients who developed FG for other reasons. Online supplementary table S2 illustrates causality assessment with Bradford-Hill criteria. Rates of SGLT2i-associated FG within the pharmacovigilance database do not inform on the true risk in clinical practice, which can only be derived from prospective studies where the population at risk is clearly defined. Nonetheless, comparisons can be made within the pharmacovigilance setting: the disproportional association of SGLT2i with FG was quantitatively similar to that calculated for ketoacidosis8 and stronger than that of amputations.9\n\nEpidemiological studies report an annual incidence of FG of 1.6 to 3.3/100 000 patients, with a 3× higher risk in diabetics.22 In the DECLARE study, six cases were reported among 17 160 diabetic patients randomised and treated for 4.2 years,3 equal to an annual rate of 8.3/100 000, perfectly in line with what is expected in diabetic patients. The nominally lower rate of FG in the dapagliflozin group (n=1) than in the placebo group (n=5) is reassuring.3 This may in fact reflect that aged patients with FG predisposing conditions were excluded from the trial or intercepted early. If the disproportionality observed in the FAERS applied to clinical practice, it could be calculated that 1 every 1200 to 1800 patients treated with SGLT2i may experience FG each year.\n\nAnother limitation is that in the FAERS, indications for drug use may drive differential reporting of AEs, leading to indication-specific rather than drug-specific signatures. Yet, the disproportional reporting of FG for SGLT2i was consistent with or without the diabetes indication and in the comparison with both any other drug or medications for the treatment of diabetes. In addition, the association of diabetes with FG was statistically significant but much weaker than the association of SGLT2i with FG. It should also be mentioned that part of the AEs have been filed by non-health care professionals, thereby limiting their reliability. Moreover, the analysis of the interaction between drugs (SGLT2i and interleukin inhibitors) and drug indications (diabetes and psoriasis) is subjected to the bias of dilution by other drug-related AEs. Finally, confounding by indication cannot be excluded considering that SGLT2i may be preferred among GLMs for patients with important comorbidities, such as CVD.\n\nA few clinical messages can be derived from this study. First, based on the solid DA and on the well-known risk of genital infections associated with SGLT2i, physicians should be aware that SGLT2i could predispose to FG and other severe genital AEs. Although FG remains rare, the predictable increase in the number of patients who will receive SGLT2i in the future implies that close monitoring and constant epidemiological surveillance are needed. In addition to paying attention to elderly patients, we suggest that patients with genital psoriasis, especially if on immunosuppressant therapy, and other patients prone to invasive infections should be carefully informed at the time of SGLT2i prescription and more closely monitored. Finally, we wish to remind that detailed AE reporting can provide valuable opportunities to identify safety signals, quantify the problem, establish risk factors and ultimately protect patients’ safety.\n\nContributors: GPF: study design, data collection, analysis and interpretation, manuscript writing. MS: data collection and analysis, manuscript revision. FDP: data analysis and interpretation, manuscript revision. AA: study design, data interpretation, manuscript revision. ER: study design, data collection, analysis and interpretation, manuscript writing. All authors provided substantial contributions to conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published.\n\nFunding: The study was supported by institutional grants from the University of Padova and received no specific funding. The corresponding author had full access to all of the data and the final responsibility to submit for publication.\n\nCompeting interests: GPF reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Mundipharma during the conduct of the study; grants, personal fees and non-financial support from Eli Lilly, personal fees and non-financial support from NovoNordisk, personal fees and non-financial support from Sanofi, non-financial support from Genzyme, personal fees and non-financial support from Abbott, personal fees and non-financial support from Novartis, personal fees from Merck Sharp & Dohme, outside the submitted work. AA reports grants, personal fees and non-financial support from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Janssen, during the conduct of the study; personal fees from Merck Sharp & Dome, personal fees and non-financial support from Novartis, personal fees from Sanofi, grants and personal fees from Mediolanum, personal fees from NovoNordisk, personal fees from Lilly, personal fees and non-financial support from Servier, personal fees from Takeda, outside the submitted work.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information.\n==== Refs\nReferences\n1. Vasilakou D , Karagiannis T , Athanasiadou E , et al \nSodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis . Ann Intern Med 2013 ;159 :262 –74 . 10.7326/0003-4819-159-4-201308200-00007 24026259 \n2. Zelniker TA , Wiviott SD , Raz I , et al \nSGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials . Lancet 2019 ;393 :31 –9 . 10.1016/S0140-6736(18)32590-X 30424892 \n3. Wiviott SD , Raz I , Bonaca MP , et al \nDapagliflozin and cardiovascular outcomes in type 2 diabetes . N Engl J Med 2019 ;380 :347 –57 . 10.1056/NEJMoa1812389 30415602 \n4. Perkovic V , Jardine MJ , Neal B , et al \nCanagliflozin and renal outcomes in type 2 diabetes and nephropathy . N Engl J Med 2019 ;380 :2295 –306 . 10.1056/NEJMoa1811744 30990260 \n5. Li D , Wang T , Shen S , et al \nUrinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials . Diabetes Obes Metab 2017 ;19 :348 –55 . 10.1111/dom.12825 27862830 \n6. Zaccardi F , Webb DR , Htike ZZ , et al \nEfficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis . Diabetes Obes Metab 2016 ;18 :783 –94 . 10.1111/dom.12670 27059700 \n7. Ruanpeng D , Ungprasert P , Sangtian J , et al \nSodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis . Diabetes Metab Res Rev 2017 ;33 . doi:10.1002/dmrr.2903 \n8. Fadini GP , Bonora BM , Avogaro A \nSGLT2 inhibitors and diabetic ketoacidosis: data from the FDA adverse event reporting system . Diabetologia 2017 ;60 :1385 –9 . 10.1007/s00125-017-4301-8 28500396 \n9. Fadini GP , Avogaro A \nSGLT2 inhibitors and amputations in the US FDA adverse event reporting system . Lancet Diabetes Endocrinol 2017 ;5 :680 –1 . 10.1016/S2213-8587(17)30257-7 28733172 \n10. Bonora BM , Avogaro A , Fadini GP \nSodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: an updated review of the literature . Diabetes Obes Metab 2018 ;20 :25 –33 . 10.1111/dom.13012 28517913 \n11. Yuan Z , DeFalco FJ , Ryan PB , et al \nRisk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study . Diabetes Obes Metab 2018 ;20 :582 –9 . 10.1111/dom.13115 28898514 \n12. Onder CE , Gursoy K , Kuskonmaz SM , et al \nFournier’s gangrene in a patient on dapagliflozin treatment for type 2 diabetes . J Diabetes 2019 ;11 :348 –50 . 10.1111/1753-0407.12896 30604507 \n13. Kumar S , Costello AJ , Colman PG \nFournier’s gangrene in a man on empagliflozin for treatment of type 2 diabetes . Diabet Med 2017 ;34 :1646 –8 . 10.1111/dme.13508 28887847 \n14. U.S. Food and Drug Administration \nFDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes , 2018 Available: https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm [Accessed May 2019 ].\n15. Bersoff-Matcha SJ , Chamberlain C , Cao C , et al \nFournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases . Ann Intern Med 2019 ;170 :764 –9 . 10.7326/M19-0085 31060053 \n16. Dias P , Penedones A , Alves C , et al \nThe role of disproportionality analysis of pharmacovigilance databases in safety regulatory actions: a systematic review . Curr Drug Saf 2015 ;10 :234 –50 . 10.2174/1574886310666150729112903 26219291 \n17. Raschi E , Piccinni C , Poluzzi E , et al \nThe association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database . Acta Diabetol 2013 ;50 :569 –77 . 10.1007/s00592-011-0340-7 22008948 \n18. Raschi E , Poluzzi E , Salvo F , et al \nPharmacovigilance of sodium-glucose co-transporter-2 inhibitors: what a clinician should know on disproportionality analysis of spontaneous reporting systems . Nutr Metab Cardiovasc Dis 2018 ;28 :533 –42 . 10.1016/j.numecd.2018.02.014 29625780 \n19. Sarangdhar M , Tabar S , Schmidt C , et al \nData mining differential clinical outcomes associated with drug regimens using adverse event reporting data . Nat Biotechnol 2016 ;34 :697 –700 . 10.1038/nbt.3623 27404875 \n20. Eke N \nFournier’s gangrene: a review of 1726 cases . Br J Surg 2000 ;87 :718 –28 . 10.1046/j.1365-2168.2000.01497.x 10848848 \n21. Davies MJ , D’Alessio DA , Fradkin J , et al \nManagement of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) . Diabetes Care 2018 ;41 :2669 –701 . 10.2337/dci18-0033 30291106 \n22. Sorensen MD , Krieger JN , Rivara FP , et al \nFournier’s gangrene: population based epidemiology and outcomes . J Urol 2009 ;181 :2120 –6 . 10.1016/j.juro.2009.01.034 19286224 \n23. Vanhove T , Remijsen Q , Kuypers D , et al \nDrug–drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus . Transplant Rev 2017 ;31 :69 –77 . 10.1016/j.trre.2016.09.001 \n24. Meeuwis KAP , de Hullu JA , Massuger LFAG , et al \nGenital psoriasis: a systematic literature review on this hidden skin disease . Acta Derm Venereol 2011 ;91 :5 –11 . 10.2340/00015555-0988 20927490 \n25. Neimann AL , Shin DB , Wang X , et al \nPrevalence of cardiovascular risk factors in patients with psoriasis . J Am Acad Dermatol 2006 ;55 :829 –35 . 10.1016/j.jaad.2006.08.040 17052489\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2052-4897",
"issue": "7(1)",
"journal": "BMJ open diabetes research & care",
"keywords": "adverse drug reactions; pharmacological therapy; sodium glucose cotransporter; type 2 diabetes",
"medline_ta": "BMJ Open Diabetes Res Care",
"mesh_terms": "D000328:Adult; D000368:Aged; D015415:Biomarkers; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D018934:Fournier Gangrene; D005831:Genital Diseases, Female; D005832:Genital Diseases, Male; D006442:Glycated Hemoglobin A; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011379:Prognosis; D012189:Retrospective Studies; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014566:Urogenital System",
"nlm_unique_id": "101641391",
"other_id": null,
"pages": "e000725",
"pmc": null,
"pmid": "31641524",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "30604507;19286224;10848848;30424892;30415602;30291106;27862830;27665059;28887847;28517913;27404875;28440590;30990260;29625780;17052489;20927490;26219291;24026259;22008948;31060053;28733172;27059700;28898514;28500396",
"title": "Pharmacovigilance assessment of the association between Fournier's gangrene and other severe genital adverse events with SGLT-2 inhibitors.",
"title_normalized": "pharmacovigilance assessment of the association between fournier s gangrene and other severe genital adverse events with sglt 2 inhibitors"
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"abstract": "Many studies confirmed the efficacy and safety of continuous infusion of intrajejunal levodopa/carbidopa gel (CIILG) for advanced Parkinson's disease (PD). Although this treatment is widely used, definite inclusion/exclusion criteria do not exist. In this prospective open-label study, we evaluated the long-term outcome in 28 consecutive patients and sought to detect any predictive factor to identify the best candidates for CIILG therapy. The assessment was carried out routinely at baseline, after 6 months and every year with UPDRS III-IV, FOG Questionnaire, non-motor symptoms scale, PD questionnaire (PDQ-8), cognitive and psychiatric status evaluation (MMSE, FAB, NPI) and caregiver's quality of life. 17/28 patients reached the 24-month follow-up. A statistically significant beneficial effect was shown on motor complications in short- and long-term follow-up, also on axial symptoms like gait disturbances. A concomitant improvement in PDQ8 score was observed, with a parallel mild amelioration, but not significant, on Caregivers QoL. When classified according to their outcome on QoL, the only predictive positive factor was less severe at Neuropsychiatric Inventory (NPI) score at baseline. Considering the improvement in motor scores (duration of \"off\" period), the more advanced age was associated with a poorer outcome. Our results confirmed a sustained efficacy and safety in long-term follow-up and suggest that younger age at operation and absence or mild presence of psychiatric/behavioural symptoms could be considered valid predicting factors in selecting the best candidates for this efficacious therapy.",
"affiliations": "Department of Neuroscience-Rehabilitation, S. Anna University- Hospital of Ferrara, via A.Moro, 44124, Ferrara, Italy, mchiasen@gmail.com.",
"authors": "Sensi|Mariachiara|M|;Preda|F|F|;Trevisani|L|L|;Contini|E|E|;Gragnaniello|D|D|;Capone|J G|JG|;Sette|E|E|;Golfre-Andreasi|N|N|;Tugnoli|V|V|;Tola|M R|MR|;Quatrale|R|R|",
"chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D000547:Amantadine; D002230:Carbidopa; D001058:Apomorphine",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00702-013-1153-3",
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"issue": "121(6)",
"journal": "Journal of neural transmission (Vienna, Austria : 1996)",
"keywords": null,
"medline_ta": "J Neural Transm (Vienna)",
"mesh_terms": "D000368:Aged; D000547:Amantadine; D000978:Antiparkinson Agents; D001058:Apomorphine; D002230:Carbidopa; D017028:Caregivers; D004333:Drug Administration Routes; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007980:Levodopa; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D010300:Parkinson Disease; D018579:Patient Selection; D012189:Retrospective Studies; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "9702341",
"other_id": null,
"pages": "633-42",
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"publication_types": "D016428:Journal Article",
"references": "23430276;19253412;23595879;18382177;22248261;18322402;15668416;23035627;23468940;22821063;19425079;21975263;22360705;15596611;12782919;16820421;23287972;23406026;18520982;8414015;16731025;19887096;22690905;16271496;9617723;19762271;19496689;10435493;17661426;22338551;18709682;22824056;23287001;22772358",
"title": "Emerging issues on selection criteria of levodopa carbidopa infusion therapy: considerations on outcome of 28 consecutive patients.",
"title_normalized": "emerging issues on selection criteria of levodopa carbidopa infusion therapy considerations on outcome of 28 consecutive patients"
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"abstract": "Although medication toxicity is uncommon in neonates, there are several medications used in this population that pose a risk. Phenytoin has an increased risk of toxicity given its narrow therapeutic window and variations in drug elimination.\n\n\n\nWe describe the case of a 3-day-old male infant who developed cardiovascular collapse secondary to severe phenytoin toxicity (max phenytoin level 86 μg/mL) and was placed on extracorporeal membrane oxygenation support (ECMO). Several ancillary treatments were utilized in an attempt to decrease serum phenytoin concentrations and limit toxicity including albumin boluses, phenobarbital administration, intravenous lipid infusion, and folic acid supplementation.\n\n\n\nAlthough uncommon, drug toxicity should be considered in patients with acute changes who are exposed to medications with potential toxicity. With elevated levels of phenytoin, the half-life can be prolonged resulting in longer exposure to elevated levels of the drug as seen in our patient. This case report highlights the importance of ECMO utilization for cardiac support in neonates with medication toxicity and other potential ancillary treatments to decrease serum phenytoin concentrations.",
"affiliations": "Louisiana State University Health Sciences Center, Department of Pediatrics, Division of Neonatology, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA.;Xavier University of Louisiana College of Pharmacy, Louisiana State University Health Sciences Center, 1 Drexel Drive, New Orleans, LA, 70125, USA.;Louisiana State University Health Sciences Center, Department of Pediatrics, Division of Neonatology, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA.;Louisiana State University Health Sciences Center, Department of Pediatrics, Division of Neonatology, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA.;Louisiana State University Health Sciences Center, Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA.;Louisiana State University Health Sciences Center, Department of Pediatrics, Division of Neonatology, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA. cmumph@lsuhsc.edu.",
"authors": "Knecht|Michelle|M|;LaRochelle|Joseph|J|;Barkemeyer|Brian|B|;Gupta|Raegan|R|;Brumund|Michael|M|;Mumphrey|Christy|C|0000-0003-0062-5900",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-019-00742-x",
"fulltext": null,
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"issn_linking": "1556-9039",
"issue": "16(2)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "ECMO; Fosphenytoin; Neonate; Phenytoin",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000927:Anticonvulsants; D015199:Extracorporeal Membrane Oxygenation; D006439:Hemodynamics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010672:Phenytoin; D020127:Recovery of Function; D012769:Shock; D016896:Treatment Outcome",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "230-235",
"pmc": null,
"pmid": "31773636",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "10516876;26013746;25998968;16174888;16434340;28811085;26578149;24974371;12059129;9057784",
"title": "Cardiac Collapse Secondary to Phenytoin Toxicity in a Neonate Treated with Extracorporeal Membrane Oxygenation Support (ECMO).",
"title_normalized": "cardiac collapse secondary to phenytoin toxicity in a neonate treated with extracorporeal membrane oxygenation support ecmo"
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"companynumb": "US-PFIZER INC-2019520678",
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"activesubstancename": "ACYCLOVIR"
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"abstract": "The discovery of adrenal lesions during routine testing for hypertension requires focused consideration for adrenal overproduction of cortisol, aldosterone or metanephrines. An otherwise healthy 25-year-old woman presented with headaches, diaphoresis and hot flushes with grossly elevated urine catecholamines, normetanephrines and norepinephrine levels, yet normal metanephrines, epinephrine/epinephrine, cortisol and aldosterone levels. Subsequent functional uptake studies and scans identified bilateral adrenal adenomas consistent with phaeochromocytomas. There was no family history of phaeochromocytomas or familial syndromes; however, a targeted genetic analysis for causes of familial phaeochromocytomas identified a heterozygous germline mutation in the VHL gene consistent with Von Hippel-Lindau syndrome. In this case, the identification of the VHL mutation led to careful screening and detection of clinically occult central nervous system hemangioblastomas and pancreatic neuroendocrine tumours. Verified genetic mutations facilitated best practices for long-term surveillance protocols, preconception counselling and screening of blood relatives. The patient responded well to surgical treatment and has ongoing multidisciplinary long-term surveillance.",
"affiliations": "Department of Medicine, University of Saskatchewan College of Medicine, Saskatoon, Saskatchewan, Canada.;Department of Medicine, University of Saskatchewan College of Medicine, Saskatoon, Saskatchewan, Canada.",
"authors": "Sivaskandarajah|Gavasker A|GA|;Arnason|Terra G|TG|http://orcid.org/0000-0002-5793-7713",
"chemical_list": "D003287:Contrast Media",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; endocrinology; genetics; hypertension",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D003287:Contrast Media; D003937:Diagnosis, Differential; D005260:Female; D005817:Genetic Counseling; D006801:Humans; D006973:Hypertension; D008279:Magnetic Resonance Imaging; D010673:Pheochromocytoma; D006623:von Hippel-Lindau Disease",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30042107",
"pubdate": "2018-07-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25563310;12000816;21519372;28925400;29748190;9156047;14993394;23512077;25119015;7728151;15132724;11821644;25026968;7987306;22648268;18617683;24169644;15145232;24355456;19825962;28919049;12574179;24893135;24745698;21262951;10458336",
"title": "Unsuspected Von Hippel-Lindau syndrome in acute-onset resistant hypertension.",
"title_normalized": "unsuspected von hippel lindau syndrome in acute onset resistant hypertension"
} | [
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONIDINE"
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"abstract": "A 61-year-old male patient being treated with intravenous antibiotics for left foot osteomyelitis presented to the hospital septic, with several days of worsening abdominal pain, bloating and watery bowel movements. Investigation revealed that the patient had severe, treatment-resistant Clostridioides difficile colitis. He was initially treated with oral vancomycin and intravenous metronidazole, which was switched to oral fidaxomicin. After no improvement in the patient's symptoms, he was treated with two faecal microbiota transplants. He was offered a third faecal microbiota transplant but declined. The patient was placed back on oral fidaxomicin and saw ultimate resolution of his symptoms. This case provides an example of a treatment pathway for refractory C. difficile infection.",
"affiliations": "Department of Family Medicine, UNC-Chapel Hill, Chapel Hill, North Carolina, USA.;Department of Family Medicine, UNC-Chapel Hill, Chapel Hill, North Carolina, USA victoria.boggiano@unchealth.unc.edu.;Department of Family Medicine, UNC-Chapel Hill, Chapel Hill, North Carolina, USA.",
"authors": "Sullivan|Mikaela Highland|MH|;Boggiano|Victoria Lynn|VL|;Smith|Kelly Lacy|KL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole; D014640:Vancomycin; D000077732:Fidaxomicin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233095",
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"issn_linking": "1757-790X",
"issue": "13(3)",
"journal": "BMJ case reports",
"keywords": "gastroenterology; hepatitis and other gastrointestinal infection; infection (gastroenterology); infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D003015:Clostridium Infections; D003092:Colitis; D003131:Combined Modality Therapy; D024901:Drug Resistance, Multiple, Bacterial; D000069467:Fecal Microbiota Transplantation; D000077732:Fidaxomicin; D005528:Foot; D006801:Humans; D008297:Male; D008795:Metronidazole; D008875:Middle Aged; D010019:Osteomyelitis; D014640:Vancomycin",
"nlm_unique_id": "101526291",
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"pmid": "32229549",
"pubdate": "2020-03-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of difficult-to-treat Clostridioides difficile in a patient with chronic osteomyelitis.",
"title_normalized": "management of difficult to treat clostridioides difficile in a patient with chronic osteomyelitis"
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... |
{
"abstract": "BACKGROUND\nResistance to immune checkpoint blockade and targeted therapy in melanoma patients is currently one of the major clinical challenges. With the approval of talimogene laherparepvec (T-VEC), oncolytic viruses are now in clinical practice for locally advanced or non-resectable melanoma. Here, we describe the usage of T-VEC in stage IVM1b-M1c melanoma patients, who achieved complete remission or stable disease upon systemic treatment but suffered from a loco-regional recurrence. To our knowledge, there are no case reports so far describing T-VEC as a means to overcome acquired resistance to immune checkpoint blockade or targeted therapy.\n\n\nMETHODS\nAll melanoma patients in our department treated with T-VEC in the period of 2016-2018 were evaluated retrospectively. Data on clinicopathological characteristics, treatment response, and toxicity were analyzed.\n\n\nRESULTS\nFourteen melanoma patients were treated with T-VEC in our center. Six patients (43%) received T-VEC first-line. In eight patients (57%), T-VEC followed a prior systemic therapy. Three patients with M1b stage and one patient with M1c stage melanoma were treated with T-VEC. These patients suffered from loco-regional progress, whilst distant metastases had regressed during prior systemic treatment. 64% of patients showed a benefit from therapy with T-VEC. The durable response rate was 36%.\n\n\nCONCLUSIONS\nT-VEC represents an effective and tolerable treatment option. This is true not only for loco-regionally advanced melanoma patients, but also for patients with stable or regressive systemic metastases who develop loco-regionally acquired resistance upon treatment with immune checkpoint blockade or targeted therapy. A sensible selection of suitable patients seems to be crucial.",
"affiliations": "Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany.;Department of Gynecology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127, Bonn, Germany. jenny.landsberg@ukbonn.de.",
"authors": "Fröhlich|Anne|A|;Niebel|Dennis|D|;Fietz|Simon|S|;Egger|Eva|E|;Buchner|Andrea|A|;Sirokay|Judith|J|;Landsberg|Jennifer|J|http://orcid.org/0000-0001-8029-3883",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D061025:Costimulatory and Inhibitory T-Cell Receptors; C000629782:talimogene laherparepvec",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-020-02487-x",
"fulltext": "\n==== Front\nCancer Immunol Immunother\nCancer Immunol. Immunother\nCancer Immunology, Immunotherapy\n0340-7004 1432-0851 Springer Berlin Heidelberg Berlin/Heidelberg \n\n2487\n10.1007/s00262-020-02487-x\nOriginal Article\nTalimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB–IV M1c melanoma patients\nFröhlich Anne 1 Niebel Dennis 1 Fietz Simon 1 Egger Eva 2 Buchner Andrea 1 Sirokay Judith 1 http://orcid.org/0000-0001-8029-3883Landsberg Jennifer jenny.landsberg@ukbonn.de 1 1 grid.10388.320000 0001 2240 3300Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, Venusberg-Campus 1, 53127 Bonn, Germany \n2 grid.10388.320000 0001 2240 3300Department of Gynecology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany \n12 2 2020 \n12 2 2020 \n2020 \n69 5 759 769\n24 1 2019 8 1 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background\nResistance to immune checkpoint blockade and targeted therapy in melanoma patients is currently one of the major clinical challenges. With the approval of talimogene laherparepvec (T-VEC), oncolytic viruses are now in clinical practice for locally advanced or non-resectable melanoma. Here, we describe the usage of T-VEC in stage IVM1b-M1c melanoma patients, who achieved complete remission or stable disease upon systemic treatment but suffered from a loco-regional recurrence. To our knowledge, there are no case reports so far describing T-VEC as a means to overcome acquired resistance to immune checkpoint blockade or targeted therapy.\n\nMethods\nAll melanoma patients in our department treated with T-VEC in the period of 2016–2018 were evaluated retrospectively. Data on clinicopathological characteristics, treatment response, and toxicity were analyzed.\n\nResults\nFourteen melanoma patients were treated with T-VEC in our center. Six patients (43%) received T-VEC first-line. In eight patients (57%), T-VEC followed a prior systemic therapy. Three patients with M1b stage and one patient with M1c stage melanoma were treated with T-VEC. These patients suffered from loco-regional progress, whilst distant metastases had regressed during prior systemic treatment. 64% of patients showed a benefit from therapy with T-VEC. The durable response rate was 36%.\n\nConclusion\nT-VEC represents an effective and tolerable treatment option. This is true not only for loco-regionally advanced melanoma patients, but also for patients with stable or regressive systemic metastases who develop loco-regionally acquired resistance upon treatment with immune checkpoint blockade or targeted therapy. A sensible selection of suitable patients seems to be crucial.\n\nKeywords\nAdvanced melanomaTalimogene laherparepvecAcquired resistanceImmunotherapyTargeted therapyDFGEXC 1023Niebel Dennis issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nOver the last decade, targeted small-molecule inhibitors and checkpoint inhibitors have revolutionized the treatment of advanced melanoma. Targeting BRAF (v-raf murine sarcoma viral oncogene homolog B1), MEK (mitogen-activated protein kinase), the immune checkpoint receptors cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed cell death PD-1 has improved the overall survival of melanoma patients. However, in a majority of patients, primary or acquired resistance still limits the durable efficacy of these new therapeutic drugs. Talimogene laherparepvec (T-VEC) is the first oncolytic viral immunotherapy to be approved for patients with locally advanced or non-resectable melanoma (in 2015 in USA and in 2016 in Europe).\n\nT-VEC is a genetically modified herpes simplex virus type 1 designed to selectively replicate in tumor cells. It is attenuated by the deletion of the genes, infectious cell protein (ICP) 34.5 and 47 [1, 2]. In its specific mode of action, T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumoral effects. The release of pro-inflammatory molecules, caused by the viral infection, leads to activation of the innate immune system, the release of interferon gamma, and T-cell infiltration [3]. Deterioration of tumor cells elicits an enhanced liberation of tumor antigens and a priming and increase of tumor-specific T cells. T-VEC is designed to express human granulocyte-macrophage colony-stimulating factor (GM-CSF) and US11 [2, 4]. This cytokine stimulus synergistically enhances the ongoing immune activation, hence promoting a local and systemic anti-tumor immune response, even at non-injected lesions and distant sites [5, 6].\n\nIn the primary analysis of the phase III randomized-controlled trial (OPTiM), T-VEC showed only a modest efficacy in visceral metastases, even though T-VEC induces both a local effect through cytolysis and a systemic anti-tumor response through enhancement of antigen presentation and promotion of cytotoxic T-cell responses. A significant improvement of overall survival with T-VEC versus GM-CSF was only observed in the subgroup of melanoma patients with stage IIIB, IIIC, and IVMa1 (41.1 months T-VEC versus 21.5 months GM-CSF, p < 0.001) [6, 7]. Therefore, T-VEC has only been approved for advanced loco-regional melanoma excluding patients with lung, brain, bone, or other visceral metastases. Subsequently, results from the final planned analysis of overall survival in the OPTiM trial 3 years after randomization have been published [8]. The final analysis demonstrated a significant improvement of overall survival in the intention-to-treat group. Consistent with the primary analysis, a subgroup analysis showed no significant beneficial effects of T-VEC on overall survival in patients with stage IVM1b/c disease. Recently, clinical studies have investigated therapy with T-VEC in diverse other tumor types and in combination with other systemic treatments, specifically immunotherapy [4, 9, 10]. More widely, there have been substantial advances in the development of oncolytic virotherapy based on diverse DNA and RNA viruses [2].\n\nIn clinical studies, strict inclusion and exclusion criteria impose a strong bias compared to the patient population seen in the clinic. More specifically, treatment in the clinical setting includes patients with complex disease history and patients with progressive disease after prior systemic treatments. Analysis of real-life data can thus be informative when considering patient subpopulations of special interest. Yet, published data about use of T-VEC in routine clinical practice are scarce. There are four recent case series from the US that report on use of T-VEC in three single institutions and one two-center retrospective analysis [11–14]. A recent multicenter chart review analyzed data from 27 patients treated with T-VEC in routine clinical practice in Germany [15]. In a current study by the Netherlands Cancer Institute, data from 26 T-VEC treated patients were analyzed based on a prospectively maintained database [16]. Recently, a real-world data study (COSMUS-1) comprising 76 patients in the USA has been published [17]. Together, these published case series and real-world-data studies describe 233 patient and treatment characteristics. However, predictive biomarkers and the identification of patients who can benefit the most from T-VEC are not included. With the growing number of treatment options for advanced melanoma, there is a high clinical need to identify the best treatment strategies and sequences for our patients. In the discussion part, we will, therefore, focus on patient selection criteria based on our single-institution observations as well as the current literature.\n\nThis case series aims to characterize the response and follow-up of melanoma patients upon single-agent treatment with talimogene laherparepvec in clinical practice in a single institution in Germany paying a special attention to patients with stable visceral metastases. Although T-VEC has only shown modest efficacy in visceral metastases, we used T-VEC in stage IVM1b-M1c melanoma patients, who had achieved complete remission or stable disease of visceral metastases upon systemic treatment but subsequently suffered from a loco-regional recurrence. To our knowledge, there are no case reports or series so far describing the response of T-VEC as a means to overcome acquired resistance to ICB and/or targeted therapy.\n\nMaterials and methods\nWe performed a retrospective single-institution review of all melanoma patients who were treated with T-VEC from 2016 to March 2018. Patients were followed up until April 2019. Follow-up was defined as the time period between the last T-VEC application and the last visit to our center, or in the case of deceased patients, the date of death. Patients demographics (age, gender, and ECOG status), clinicopathologic characteristics (melanoma history including prior treatments, disease stage according to the AJCC 7th edition, BRAF status, lactate dehydrogenase LDH, and S100), details of the T-VEC therapy (number of injections, toxicity, and discontinuation), and response to treatment [complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD)] were reviewed. All injections were performed in cutaneous, subcutaneous, or nodal metastases of melanoma patients at the Skin Cancer Center at the University Hospital in Bonn, Germany. Patients were injected according to the guidelines and recommendations of the manufacturer (≤ 4 ml, 106 plaque-forming units (PFU)/ml on day 1, then after 3 weeks ≤ 4 ml 108 PFU/ml consecutively continued once every 2 weeks. AMGEN, Applied Molecular Genetics, Thousand Oaks, CA, USA). Response to treatment with T-VEC was evaluated clinically in case of cutaneous metastases or using imaging methods such as ultrasound, CT-, or MRI-Scan in the case of subcutaneous, lymph nodes, or visceral metastases. Imaging was conducted before induction of T-VEC and every 12 weeks thereafter. In the analysis of our data, we delineated a subgroup of patients with in-transit metastatic disease and normal baseline LDH levels regardless of tumor stage or line of therapy. We defined these criteria as “low tumor burden”.\n\nResults\nPatient characteristics and treatment\nFourteen patients with advanced, unresectable melanoma were treated with T-VEC in our center between March 2016 and March 2018. Table 1 gives a detailed overview of the characteristics, treatment, and outcome of each patient. Patients received intralesional T-VEC according to the manufacturer’s recommended dosing. Treatment was continued until no injectable tumor lesions remained, or until intolerable adverse events or progressive disease occurred. Six patients (43%) received T-VEC first-line. In eight patients (57%), therapy with T-VEC followed a prior systemic therapy (75% immunotherapy, 37.5% targeted therapy, 12.5% both, and adjuvant therapy with interferon was not considered as pretreatment). Three patients with M1b stage melanoma and one patient with M1c stage melanoma were treated with T-VEC. These patients suffered from a loco-regional progress, while distant metastases had been stable or regressive during prior systemic treatment. The demographic data are listed in Table 2.Table 1 Patient characteristics, prior treatment, and outcome of n = 14 melanoma patients treated with T-VEC\n\nPatient No\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t\nStage\tIIIB\tIIIC\tIIIC\tIIIC\tIIIC\tIIIC\tIIIC\tIIIC\tIIID\tIV M1a\tIV M1b\tIV M1b\tIV M1b\tM1c\t\nBaseline LDH ≥ 1.5 × ULN\t−\t−\t−\t−\t−\t−\t−\t−\t+\t−\t−\t++\t−\t++\t\nBRAF mutation status\tBRAF V600E\t−\tUN\tBRAF V600E\t−\t−\tBRAF V600D\tBRAF V600K\tBRAF V600E\t−\t−\t−\t−\tBRAF G469R\t\nLymph-node metatases present\t−\t−\t+\t+\t−\t+\t+\t+\t+\t+\t−\t+\t−\t+\t\nLymph-node metastases injected (T-VEC)\t−\t−\t+\t−\t−\t−\t−\t−\t−\t−\t−\t+\t−\t+\t\nAdjuvant therapy (months)\tIFN (2)\t0\t0\t0\t0\t0\t0\t0\t0\t0\tIFN (16)\t0\t0\t0\t\nFirst-line T-VEC\tNo\tYes\tYes\tYes\tYes\tYes\tNo\tYes\tNo\tNo\tNo\tNo\tNo\tNo\t\nPrior immunotherapy\tNo\tNo\tNo\tNo\tNo\tNo\tIpi; Nivo\tNo\tNo\tPembro\tPembro\tIpi + Nivo; Pembro\tPembro\tIpi + Nivo; Pembrol\t\nPrior targeted therapy\tBRAF/MEK\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tBRAF/MEK\tNo\tNo\tNo\tNo\tBRAF/MEK\t\nNumber of prior treatment lines\t1\t0\t0\t0\t0\t0\t2\t0\t1\t1\t1\t1\t1\t2\t\nNumber of injections\t15\t13\t12\t20\t10\t7\t3\t3\t3\t9\t3\t1\t7\t1\t\nTime between prior therapy to T-VEC (weeks)\t33\tN.A.\tN.A.\tN.A.\tN.A.\tN.A.\t21\tN.A.\t0\t5\t7\t3\t9\t4\t\nBest response\tCR\tPR\tSD\tPR\tCR\tPR\tPR\tPD\tPD\tPR\tPD\tPD\tPR\tPD\t\nPFS (weeks)\t87\t83\t24\t77\t101\t67\t12\t0\t0\t22\t0\t0\t18\t0\t\nFU (weeks)\t56\tN.A.; on treatment\tN.A.; Lost to follow-up\t16\t81\tN.A.; on treatment\t55\t17\t43\t59\t5\t20\t68\t4\t\nDeath (PD)\t\t\t\t\t\t\t\t+\t+\t\t+\t+\t\t+\t\nTable 2 Patient demographics and clinicopathologic characteristics of n = 14 melanoma patients treated with T-VEC\n\n\tTotal (N = 14)\t\nGender, n (%)\t\n Men\t6 (43)\t\n Women\t8 (57)\t\nMedian age, years (min; max)\t72.5 (41; 89)\t\nDisease stage (AJCC 2017), n (%)\t\n III B\t1 (7)\t\n III C\t7 (50)\t\n III D\t1 (7)\t\n IVM1a\t1 (7)\t\n IVM1b\t3 (21)\t\n IVM1c\t1 (7)\t\nLine of therapy\t\n First, n (%)\t5 (36)\t\n Second or later, n (%)\t9 (64)\t\nBaseline LDH\t240\t\n < ULN\t7 (50)\t\n ≥ ULN\t7 (50)\t\n ≥ 1.5 × ULN\t3 (21)\t\nBaseline S-100\t\n < ULN\t9 (64)\t\n ≥ ULN\t5 (36)\t\nBRAF mutation status, n (%)\t\n Mutant\t6 (43)\t\n Wildtyp\t7 (50)\t\n Unknown\t1 (7)\t\nPrimary diagnosis, n (%)\t\n Acrolentiginous melanoma\t3 (21)\t\n Nodular melanoma\t10 (71) \t\n Mucosal melanoma\t1 (7)\t\nTumor thickness, median (min; max)\t4.23 (1.0; 11.0)\t\n\n\nBy the time of database lock (April 2019) on average (median), eight injections were applied (range: 1–41 injections). Two patients were still being treated. In 11 patients (79%), T-VEC was injected in cutaneous metastases. In three patients, T-VEC was injected in subcutaneous or nodal metastases (21%). LDH levels at baseline were elevated in 50% (n = 7) of the patients.\n\nTolerability/toxicity\nT-VEC was in general well tolerated with the toxicity profile as expected from published clinical trials. There were no grade 3 or 4 AEs (according to CTCAE). 89% of the AEs occurred directly after the first injection of T-VEC. Adverse events are shown in Table 3.Table 3 Treatment-related adverse events observed during T-VEC treatment in all patients (n = 14)\n\nAE\tGrade 1/2, n (%)\tGrade 3/4, n (%)\t\nAny treatment-related AE\t9 (64)\t0\t\nChills\t6 (43)\t0\t\nPyrexia\t5 (36)\t0\t\nFatigue\t1 (7)\t0\t\nInfluenza-like illness\t2 (14)\t0\t\nGastrointestinal disorders\t5 (36)\t0\t\nInjection site reaction\t3 (21)\t0\t\nPruritus\t1 (7)\t0\t\n\n\nEfficacy–response rate\nIn nine patients (64%), a local response to therapy with T-VEC was achieved. Two patients (14%) (No 1 and 5) showed a complete response (CR) and six patients (43%) had a partial response. One patient (No 3) remained at stable disease (7%). Five patients (36%) had a loco-regional or systemic progressive disease. Examples of response and follow-up in four patients treated with T-VEC are shown in Fig. 1.Fig. 1 Representative clinical images of four melanoma patients treated with T-VEC over time showing a complete response, b, c partial response, and d progressive disease. d Baseline image of an ulcerated melanoma metastasis of the left axilla of a melanoma patient (M1c) with prior systemic treatment. Patient received one T-VEC injection and died from rapid progressive disease\n\n\n\nThe median progression-free survival (PFS) was 20 weeks (CI 0; 101). The durable response rate (DRR), defined as complete responses (CR) and partial responses (PR) lasting ≥ 6 months, was 36% (5/14). The five patients (No 1, 2, 4, 5, 6) in our setting showing DRR had stage IIIB and stage IIIC disease. Four of them were treatment-naïve to T-VEC (75%).\n\nA subgroup analysis of patients who received T-VEC treatment first-line (6/14) showed that 83% of these patients had a benefit from treatment with T-VEC. One patient had a complete response. Median PFS was 72 weeks. The DRR in this subgroup was 67%.\n\nDuration of treatment and response on T-VEC are visualized in a swimmer plot (Fig. 2). Outcomes, best response rates, and PFS are summarized in Table 4.Fig. 2 Swimmer plot showing time on prior systemic treatment (in blue) and on T-VEC treatment (in orange) of individual melanoma patients at stage IIIB to M1c (indicated at y-axis). Prior systemic treatment includes ICB, targeted therapy, or both. Treatment-free intervals were left out in favor of clarity. Therapeutic responses were defined as best response upon time of data base lock (April 2019). Further systemic therapies following on T-VEC were not considered\n\nTable 4 Best response to T-VEC of all patients and dependent on first-line treatment or with no prior systemic treatment (n = 6 patients received T-VEC as first-line treatment; n = 8 patients received T-VEC after systemic treatment with immune checkpoint blockade and/or targeted therapy)\n\n\tBest response all patients (N = 14), n (%)\tBest response, first-line T-VEC (N = 6), n (%)\tBest response, patients with prior systemic treatment (N = 8), n (%)\t\nPatients with a response 95% CI\t\n Complete response\t2 (14)\t1 (17)\t1 (12.5)\t\n Partial response\t6 (43)\t3 (50)\t3 (37.5)\t\n Stable disease\t1 (7)\t1 (17)\t0 (0)\t\n Progressive disease\t5 (36)\t1 (17)\t4 (50)\t\n Overall response rate\t9 (64)\t5 (83)\t4 (50)\t\n Durable response rate\t5 (36)\t4 (67)\t1 (12.5)\t\n Progression-free survival, median (weeks)\t20\t72\t10\t\n Death \t5 (36)\t1 (17)\t4 (50)\t\n\n\nEight patients (57%) received T-VEC following a prior systemic therapy. Six patients had received a prior treatment with anti-PD1-therapy (No 7, 10–14). The median period of time between two therapies was 6 weeks (CI 3; 21). In five patients (No 10–14), treatment with T-VEC almost continuously followed prior anti-PD1-therapy (CI 3; 9 weeks). Two patients were treated with a BRAF and MEK inhibitor prior T-VEC therapy (No 1, 9). One patient (No 14) with tumor stage M1c had received anti-PD1 followed by BRAF inhibition with vemurafenib, and a third line combined anti-PD1 and anti-CTLA4 immunotherapy before treatment with T-VEC was induced. The median PFS in patients treated with T-VEC second-line was 10 weeks (CI 0; 87), compared to 72 weeks (CI 6; 101) in the first-line treated patients.\n\nOne patient with in-transit metastatic melanoma, stage IIIB (patient No 1) received T-VEC after prior targeted therapy with BRAF/MEK inhibitor and obtained a long-lasting, complete response. Another patient (patient No 10) with M1a stage melanoma received prior anti-PD1-therapy, which led to a regression of lymph-node metastases, whereas in-transit metastases showed loco-regional resistance to immunotherapy. Here, treatment with T-VEC achieved a partial response in in-transit metastases. A stage IIIC melanoma patient (No 8) received T-VEC following two lines of prior immunotherapy. These three patients who responded to T-VEC all showed low tumor burden, as defined by in-transit metastases and normal LDH levels. Patient No 9, with irresectable tumor stage IIID melanoma, received T-VEC following a targeted therapy with BRAF/MEK inhibition. The patient suffered from a large tumor, increased LDH levels, and did not respond to T-VEC therapy.\n\nFour patients with advanced melanoma, stage M1b-M1c, who had received one or more prior systemic therapies were treated with T-VEC (patients No 11–14). These patients suffered from a loco-regional progression, while distant metastases had been stable or regressive during prior systemic treatment.\n\nThree of these patients (No 11, 12, 14) did not respond to T-VEC and had a rapid progressive systemic disease. Hence, T-VEC could only be applied once and three times, respectively. These patients suffered from a high loco-regional tumor burden with elevated S-100 and LDH levels at baseline.\n\nOne patient with advanced melanoma (patient No 13) showed a partial response from treatment with T-VEC. The patient had received prior anti-PD1 treatment with pembrolizumab in M1b stage melanoma, upon which a complete response of the known lung metastases was documented by repeated CT-scans every 12 weeks. In the course of time, the patient developed multiple cutaneous in-transit metastases of the lower extremity without any systemic progression. LDH levels were within normal range and tumor burden as per our definition was low. Cutaneous metastases were treated with seven cycles of T-VEC and lesions showed a partial response for 18 weeks before the patient developed progressive disease with new pulmonal metastases. Immunotherapy with anti-PD-1 was re-induced and achieved a complete response.\n\nIn total, three patients in our center (21%) had baseline LDH levels ≥ 1.5-fold above upper limit normal (ULN); all of them had received a prior systemic treatment. None of these patients responded to T-VEC.\n\nOur results show that treatment with T-VEC achieved a response in patients with low tumor burden, having limited in-transit metastases and normal LDH levels at baseline. This held true even for patients with prior systemic therapy and for a patient with M1b melanoma.\n\nDiscussion\nWe present a retrospective single-institution case series of 14 patients who were treated with T-VEC for locally advanced metastatic melanoma. In contrast to recently published case series, in our study, four stage IVM1b-M1c patients, who developed loco-regional progression, while distant metastases showed complete remission upon ICB or/and targeted therapy, received T-VEC treatment. A recent case series from USA reported about 26 melanoma patients in stage IIIB–IVM1a and one patient in stage IVM1c receiving T-VEC in a single institution [12]. This work does not report detailed information about the IVM1c melanoma patient. A recent multicenter chart review analyzed data from 27 T-VEC treated melanoma patients and aimed to characterize the first patients in Germany treated with T-VEC [15]. This trial included seven patients who had received prior immunotherapy, but all these patients had stage IIIB–IVM1a disease. A third recently published case series, again from the US, reviewed ten patients in a participating center of the Masterkey-256 study, who did not meet the eligibility criteria, but were treated off-label with T-VEC plus checkpoint inhibitors [11]. A current study based on a prospectively maintained database from the Netherlands Cancer Institute showed high complete and overall response rates in 26 stage IIIB/C in-transit melanoma patients. Twenty-three patients were treatment-naïve [16]. The COSMUS-1 study investigated T-VEC treatment in the clinical practice setting in 78 patients in the USA, including 43.4% patients who received checkpoint inhibitors before T-VEC treatment or in combination and 30 patients with tumor stage IVM1b/c disease [17].\n\nThe overall response rate (ORR) in our study was 64%. The ORR is similar to the observed ORR of 56.5% in the US case series published by Sun et al. [11] but significantly higher than the observed ORR in the primary analysis of the phase III OPTiM trial (26.4%) [6, 12] and the final analysis of the OPTiM data (31.5%) [8]. The difference in ORR between our study and the OPTiM trial is mainly related to the higher number of stage IVM1b/c melanoma stages (43 in the primary analysis [6], 45 in the final analysis [8] vs 29% in our study). Andtbacka et al. stated that T-VEC efficacy was most pronounced in patients with stage IIIB–IVM1a disease and in treatment-naïve patients. The DRR in our subgroup of first-line patients was 67%. This is a considerably high response rate compared to the primary subgroup analysis in the OPTiM trial which produced a DRR of 24% in first-line patients. The recently published final planned OPTiM trial analysis confirmed the results of the primary analysis, showing significant beneficial effects of T-VEC on overall survival in the subgroup of patients receiving T-VEC first-line [8]. The recent study of Franke et al. demonstrated a high ORR of 88.5% and best CR rates of 61.5% in a mainly treatment-naïve population of IIIB/IIIC in-transit melanoma patients (median duration of response not yet reached) [16]. The authors suggested patients with early metastatic disease stage IIIC-M1a and low tumor burden to be the subgroup of patients who are most likely to benefit from T-VEC. This applied to patients with in-transit metastatic disease, as patients with lymph-node involvement were excluded from the trial. Our data support the assumption that patients with low tumor burden, indicated by in-transit metastatic disease and by normal LDH values, are a highly favorable subgroup for treatment with T-VEC. The primary effect of oncolytic therapy is mediated by induction of a local anti-tumor response, which is more likely to control a locally limited tumor disease. However, it is unclear if the favorable effects of T-VEC in early stage melanoma are based on better activity in early stage disease, or merely reflect the natural history of melanoma. As demonstrated in the current AJCC cancer staging manual, the 5-year melanoma-specific survival rate significantly ranges according to disease subgroups, e.g. from 83% in patients with stage IIIB disease to 32% for those with stage IIID disease [18].\n\nIn our study, only patients with normal LDH levels responded to T-VEC therapy. The OPTiM study excluded patients with baseline serum lactate dehydrogenase (LDH) ≥ 1.5 × ULN. The enzyme LDH is a serological biomarker in melanoma and one of the strongest prognostic indicators found to be correlated with tumor burden [19, 20]. The exclusion of patients with baseline serum LDH ≥ 1.5 × ULN leads to a strong bias towards patients with lower tumor burden. In our cases, three patients (21%) had baseline LDH levels ≥ 1.5 × ULN, with all of them having received a prior systemic treatment. None of these patients responded to T-VEC. In these three patients, staging imaging preceding induction of T-VEC had demonstrated visceral disease to be stable or absent and progressive disease was limited to in-transit or lymph-node metastases. Yet, we can assume that increased LDH levels in these patients not only reflected high tumor load, but, as a marker for active progressive disease, indicated the rapid progression of the melanoma. Patients with complete or partial response to T-VEC (≥ 6 months) all showed baseline LDH levels ≤ 1.5-fold above limit. This is in line with the assumption that therapy with T-VEC is particularly effective in patients with low tumor load. This criterion is met more often in the absence of visceral disease which applies to the approved indication of the drug and our definition of low tumor burden. However, this is also true for other systemic melanoma therapies as low tumor burden is a favorable prognostic factor for overall survival and overall response rate to systemic therapy in general. For targeted therapy with BRAF/MEK inhibitors, there is a known correlation between baseline tumor burden, response rate, and progression-free survival [21, 22]. Another recent study investigated the connection between T-cell invigoration, tumor burden, and anti-PD1 response in immunotherapy with pembrolizumab [23].\n\nBaseline tumor burden has been demonstrated to be a predictive factor in diverse malignancies, including melanoma [24]. In T-VEC-treated patients included in the OPTiM trial, achievement of CR showed a significant negative association with baseline tumor burden [25]. Based on a multivariate analysis in this trial, the cut-off for baseline tumor burden was > 14.5 cm [8]. The two-center retrospective analysis including 40 patients in USA reported increased overall survival and PFS in patients with smaller tumors [14]. The retrospective single-center analysis in 27 patients demonstrated decreased efficacy of T-VEC with increasing lesion size [13]. However, a general definition for tumor burden does not exist. Depending on the study design, tumor burden has been defined in several ways, including number of metastases, tumor diameter, or volume [24]. Kaufman et al. stated that tumor burden was prognostic for overall survival and achieving a complete response in the OPTiM trial. Hereby, multivariate analysis showed a significant association of tumor burden and tumor stage (IIIB–IVM1a vs. IVM1b/c) and treatment line (fist line vs. latter line) [25]. This held true for the majority of our patients as well. However, in our case series, we particularly focus on stage IV melanoma patients who received a loco-regional response to T-VEC after having received a systemic response to immune checkpoint blockade. These patients did not fulfill the criteria of tumor stage IIIB–IVM1a and T-VEC treatment first-line. However, these patients suffered only from in-transit metastatic disease and showed normal baseline LDH levels. In our study, no prospective quantification of tumor volume, diameter, or RECIST evaluation was performed, limiting our ability to define a quantitative cut-off for tumor burden. We, therefore, refer to “low tumor burden” as in-transit metastatic disease with normal baseline LDH to differentiate this subgroup of patients irrespective of tumor stage or line of therapy.\n\nIn general, the criteria of early metastatic melanoma and low tumor burden might more often be met in treatment-naïve patients. Efficacy in patients treated with T-VEC first-line is suggested to be most pronounced [6]. However, data on the influence of prior systemic treatment are scarce.\n\nTwo case series highlight the clinical efficacy of T-VEC after progression on multiple previous therapies [26, 27]. In accordance with these publications, in our center, four out of eight patients profited from T-VEC after ICB or/and targeted therapy. In contrast to the afore mentioned case series, we present not only data on stage IIIB/C and IVM1a pre-treated melanoma patients, but also four stage M1b-M1c patients who achieved complete remission of visceral metastases with ICB or/and targeted therapy and developed loco-regional progression. In the COSMUS-1 observational study, 21 patients received immune checkpoint blockade prior T-VEC treatment and 3 out of 21 showed complete response [17]. The study included 30 patients with tumor stage IVM1b/c disease. However, the authors did not investigate in depth which of those patients benefited from treatment with T-VEC. Six patients treated in our center had received a prior therapy with anti-PD1-therapy, two patients responded to T-VEC. In our institution, three patients had received a prior treatment with targeted therapy (BRAF/MEK inhibitors), and one patient profited from treatment with T-VEC.\n\nIt has been suggested that previous treatment exposure may have an effect on outcome to different therapeutic agents [28]. In the OPTiM trial, patient enrolment took place from May 2009 to July 2011. This indicates that options for prior therapy were limited compared to contemporary state of the art therapy. The impact of previous systemic therapy on response to T-VEC thus remains an open question [26]. A retrospective analysis of 27 melanoma patients treated with T-VEV found a decreased ORR for pre-treated patients without describing details of these patients [13]. Our data suggest that some patients’ clinical course may benefit from prior therapy with T-VEC and may even pave the way to long-term response. In our center, all patients that profited from T-VEC as the second-line treatment had low tumor burden, defined as disease limited to in-transit metastases and normal LDH levels. Patients with high tumor burden and a rapid tumor progression did not respond to second-line T-VEC treatment. Even though LDH level is not reported or not correlated to clinical response in other case series with pre-treated melanoma patients who received T-VEC as second-line treatment [12, 15, 26, 27], we suggest that elevated LDH level can serve as a useful indicator. A sensible selection of suitable patients seems to be crucial and high medical need patients seem to require more aggressive therapeutic intervention.\n\nThe combination of oncolytic virotherapy and immunotherapy is a promising approach. As described in the patient characteristics, one patient with M1b disease (No 13) profited from T-VEC treatment in in-transit metastases, which had occurred under prior treatment with anti-PD-1 therapy. The patient showed a low tumor burden with normal LDH levels and in-transit metastases. We conjecture that T-VEC injections provoked an anti-tumor response, which helped to overcome acquired resistance to immunotherapy. It is remarkable that upon progressive disease with new lung metastases after 18 weeks on T-VEC, re-induced anti-PD-1 therapy yielded a complete response. It is probable that in this case, T-VEC provided synergistic efficacy in reinvigorating the exhausted immune response. The combination of T-VEC and anti-PD1-therapy has currently been tested in a phase Ib trial (Masterkey-256) [9]. Twenty-one patients with advanced melanoma were treated with T-VEC followed by combination with pembrolizumab. The objective response rate was 62% with a complete response rate of 33%. The authors suggested that oncolytic therapy may improve the efficacy of immunotherapy with anti-PD1-antibodies mainly by affecting the tumor microenvironment [9]. Sun et al. recently published a case series of ten patients who were treated off-label with T-VEC plus checkpoint inhibitors [11]. The surveyed data support the idea that combination of checkpoint inhibitors with T-VEC may provide a synergistic effect. Outcome was even superior in comparison to published studies on similar therapeutic regimes, although validity might be limited by the small number of patients. To our knowledge, there is no clinical trial investigating the combination of targeted therapy and T-VEC at this point. A recently published case report describes the clinical course of a heavily pre-treated 71-year-old patient with stage IIIB disease who profited from T-VEC. Prior therapies included GM-CSF, vemurafenib, dabrafenib, trametinib, ipilimumab, and pembrolizumab [26].\n\nWe are aware of the limitations of our study. Response to treatment with T-VEC was evaluated in some patients by clinical and/or sonographic measurement of the injected lesions and might, therefore, in part vary depending on the investigators’ experience. Limited by the retrospective nature of our study, we decided against the definition of a quantitative measurement of tumor burden. Due to the small number of patients, the heterogeneity of our cohort, the retrospective setting, as well as unknown potential confounding variables, the possibility to draw generalizable conclusions from our case series is limited. In summary, we observed a positive response in 9/14 T-VEC-treated patients with loco-regionally advanced melanoma. As stated in previous trials, there was a trend towards greater therapeutic benefit in patients with low tumor burden and stage IIIB-M1a disease. We observed a better DRR in the first-line patients in comparison to the approval trial. We observed a partial response from T-VEC in a patient who developed loco-regional resistance to anti-PD1 therapy. Moreover, our data suggest that patients who have previously received systemic therapy can still profit from therapy with T-VEC and, in some cases, even achieve long-term responses. This was true for patients with low tumor burden, characterized by normal baseline LDH levels and in-transit metastatic disease, which can serve as an identification mark for characterizing this group of patients. We, therefore, suggest that tumor burden rather than tumor stage is crucial for the identification of patients who are most likely to benefit from treatment with T-VEC.\n\nWe propose that T-VEC treatment is an attractive option not only for pre-treated stage IIIB/C and IVM1a patients but also for patients with stable visceral metastases who acquired loco-regional resistance to ICB and/or targeted therapy. A sensible selection of suitable patients seems to be crucial. Moreover, the combination of T-VEC with other systemic therapies, specifically immunotherapy, seems to be a promising prospect.\n\nAbbreviations\nBRAFV-raf murine sarcoma viral oncogene homolog B1\n\nCRComplete response\n\nDRRDurable response rate\n\nICBImmune checkpoint blockade\n\nORROverall response rate\n\nPDProgressive disease\n\nPRPartial response\n\nSDStable disease\n\nT-VECTalimogene laherparepvec\n\nULNAbove upper limit normal\n\nUS 11Accessory factor US11\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nOpen Access funding provided by Projekt DEAL. We thank Holger Fröhlich, University of Bonn, for initial corrections and helpful comments.\n\nAuthor contributions\nAF and JL were involved in the study design and concept. AF, DN, SF, EE, AB, and JS were involved in the data acquisition. All authors were involved in the review and editing of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nDennis Niebel was funded in part by DFG (German Research Foundation) Cluster of Excellence ImmunoSensation (EXC 1023).\n\nCompliance with ethical standards\nConflict of interest\nAnne Fröhlich has received speaker’s honoraria or travel expense reimbursements from the following companies: Novartis, Bristol-Myers Squibb (BMS), Almirall, and Eli Lilly Pharma. Dennis Niebel has received speaker’s honoraria or travel expense reimbursements from the following companies: BMS, Novartis, GlaxoSmithKline (GSK), Celgene, and Merck Sharp & Dohme (MSD). Judith Sirokay received speaker’s honoraria from Novartis, BMS, MSD, and Roche. Jennifer Landsberg is a consultant/advisory board member of BMS, MSD, Novartis, and Roche, and has received speaker’s honoraria or travel expense reimbursements. No potential conflicts of interest were disclosed by all the other authors.\n\nEthical approval\nOur study was approved by the Institutional Review Board (Vote No 187/16, Ethics commission, Faculty of Medicine, Bonn). Our study was conducted in accordance with the Helsinki Declaration of 1975.\n\nInformed consent\nWe obtained written informed consent from all patients or their authorized caregivers. Patients consented to the treatment and the use of their data, including photos, for research and publication.\n==== Refs\nReferences\n1. Hu JCC Coffin RS Davis CJ A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor Clin Cancer Res Off J Am Assoc Cancer Res 2006 12 6737 6747 10.1158/1078-0432.CCR-06-0759 \n2. Fountzilas C Patel S Mahalingam D Review: oncolytic virotherapy, updates and future directions Oncotarget 2017 8 102617 102639 10.18632/oncotarget.18309 29254276 \n3. Bommareddy PK Patel A Hossain S Kaufman HL Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma Am J Clin Dermatol 2017 18 1 15 10.1007/s40257-016-0238-9 27988837 \n4. Blackmon JT Dhawan R Viator TM Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: a report of 2 cases JAAD Case Rep 2017 3 185 189 10.1016/j.jdcr.2017.02.003 28443305 \n5. Kaufman HL Amatruda T Reid T Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study J Immunother Cancer 2016 4 12 10.1186/s40425-016-0116-2 26981242 \n6. Andtbacka RHI Kaufman HL Collichio F Talimogene laherparepvec improves durable response rate in patients with advanced melanoma J Clin Oncol Off J Am Soc Clin Oncol 2015 33 2780 2788 10.1200/JCO.2014.58.3377 \n7. Harrington KJ Andtbacka RH Collichio F Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase III OPTiM trial OncoTargets Ther 2016 9 7081 7093 10.2147/OTT.S115245 \n8. Andtbacka RHI Collichio F Harrington KJ Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma J Immunother Cancer 2019 7 145 10.1186/s40425-019-0623-z 31171039 \n9. Ribas A Dummer R Puzanov I Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy Cell 2017 170 1109 1119.e10 10.1016/j.cell.2017.08.027 28886381 \n10. Chesney J Puzanov I Collichio F Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma J Clin Oncol Off J Am Soc Clin Oncol 2017 10.1200/JCO.2017.73.7379 \n11. Sun L Funchain P Song JM Talimogene laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III–IV melanoma: a case series J Immunother Cancer 2018 6 36 10.1186/s40425-018-0337-7 29764498 \n12. Perez MC Miura JT Naqvi SMH Talimogene laherparepvec (TVEC) for the treatment of advanced melanoma: a single-institution experience Ann Surg Oncol 2018 25 3960 3965 10.1245/s10434-018-6803-0 30298318 \n13. Masoud SJ Hu JB Beasley GM Efficacy of talimogene laherparepvec (T-VEC) therapy in patients with in-transit melanoma metastasis decreases with increasing lesion size Ann Surg Oncol 2019 26 4633 4641 10.1245/s10434-019-07691-3 31414290 \n14. Zhou AY Wang DY McKee S Correlates of response and outcomes with talimogene laherperpvec J Surg Oncol 2019 120 558 564 10.1002/jso.25601 31264725 \n15. Mohr P Haferkamp S Pinter A Real-world use of talimogene laherparepvec in German patients with stage IIIB to IVM1a melanoma: a retrospective chart review and physician survey Adv Ther 2019 36 101 117 10.1007/s12325-018-0850-6 30536143 \n16. Franke V Berger DMS Klop WMC High response rates for T-VEC in early metastatic melanoma (stage IIIB/C–IVM1a) Int J Cancer 2019 10.1002/ijc.32172 30694555 \n17. Perez MC Zager JS Amatruda T Observational study of talimogene laherparepvec use for melanoma in clinical practice in the United States (COSMUS-1) Melanoma Manag 2019 6 2 MMT19 10.2217/mmt-2019-0012 31406563 \n18. Gershenwald JE Scolyer RA Hess KR Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual CA Cancer J Clin 2017 67 472 492 10.3322/caac.21409 29028110 \n19. Karagiannis P Fittall M Karagiannis SN Evaluating biomarkers in melanoma Front Oncol 2015 10.3389/fonc.2014.00383 25667918 \n20. Solassol J Du-Thanh A Maudelonde T Guillot B Serum proteomic profiling reveals potential biomarkers for cutaneous malignant melanoma Int J Biol Markers 2011 26 82 87 10.5301/JBM.2011.8344 21607923 \n21. Menzies AM Long GV Dabrafenib and trametinib, alone and in combination for BRAF -mutant metastatic melanoma Clin Cancer Res 2014 20 2035 2043 10.1158/1078-0432.CCR-13-2054 24583796 \n22. Amaravadi R, Kim K, Flaherty K et al (2011) Prolonged responses to vemurafenib in patients with: SMR-P3BRAFV600: SMR-P3-mutant melanoma with low tumor burden at baseline: SMR-P3. Pigment Cell Melanoma Res 24\n23. Huang AC Postow MA Orlowski RJ T-cell invigoration to tumour burden ratio associated with anti-PD-1 response Nature 2017 545 60 65 10.1038/nature22079 28397821 \n24. Andrew S, Poklepovic MD (2018) Prognostic value of low tumor burden in patients with melanoma. In: Cancer Netw. https://www.cancernetwork.com/article/prognostic-value-low-tumor-burden-patients-melanoma. Accessed 5 Dec 2019\n25. Kaufman H Amatruda T Nemunaitis JJ Tumor size and clinical outcomes in melanoma patients (MEL pts) treated with talimogene laherparepvec (T-VEC) J Clin Oncol 2015 33 9074 9074 10.1200/jco.2015.33.15_suppl.9074 \n26. Chesney J Imbert-Fernandez Y Telang S Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors Melanoma Res 2018 28 250 255 10.1097/CMR.0000000000000444 29561296 \n27. Seremet T Planken S Schwarze JK Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma Melanoma Res 2019 29 85 88 10.1097/CMR.0000000000000501 30211812 \n28. Ackerman A Klein O McDermott DF Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors Cancer 2014 120 1695 1701 10.1002/cncr.28620 24577748\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0340-7004",
"issue": "69(5)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Acquired resistance; Advanced melanoma; Immunotherapy; Talimogene laherparepvec; Targeted therapy",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D061025:Costimulatory and Inhibitory T-Cell Receptors; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D018259:Herpesvirus 1, Human; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D050130:Oncolytic Virotherapy; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "759-769",
"pmc": null,
"pmid": "32052079",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "26014293;30211812;28443305;29254276;29561296;26981242;25667918;30694555;31264725;29028110;24583796;17121894;21607923;27895500;31414290;30298318;28981385;30536143;31171039;28397821;28886381;24577748;31406563;27988837;29764498",
"title": "Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB-IV M1c melanoma patients.",
"title_normalized": "talimogene laherparepvec treatment to overcome loco regional acquired resistance to immune checkpoint blockade in tumor stage iiib iv m1c melanoma patients"
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"abstract": "Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.",
"affiliations": "Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, 60528 Frankfurt, Germany. michael.burger@kgu.de.;University Cancer Center Frankfurt (UCT), 60590 Frankfurt, Germany. marlies.wagner@kgu.de.;University Cancer Center Frankfurt (UCT), 60590 Frankfurt, Germany. k.franz@em.uni-frankfurt.de.;University Cancer Center Frankfurt (UCT), 60590 Frankfurt, Germany. patrick.harter@kgu.de.;Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, 60528 Frankfurt, Germany. oliver.baehr@kgu.de.;Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, 60528 Frankfurt, Germany. joachim.steinbach@kgu.de.;University Cancer Center Frankfurt (UCT), 60590 Frankfurt, Germany. c.senft@med.uni-frankfurt.de.",
"authors": "Burger|Michael C|MC|0000-0002-6927-0987;Wagner|Marlies|M|;Franz|Kea|K|;Harter|Patrick N|PN|;Bähr|Oliver|O|;Steinbach|Joachim P|JP|;Senft|Christian|C|0000-0003-1288-6913",
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"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm7080216jcm-07-00216ArticleVentriculoperitoneal Shunts Equipped with On-Off Valves for Intraventricular Therapies in Patients with Communicating Hydrocephalus due to Leptomeningeal Metastases https://orcid.org/0000-0002-6927-0987Burger Michael C. 12*Wagner Marlies 23Franz Kea 24Harter Patrick N. 256Bähr Oliver 126Steinbach Joachim P. 126https://orcid.org/0000-0003-1288-6913Senft Christian 2461 Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, 60528 Frankfurt, Germany; oliver.baehr@kgu.de (O.B.); joachim.steinbach@kgu.de (J.P.S.)2 University Cancer Center Frankfurt (UCT), 60590 Frankfurt, Germany3 Institute of Neuroradiology, Goethe University Hospital, 60528 Frankfurt, Germany; marlies.wagner@kgu.de4 Department of Neurosurgery, Goethe University Hospital, 60528 Frankfurt, Germany; k.franz@em.uni-frankfurt.de (K.F.); c.senft@med.uni-frankfurt.de (C.S.)5 Institute of Neurology (Edinger Institute), Goethe University Hospital, 60528 Frankfurt, Germany; patrick.harter@kgu.de6 German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt, Germany* Correspondence: michael.burger@kgu.de; Tel.: +49-69-6301-8771114 8 2018 8 2018 7 8 21617 7 2018 10 8 2018 © 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.\n\nleptomeningeal metastaseshydrocephalusintraventricular chemotherapyventriculoperitoneal shunt\n==== Body\n1. Introduction\nVentriculoperitoneal shunts (VP shunts) equipped with a valve to manually switch the shunt function off and a reservoir for the application of intraventricular chemotherapy are an elegant way for intraventricular delivery of therapeutics in patients suffering from a communicating hydrocephalus (hydrocephalus malresorptivus) due to leptomeningeal metastases. We postulate that VP shunts equipped with an on-off valve and a reservoir may be increasingly used in the nearer future in clinical studies exploring local cell-based immunotherapeutics. Therefore, we wanted to determine which shunting devices would be the most appropriate for intraventricular application of therapeutics in patients with leptomeningeal metastases and a communicating hydrocephalus. We decided to screen all adult patients who received a VP shunt with an on-off valve and a reservoir at our institution and performed a retrospective analysis of the clinical course of these patients. We screened the patients– records for reports about problems involving the configuration of the valve settings and during the intraventricular injections and for any shunt-related complications. Furthermore, we investigated the number of intrathecal chemotherapies that were applied using these shunting devices and their clinical outcomes. Intrathecal chemotherapy applied through a reservoir (Rickham or Ommaya reservoir) is usually indicated in patients with leptomeningeal metastases of the diffuse subtype [1]. Alternatively, the use of DepoCyt® obviates the need for intraventricular chemotherapy, as the distribution achieved in the cerebrospinal fluid (CSF) after intralumbar application has been shown to be sufficient as well [2,3]. However, there is no data available on the intrathecal pharmacokinetics of DepoCyt® in patients equipped with a VP shunt [2,4,5]. Rapid drainage through the VP shunt may lead to a loss of efficacy of DepoCyt®. In patients suffering from a hydrocephalus due to diffuse leptomeningeal metastases, a connection of the reservoir to a VP shunt is indispensable to drain the CSF and so relieve intracranial hypertension. To ensure a sufficient intrathecal exposure time of the chemotherapeutics, these VP shunts should be furthermore equipped with a valve so that the shunt function can be temporarily switched off. With intraventricular injection of chemotherapeutics, sufficient and uniform concentrations within the subarachnoid space can be achieved [6,7]. There are different types of valves available for this purpose. In type (I), some valves can be switched on and off by pressing a button, while in type (II), the opening pressure can be changed with a specialized device. In the latter type, the opening pressure can be temporarily raised so high that the shunt should not drain cerebrospinal fluid, and therapeutics can be injected fairly reliably through the reservoir into the ventricles [8,9,10]. For the application of intrathecal therapies, those valves that can be switched on and off—type (I)—may be more useful. Shunts equipped with an on-off valve have been shown to allow for effective intrathecal administration of chemotherapeutics in patients suffering from communicating hydrocephalus due to leptomeningeal metastases [11]. Trained practitioners can easily switch the shunt function on and off (“on-off shunts”) without the need for any device-specific equipment. Another advantage is that the configuration of the valve can be checked manually (i.e., after magnetic resonance imaging) on the basis of the position of the button without the need to perform a radiography. Most importantly, when the valve is switched off, the practitioner can be definitively sure that the therapeutics applied do not flow directly through the distal leg of the shunt system into the intraperitoneal space. In this case, it would not be possible to achieve an intrathecal concentration sufficiently high to reach therapeutic efficacy.\n\nIntrathecal chemotherapy is not indicated in patients with an obstructive hydrocephalus because intraventricular injection of chemotherapeutics in these patients fails to result in the uniform distribution of the therapeutic in the CSF necessary for therapeutic efficacy [12]. Another problem in patients with an obstructive hydrocephalus is that the intraventricular concentrations achieved may be locally too high and therefore toxic [13]. Intraventricular chemotherapies are also not effective in patients with a predominantly nodular type of leptomeningeal metastases because chemotherapeutics applied intrathecally can penetrate tissue only a few millimeters deep and do not reach sufficient tissue levels in bigger leptomeningeal metastases [14]. In addition, for many malignancies, more and more targeted therapies are becoming available, which are applied systemically and which are also used in patients with leptomeningeal metastases [15,16]. This has led to a diminished use of intrathecal chemotherapy in general—and VP shunts with on-off valves and a reservoir function in particular—over the course of recent years, at least in our institution.\n\nHowever, the recent investigation of cellular immunotherapeutic approaches has emphasized new requirements for local treatment modalities in the brain [17,18]. Systemic application of cellular therapeutics may not be an ideal approach for primary brain tumors, brain metastases, and leptomeningeal metastases. Molecular targeted cellular therapeutics may experience difficulties crossing the blood–brain barrier (BBB), adhere in pulmonary capillaries, home to other organs, or trigger systemic toxicity [19]. Similarly, the local treatment of brain tumors poses specific challenges that may be equally difficult to overcome. Primary brain tumors and brain metastases are often located deep within the brain surrounded by functional brain tissue. In particular, glioblastomas are highly infiltrative tumors with tumor cells widely spread in the brain tissue far off from the main tumor masses [20]. Even though tumor cells in leptomeningeal metastases are often distributed over a large area as well, they may be comparatively easy to reach for cellular immunotherapeutics. A recent publication has shown an impressive response of an intrathecal CAR-T cell therapy in a patient suffering from leptomeningeal metastases of a glioblastoma (GB) [21]. Similar approaches probably will be tested in other entities of leptomeningeal metastases from systemic malignancies and primary brain tumors. This is highly relevant as patients who suffer from leptomeningeal metastases often have a dismal prognosis [22,23,24]. A VP shunt with an on-off valve and an injection reservoir may be an ideal device for repeated intrathecal application of cellular immunotherapeutics in patients suffering from a communicating hydrocephalus.\n\n2. Results\nNo specific difficulties occurred in the implantation of the shunt systems, and there was no perioperative mortality or morbidity. We recorded the duration of the implantation procedure (time interval between the skin incision and the skin suture) to see if there was a learning effect in the neurosurgeons, possibly leading to shorter surgery durations in consecutive patients. The median duration of implantation procedure (time interval between skin incision until skin suture) was 66.5 min (49–96 min). There was a trend for shorter surgery durations; however, it was not significant (p = 0.31; Figure 1).\n\nOut of the six patients who received a VP shunt with an on-off valve, intraventricular chemotherapies were subsequently applied in two patients (Table 1). No problems occurred in the configuration of the on-off valve. This can be done easily by oncologist practitioners after a short instruction. In all patients, temporary closure of the shunt system was tolerated, which was tested by switching the shunt function off overnight while the patients were in our in-patient treatment. None of our six patients suffered from symptoms caused by pressure fluctuations in the standing position. This may be probably due to the equipment of our shunt systems with a gravitational unit. In the two patients where an intraventricular chemotherapy was applied, the shunt system was switched off for 24 h after intraventricular application of the chemotherapy. Both patients tolerated this temporary closure of the shunt system without showing clinical signs of a raised intracranial pressure. In four patients, the intrathecal chemotherapy was omitted due to the development of a nodular type of leptomeningeal metastases or rapid clinical deterioration.\n\nPatient 4 received a total of nine intraventricular injections of methotrexate (MTX). Due to a lack of response, the intrathecal chemotherapy was switched to thiotepa. After nine weekly intraventricular injections, a durable remission of CSF parameters was reached. In follow-up CSF examinations, CSF cytologies repeatedly did not evidence malignant cells, an elevated cell number, or elevated lactate concentrations. Therefore, the intraventricular therapy was stopped. However, 34 weeks after shunt implantation, the leptomeningeal metastases relapsed. Intraventricular thiothepa injections were resumed, but by then they were no longer effective. After a total of eight thiothepa injections, the therapy was switched to a systemic therapy with Gefitinib. As the patient did not respond to Gefitinib either, the therapy was changed after eight weeks to a pulsatile scheme with Erlotinib, which had a good effect. After 68 weeks under therapy with Erlotinib, the patient progressed and succumbed to her disease 116 weeks after shunt implantation (Table 2).\n\nOne patient experienced complications involving the VP shunts. Patient 6 developed strong headaches immediately after the first intaventricular injection of thiotepa through the shunt system. The total volume injected was 11 mL (5 mL thiotepa and then 6 mL of 0.9% sodium chloride solution to flush the proximal shunt system). During the injection procedure, we did not observe an elevated resistance of the shunt system. We suspected a shunt dysfunction and performed computertomography (CT) imaging of the brain before and after injecting iodinated contrast enhancer through the shunt system. The volume injected for the radiography was similar to the volume injected for the application of the chemotherapy. We injected a volume of 9 mL (3 mL contrast enhancer and then 6 mL of 0.9% sodium chloride solution). The shunt was again easily passable without posing resistance to the injection, and the ventricles were promptly filled by the contrast enhancer. Notably, the headaches did not deteriorate during the injection of the contrast enhancer. Nonetheless, a shunt leakage near the insertion point of the shunt catheter in the brain was detected (Figure 2). The patient described the headaches as bilateral equally pressing in the forehead and lasting for approximately 30 h. The headaches were responsive to both ibuprofen and piritramide. Due to the long duration of the headaches, the relatively low volume of the leakage, the patency of the shunt system, and the missing deterioration during the injection of the contrast enhancer, we suspect that the headaches were triggered by a toxic irritation of the meninges rather than compression of adjacent brain tissue. As the patient did not present with the complete triad of meningism (only headaches; no nuchal rigidity and no photophobia) this meningeal irritation seemed to be local. We estimate the possibility of the shunt catheter leakage being caused by the injection of the chemotherapy itself as rather unlikely because we injected the intrathecal chemotherapy very slowly and without inducing much pressure in the shunt system. We suspect that the leakage may have occurred unnoticed during the implantation procedure. In addition, we cannot rule out a preexisting hidden material defect in the shunt catheter.\n\nThe intrathecal chemotherapy was therefore omitted and a whole brain radiotherapy was instead applied. The shunt system was not replaced because the drainage function of the shunt system was not impaired.\n\nFour out of the six patients eventually did not receive any intrathecal chemotherapy. Patients 1, 2, and 5 showed an increasingly nodular type of leptomeningeal metastasis and therefore the initially planned intrathecal therapy was skipped. Patient 1 received a systemic therapy with Afatinib. Patients 2 and 5 received a whole brain radiation therapy. In patient 3, the intrathecal chemotherapy was omitted due to a rapid clinical decline and the patient therefore received best supportive care (BSC). \n\nThe median progression-free survival (PFS) of the patients reported in this series was 8.5 weeks and the median overall survival (OS) was 13.5 weeks (Figure 3).\n\n3. Discussion\nSimilarly to the results reported by Lin et al. [11], we have shown that shunts equipped with an on-off valve and a reservoir function allow for uncomplicated and effective intraventricular administration of chemotherapies in patients with leptomeningeal metastases. We used shunt systems that differed from the ones used by Lin et al. [11] as they were additionally equipped with gravitational units. These shunts are reliable tools for injecting therapeutics intraventricular without running the risk of injecting intraperitoneally. Avoiding unintentional intraperitoneal injections and ensuring intraventricular injections is of high significance when applying intraventricular chemotherapies. For effective intrathecal treatment of leptomeningeal metastases, achieving sufficient concentrations over prolonged time intervals is paramount. Intrathecal application of chemotherapeutics through repeated lumbar punctures is only effective if prolonged-release formulations are used because only then can sufficient intraventricular concentrations be achieved [4,12]. Similarly, an effect of intraventricular therapy should only be expected if the chemotherapeutics applied are not drained immediately through a ventriculoperitoneal shunt [25]. Most importantly, VP shunts equipped with an on-off valve and a reservoir serve two different requirements in patients with communicating hydrocephalus due to leptomeningeal metastases—(I) to enable the drainage of CSF and (II) to establish a reliable route of intraventricular access for chemotherapeutics.\n\nIn the setting of cellular immunotherapies intended for intrathecal application, this may be of an even higher significance as systemic toxicities may be even more of a concern. Shunts with on-off valves are very easy to handle, including in the setting of a neuro-oncology outpatient-department. There is no need to provide specialized equipment to change the opening pressure of shunt valves. Practitioners who are not familiar with this specialized equipment are nevertheless easily able to switch the shunt function on and off after a short one-time instruction without major problems.\n\nThe complication of shunt leakage that occurred in one patient of this series is a typical and common shunt complication [26,27]. The causation of the shunt leakage in patient 6 is not entirely clear. It may have occurred unnoticed during the implantation procedure or may be the result of a hidden material defect. We did not experience problems with the function of the programmable differential pressure units or the gravitational units. We purposely positioned the on-off valve between the Rickham reservoir and the programmable differential pressure units (and not distal to the pressure units or the gravitational units). We consider this sequence as highly important to protect these very vulnerable components from pressure fluctuations during the injection procedures. However, the number of patients of our series is too low to draw any conclusion about the frequency of complications, which is a main limitation of this study. It is therefore also not possible to determine if the rate of complications is different compared to patients who received shunts not equipped with on-off valves. However, this patient series still demonstrates the usefulness, in principle, of VP-shunts equipped with on-off valves for the intrathecal administration of chemotherapies in patients with a communicating hydrocephalus due to leptomeningeal metastases.\n\nFour out of six patients in our cohort finally did not receive an intraventricular chemotherapy because they developed a nodular distribution pattern of leptomeningeal metastases or declined rapidly. This considerable high proportion was to be expected due to the dismal prognosis of leptomeningeal metastases in most malignancies, with a median survival of only several weeks. The survival times recorded here (median PFS of 8.5 weeks and median OS of 13.5 weeks) are in accordance with the data documented in the literature [28,29,30,31,32].\n\nWe are currently performing a phase I clinical trial testing the safety and tolerability of NK-92 cells ectopically expressing a chimeric antigen receptor (CAR) targeting HER2 in patients with recurring HER2 positive GB (CAR2BRAIN study) [33,34]. These CAR-NK cells are injected into the resection wall during relapse surgery. In an escalation cohort, these cells will be subsequently repeatedly injected through a conventional Rickham reservoir into the resection cavity. An intraventricular injection of the CAR-NK cells is not planned as part of the study. However, an intraventricular injection of CAR-NK cells may be an option for patients with leptomeningeal metastases and communicating hydrocephalus. Brown et al. have shown an impressive effect of intraventricular application of CAR-T cells targeted against IL13Rα2 in a patient suffering from a GB and leptomeningeal metastases. Several leptomeningeal metastases of the cerebrum and the spine regressed [21]. To avoid systemic toxicity as far as possible, an intraperitoneal injection of CAR-NK cells should be ruled out. A VP shunt equipped with a reservoir function and an on-off valve should therefore be an appropriate solution for the intraventricular application of cellular immunotherapeutics in patients with a communicating hydrocephalus due to leptomeningeal metastases.\n\n4. Patients and Methods\nWe report on six consecutive adult patients who had a VP shunt with an on-off valve implanted at the Department of Neurosurgery at the Goethe University Hospital between April 2008 and July 2017. All patients received an Aeskulap-Miethke proGAV® shunt (FV435T) with an additional Integra® on-off flushing reservoir (NL8500150) positioned in the proximal leg of the shunt system (Figure 4). Similarly to the on-off shunts reported by Lin et al. [11], these shunts were composed of a reservoir connected in series with an on-off valve, a programmable differential pressure unit, and a distal peritoneal shunt. However, our shunt systems were additionally equipped with a control reservoir to allow for manually checking if the shunt system is passable as well as a gravitational unit.\n\nFirst, we screened our database for all adult patients (at least 18 years old) with brain metastases, leptomeningeal metastases, or a primary brain tumor who had a VP shunt implanted. We excluded pediatric patients from our analysis because they had received a different shunt system. Furthermore, pediatric patients typically received their VP shunt in a different therapeutic situation shortly after initial diagnosis of pediatric brain tumors to allow for the intrathecal application of intrathecal chemotherapies as part of combination chemotherapy schemes.\n\nThen, we singled out six patients—from the 126 patients who fulfilled these criteria—whose shunt was equipped with an on-off valve. We analyzed the patient records for complications and the amount of intrathecal chemotherapies applied. All six patients suffered from a communicating hydrocephalus caused by leptomeningeal metastases of a systemic malignancy (Table 3). All patients had a diffuse subtype of leptomeningeal metastases without nodular leptomeningeal contrast enhancement at the time of shunt implantation. In all patients, the diagnosis of leptomeningeal metastases was established by CSF cytology. The duration of the implantation procedure was extracted from the surgical record. The possible significance in reduction of the duration of the implantation procedure in consecutive patients was calculated with the simple linear regression model.\n\nOur institutional review board approved this retrospective study, and all patients or their legal guardian gave their written consent for scientific work with clinical data, including radiological imaging (ethics committee at the University Hospital; reference number 04/09-SNO-03-2018).\n\n5. Conclusions\nVentriculoperitoneal shunts equipped with a valve to switch the shunt function on and off are a useful and reliable tool for the intraventricular administration of therapeutics in patients suffering from a hydrocephalus due to diffuse leptomeningeal metastases. These shunts may also be used for the intraventricular application of cellular immunotherapeutics.\n\nAuthor Contributions\nM.C.B., M.W., K.F., P.N.H., O.B., J.P.S., and C.S. planned and carried out the entire work; M.C.B. and C.S. drafted the manuscript; M.C.B., M.W., K.F., P.N.H., O.B., J.P.S., and C.S. reviewed and analyzed the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Duration of the shunt implantation procedure of consecutive patients as measured by the time interval from skin incision until skin suture.\n\nFigure 2 Shunt leakage in patient 6. This patient developed severe headaches immediately after the first intraventricular injection of thiotepa. The ventricles were promptly filled with the iodinated contrast enhancer after injection through the shunt catheter (black arrow). However, we detected a shunt leakage shortly after the entry point of the shunt catheter in the brain (white arrow). The hypodense area over the left hemisphere (white asterisks) is a pre-existing chronic subdural hematoma.\n\nFigure 3 Progression-free survival (PFS) and overall survival (OS) after shunt implantation.\n\nFigure 4 Radiography immediately after shunt implantation in patient 1 and scheme depicting the arrangement of the shunt components. 1 = proximal ventricular catheter; 2 = Rickham reservoir; 3a = on-off valve; 3b = button of the on-off valve; 4 = control reservoir; 5 = programmable differential pressure unit; 6 = gravitational unit; 7 = distal peritoneal catheter.\n\njcm-07-00216-t001_Table 1Table 1 Intrathecal chemotherapy.\n\nPat. No.\tIntrathecal Chemotherapy Applied\tReasons for Omitting Intrathecal Chemotherapy\tComplications\tNumber of Intraventricular Injections\t\n1\tNone\tNodular type of meningeal metastases\tNone\t0\t\n2\tNone\tNodular type of meningeal metastases\tNone\t0\t\n3\tNone\tclinical deterioration\tNone\t0\t\n4\tMTX, thiotepa\t-\tNone\t9 MTX \n17 thiotepa\t\n5\tNone\tnodular type of meningeal metastases\tNone\t0\t\n6\tThiotepa\t-\tShunt leakage\t1\t\nMTX = methotrexate; Pat. No. = patient number.\n\njcm-07-00216-t002_Table 2Table 2 Progression-free and overall survival.\n\nPat. No.\tPFS (Weeks)\tOS (Weeks)\t\n1\t7\t12\t\n2\t10\t11\t\n3\t3\t9\t\n4\t34\t116\t\n5\t6\t15\t\n6\t13\t17\t\nOS = overall survival after shunt implantation; PFS = progression-free survival after shunt implantation.\n\njcm-07-00216-t003_Table 3Table 3 Patient characteristics.\n\nPat. No.\tAge at Shunt Implantation\tSex\tUnderlying Disease\t\n1\t33 years\tF\tNSCLC\t\n2\t50 years\tF\tbreast cancer\t\n3\t57 years\tM\ttransitional cell carcinoma\t\n4\t60 years\tF\tNSCLC\t\n5\t63 years\tF\tbreast cancer\t\n6\t70 years\tM\tprostate cancer\t\nF = female; M = male; NSCLC = non-small-cell lung cancer; Pat. No. = patient number.\n==== Refs\nReferences\n1. Le Rhun E. Weller M. Brandsma D. Van den Bent M. de Azambuja E. Henriksson R. Boulanger T. Peters S. Watts C. Wick W. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours Ann. Oncol. 2017 28 iv84 iv99 10.1093/annonc/mdx221 28881917 \n2. Phuphanich S. Maria B. Braeckman R. Chamberlain M. A pharmacokinetic study of intra-CSF administered encapsulated cytarabine (DepoCyt) for the treatment of neoplastic meningitis in patients with leukemia, lymphoma, or solid tumors as part of a phase III study J. 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"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "7(8)",
"journal": "Journal of clinical medicine",
"keywords": "hydrocephalus; intraventricular chemotherapy; leptomeningeal metastases; ventriculoperitoneal shunt",
"medline_ta": "J Clin Med",
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"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30110924",
"pubdate": "2018-08-14",
"publication_types": "D016428:Journal Article",
"references": "20151421;8229133;15337619;25287959;28178712;28879551;16941075;17881969;16769420;10023723;28029927;18708343;10728905;23422833;23456656;26640245;20679917;25225619;27826086;10917346;7661730;28718815;22487060;29307353;15908671;26059190;21865399;10589750;19015650;288969;14607296;21721878;9347977;28881917",
"title": "Ventriculoperitoneal Shunts Equipped with On-Off Valves for Intraventricular Therapies in Patients with Communicating Hydrocephalus due to Leptomeningeal Metastases.",
"title_normalized": "ventriculoperitoneal shunts equipped with on off valves for intraventricular therapies in patients with communicating hydrocephalus due to leptomeningeal metastases"
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"abstract": "Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS).\n\n\n\nA 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably.\n\n\n\nThis is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity.",
"affiliations": "a Department of Neurology , Chosun University Hospital , Gwang-ju , South Korea.;b Department of Internal Medicine , Chonbuk National University Hospital , Jeonju , South Korea.;c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea.;c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea.;c Department of Neurology , Chonbuk National University Hospital , Jeonju , South Korea.",
"authors": "Kang|Hyun Goo|HG|;Park|Sung Kwang|SK|;Wang|Su Jeong|SJ|;Oh|Sun-Young|SY|;Ryu|Han Uk|HU|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1375511",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Cyclosporine; neurotoxicity; opsoclonus-myoclonus syndrome",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D053578:Opsoclonus-Myoclonus Syndrome",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "373-376",
"pmc": null,
"pmid": "28905654",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opsoclonus-myoclonus syndrome following long-term use of cyclosporine.",
"title_normalized": "opsoclonus myoclonus syndrome following long term use of cyclosporine"
} | [
{
"companynumb": "KR-MAYNE PHARMA-2017MYN001809",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "Statins are one of the most commonly used medications to lower cholesterol and have been known to cause various side effects including myalgias, myopathies, and rhabdomyolysis. Statin-induced necrotizing autoimmune myopathy (SINAM), a subtype of inflammatory myopathy, is an exceedingly rare but severe side effect of statin use that manifests as progressive muscle weakness. We describe a rapidly progressive case of SINAM in a 66-year-old Haitian female who developed debilitating symptoms after one month of statin use. Despite aggressive treatment with steroids and immunosuppressants, she failed to regain muscle strength and functional status, and remains on therapy. Given the widespread use of statins, it is important for clinicians to be aware of this condition and its presenting symptoms in order to initiate prompt treatment.",
"affiliations": "Internal Medicine, Kings County Hospital Center, Brooklyn, USA.;Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA.;Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA.;Internal Medicine, Kings County Hospital Center, Brooklyn, USA.",
"authors": "Ahmed|Sundus|S|;Capric|Violeta|V|;Khan|Muhammad|M|;Koneru|Prabash|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.7021",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7021\nInternal Medicine\nAllergy/Immunology\nRheumatology\nA Rapidly Progressive Case of Statin-induced Necrotizing Autoimmune Myopathy\nMuacevic Alexander Adler John R Ahmed Sundus 1 Capric Violeta 2 Khan Muhammad 2 Koneru Prabash 1 \n1 \nInternal Medicine, Kings County Hospital Center, Brooklyn, USA \n\n2 \nInternal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA \n\nPrabash Koneru prabash.koneru@nychhc.org\n17 2 2020 \n2 2020 \n12 2 e702120 1 2020 16 2 2020 Copyright © 2020, Ahmed et al.2020Ahmed et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/27186-a-rapidly-progressive-case-of-statin-induced-necrotizing-autoimmune-myopathyStatins are one of the most commonly used medications to lower cholesterol and have been known to cause various side effects including myalgias, myopathies, and rhabdomyolysis. Statin-induced necrotizing autoimmune myopathy (SINAM), a subtype of inflammatory myopathy, is an exceedingly rare but severe side effect of statin use that manifests as progressive muscle weakness. We describe a rapidly progressive case of SINAM in a 66-year-old Haitian female who developed debilitating symptoms after one month of statin use. Despite aggressive treatment with steroids and immunosuppressants, she failed to regain muscle strength and functional status, and remains on therapy. Given the widespread use of statins, it is important for clinicians to be aware of this condition and its presenting symptoms in order to initiate prompt treatment. \n\nstatinmyopathystatin-induced necrotizing autoimmune myopathyanti-hmgcrproximal muscle weaknessrheumatologyThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nStatin-induced necrotizing autoimmune myopathy (SINAM) is a rare type of inflammatory myopathy characterized by widespread muscle necrosis and antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis that is also the site of statin inhibition. It typically presents with proximal muscle weakness and an elevated creatine kinase (CK), findings that are also common in other autoimmune myopathies. Diagnosis thus requires a high index of suspicion and is especially likely when discontinuation of the statin leads to no improvement in symptoms. We present a case of SINAM in a patient who developed debilitating symptoms one month after initiating atorvastatin therapy.\n\nCase presentation\nA 66-year-old Haitian female with a history of diabetes mellitus and sickle cell trait presented with one week of proximal muscle weakness and myalgias (most prominent in the upper arms and legs) after having started atorvastatin 40 mg one month prior (indicated for hyperlipidemia in the setting of diabetes). Physical exam showed muscle strength of 5/5 in all extremities and normal gait; however, pain was reproducible on palpation of the proximal muscles in both the upper and lower extremities. No obvious joint swelling or tenderness was found, and vitals were within normal limits. Laboratory tests were significant for an elevated CK of 16,252 U/L (N: 25-170 U/L), aspartate aminotransferase (AST) of 551 (N: 10-40 U/L), alanine aminotransferase (ALT) of 602 (N: 10-45 U/L), and 2+ hemoglobin (HgB) without red blood cells (RBCs) on urinalysis (i.e. myoglobinuria). The patient was suspected to have rhabdomyolysis, and the treatment was initiated with aggressive fluid hydration and discontinuation of the statin. She was discharged three days later upon downtrending of her CK.\n\nThe patient presented again two weeks later with rapidly progressing proximal muscle weakness. She endorsed difficulty standing from a seated position, ambulating, and holding her head up without support, and a new-onset dysphagia to both solids and liquids. Physical exam was significant for diminished muscle strength of 3/5 in the proximal muscles and 4/5 in the distal muscles bilaterally in both the upper and lower extremities, and gait was noted to be wide based and cautious. Laboratory tests showed an increasingly elevated CK of 18,310 U/L (N: 25-170 U/L), an AST of 709 (N: 10-40 U/L), an ALT of 897 (N: 10-45 U/L), an elevated C-reactive protein of 56 mg/L (N: <3 mg/L), and an elevated troponin of 0.733 ng/mL (N: <0.4 ng/mL, without electrocardiographic changes or chest pain). Urinalysis was significant for 3+ protein and Hgb without RBCs. Thyroid function tests were within normal limits, and HIV testing was negative. The patient was admitted for an inability to ambulate and myositis of unknown etiology, and aggressive fluid hydration was provided. Additional laboratory studies were performed to rule out autoimmune myositis, and the patient underwent a bedside ultrasound which showed diffuse edema in the rectus femoris muscle. Muscle biopsy of this site showed widespread myofiber necrosis, and an electromyography was significant for irritative myopathy. Laboratory studies showed negative antinuclear antibody (ANA) and anti-Jo-1 antibodies and strongly positive anti-HMGCR antibodies at >200 (N: 0-19), after which a diagnosis of SINAM was made.\n\nTreatment was initiated with methylprednisolone 1 g/day (tapered to oral prednisone 40 mg/day over one week), which caused a rapid decline in the patient’s CK but no improvement in muscle strength. Barium esophagram and videofluoroscopy were performed due to worsening symptoms and showed that the patient had severe esophageal dysmotility, at which point dietary modifications were provided. Due to a lack of improvement, the patient then received a five-day course of intravenous immunoglobulin (IVIG). Muscle strength and functional status continued to decline, requiring nasogastric tube for feeds. The patient was transferred to the intensive care unit for close monitoring and impending respiratory failure. Due to poor response to therapy, the patient underwent five days of plasma exchange, rituximab infusion, and azathioprine 50 mg/day. Despite her CK decreasing to 415 U/L, no improvement was seen in muscle strength. The patient was discharged on azathioprine 150 mg/day, tacrolimus 4 mg/day, and prednisone 5 mg/day after a total seven-week hospital stay.\n\nDiscussion\nSince their introduction in 1982, statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have become one of the most commonly prescribed medications worldwide [1]. Deemed the only lipid-lowering agents causing a significant decrease in mortality from cardiovascular disease by the American College of Cardiology/American Heart Association Blooddown Cholesterol Treatment Task Force, statins are currently recommended for an estimated 56 million U.S. adults (almost 50% of the total population) [2,3].\n\nAlthough generally well tolerated, statins have been associated with a number of skeletal muscle-related side effects including self-limiting myalgias, symptomatic myopathy, and rhabdomyolysis [4]. Interestingly, Caribbean and Black Africans were found to have the highest risk of myopathy compared to other races [5].\n\nSINAM is an extremely rare and severe complication of statin use that presents as rapidly progressing symmetrical proximal muscle weakness and dysphagia with significantly elevated serum CK levels (usually >3,000 U/L) that does not resolve with discontinuation of the drug [6]. Biopsy results typically show necrotic and regenerating myofibers with minimal or no inflammatory infiltrates [7]. SINAM is known to involve the development of autoantibodies against HMGCR (first identified in 2010), which are used to distinguish it from other causes of necrotizing autoimmune myopathy [8]. HMGCR is the rate-limiting enzyme in cholesterol synthesis and is also the target site of statin inhibition; it is known to have increased levels in muscle cells exposed to statins [9]. Although the pathophysiology remains unclear, multiple immune processes are believed to contribute. There is also believed to be a genetic predisposition to the condition, suggested by the increase incidence of DRB1*11:01 in patients with positive anti-HMGCR antibody [10]. Although most cases reported have been due to atorvastatin (as opposed to other statins), an association has not been established [11]. \n\nA number of similar cases have been reported in recent years. Often times, the presenting symptoms mimicked other more common autoimmune myopathies such as polymyositis [11]. A systematic literature review of 100 SINAM cases by Nazir et al. found that the mean duration of statin use prior to the onset of myopathy symptoms was 40.48 months, which is much longer than our patient’s presentation after only one month of use [12]. Treatment outcomes for SINAM patients were favorable, with 91% of patients having a complete resolution of symptoms. However, methods of treatment varied greatly. Remission was induced by steroids alone in only 8.82% of the cases; most patients required azathioprine, IVIG, or plasmapheresis. The majority of patients (83.82%) required two or more immunosuppressants. In comparison to these studies, our patient had a protracted course of illness despite early detection in atorvastatin course, and showed no significant improvement despite a wide array of treatments attempted.\n\nConclusions\nSINAM is a recently described subset of myopathy and severe potential side effect of statin use that should be suspected in patients who develop persistent progressive muscle weakness and CK elevation despite discontinuation of the drug. Due to the similarity of its presentation to other causes of inflammatory myopathy and rhabdomyolysis, SINAM is often difficult to diagnose. It is important for clinicians to be aware of this condition and its presenting symptoms. Appropriate antibody testing including anti-HMGCR and muscle biopsy should be undertaken in suspected patients to avoid a misdiagnosis and delay in treatment onset. Further research is needed to better elucidate optimal management of this rare condition.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 A historical perspective on the discovery of statins Proc Jpn Acad Ser B Phys Biol Sci Endo A 484 493 86 2010 \n2 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol Stone NJ Robinson JG Lichtenstein AH 2889 2934 63 2014 24239923 \n3 Application of new cholesterol guidelines to a population-based sample\n\n N Engl J Med Pencina MJ Navar-Boggan AM D’Agostino RB 1422 1431 370 2014 24645848 \n4 Statin-induced myopathies Pharmacol Rep Tomaszewski M Stêpieñ KM Tomaszewska J Czuczwar SJ 859 866 63 2011 22001973 \n5 Individualising the risks of statins in men and women in England and Wales: population-based cohort study Heart Hippisley-Cox J Coupland C 939 947 96 2010 20489220 \n6 Statin-induced necrotizing myositis: a discrete autoimmune entity within the “statin-induced myopathy spectrum” Autoimmun Rev Hamann PDH Cooper RG McHugh NJ Chinoy H 1177 1181 12 2013 23851103 \n7 Clinical features and treatment outcomes of necrotizing autoimmune myopathy JAMA Neurol Kassardjian CD Lennon VA Alfugham NB Mahler M Milone M 996 1003 72 2015 26192196 \n8 A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy Arthritis Rheumatol Christopher-Stine L Casciola-Rosen LA Hong G Chung T Corse AM Mammen AL 2757 2766 62 2010 \n9 Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells J Atheroscler Thromb Morikawa S Umetani M Nakagawa S 138 144 7 2000 11480454 \n10 Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy Arthritis Care Res (Hoboken) Mammen AL Gaudet D Brisson D 1233 1237 64 2012 22422616 \n11 A case of atorvastatin-associated necrotizing autoimmune myopathy, mimicking idiopathic polymyositis Case Rep Rheumatol 12 2019 Dixit A Abrudescu A 2018 https://new.hindawi.com/journals/crirh/2018/5931046/ \n12 Statin-associated autoimmune myopathy: a systematic review of 100 cases J Clin Rheumatol Nazir S Lohani S Tachamo N Poudel D Donato A 149 154 23 2017 28277343\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(2)",
"journal": "Cureus",
"keywords": "anti-hmgcr; myopathy; proximal muscle weakness; rheumatology; statin; statin-induced necrotizing autoimmune myopathy",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e7021",
"pmc": null,
"pmid": "32211257",
"pubdate": "2020-02-17",
"publication_types": "D002363:Case Reports",
"references": "26192196;30026996;22422616;22001973;28277343;11480454;20496415;20489220;23851103;20467214;24239923;24645848",
"title": "A Rapidly Progressive Case of Statin-induced Necrotizing Autoimmune Myopathy.",
"title_normalized": "a rapidly progressive case of statin induced necrotizing autoimmune myopathy"
} | [
{
"companynumb": "US-PFIZER INC-2020094124",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN CALCIUM"
},
"drugadditional": "2"... |
{
"abstract": "Bardet-Biedl Syndrome (BBS) is a rare multi-systemic disease with autosomal recessive transmission. BBS was at first considered to be homogeneous as for its genetics, but subsequent studies have shown an extensive gene variability. Currently, 21 genes (BBS1-21) present on different chromosomes have been mapped: these genes are responsible for BBS phenotypes and they show a great heterogeneity of mutations.The most common genes are BBS1 (locus 11q13) and BBS10.We show here the case of a 50 year old patient with BBS. Medical History: retinitis pigmentosa at 4 years of age evolved to complete blindness, generalized epilepsy crises, poly-syndactyly, left-hand malformation. In April 1986 developed an epileptic episode: on that occasion Chronic Kidney Failure (CKF) diagnosis and starting of haemodialysis. In 1989, hospitalization for epileptic seizures. In 2009 the patient underwent kidney transplantation from deceased donor. Immunosuppressive initial protocol: Basiliximab, Azathioprine, Tacrolimus, Steroid, and Tacrolimus, Azathioprine, Steroid at hospital discharge. Post-operative care complicated by respiratory failure with mechanical ventilation assistance. During hospitalization, the neurological picture remained stable. At hospital discharge Creatinine 1.8 mg/dl. Subsequently, immunosuppressant were gradually tapered until monotherapy with Tacrolimus. At present the patient's conditions appear to be good, renal function has remained substantially stable with Creatinine between 1.4-1.5 mg/dl and glomerular filtration rate (GFR) estimated at 39-42 mL/min/1.73 m ² according to MDRD study Equation. This case shows the possibility to successfully manage a BBS-affected uremic patient, despite the complexity of the pathology and the aggravating factor of extreme rarity in diagnostic pathway.",
"affiliations": "S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.;S.C. Nefrologia e Dialisi ASLCN1, Ospedali di Ceva, Mondovì, Savigliano e Saluzzo.",
"authors": "Tattoli|Fabio|F|;Falconi|Daniela|D|;Bottaro|Chiara|C|;Gherzi|Maurizio|M|;Marazzi|Federico|F|;Marengo|Marita|M|;Serra|Ilaria|I|;Tamagnone|Michela|M|;Formica|Marco|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D003404:Creatinine; D016559:Tacrolimus",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "35(1)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": " Bardet-Biedl syndrome (BBS); renal failure; renal transplantation",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D020788:Bardet-Biedl Syndrome; D003404:Creatinine; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016559:Tacrolimus",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29390243",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Bardet-Biedl syndrome and Kidney failure: a case report.",
"title_normalized": "bardet biedl syndrome and kidney failure a case report"
} | [
{
"companynumb": "IT-ASTELLAS-2018US006820",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE SODIUM"
},
"drugadditional": "1"... |
{
"abstract": "Patients with sickle cell disease (SCD) experience initial and recurrent venous thromboembolism (VTE) more commonly and at a younger age than the general population, and it confers a higher mortality for patients with SCD. However, limited evidence is available to guide anticoagulant use for VTE treatment in this population. The primary objective of this study is to characterize the effectiveness and safety of direct oral anticoagulants (DOAC) and warfarin for VTE treatment among patients with SCD. This single-center retrospective study includes adult patients with SCD who were diagnosed with VTE. Data was obtained from review of electronic health records for the 6 months after VTE diagnosis. Among the 22 patients treated initially with a DOAC, 6 (27%) developed recurrent VTE, none experienced major bleeding, and 3 (14%) experienced clinically relevant non-major bleeding (CRNMB). Similarly, of 15 patients initially treated with warfarin, 3 (20%) developed a recurrent VTE, 1 (7%) experienced major bleeding, and 2 (13%) experienced CRNMB. Twelve patients received more than one oral anticoagulant during the study period, most commonly due to a recurrent VTE, concern for non-adherence, or subtherapeutic INR. Overall, the incidence of VTE recurrence and bleeding events were similar between groups, but occurred at a higher rate than those found in major clinical trials of anticoagulant agents. Prescribers should continue to individualize therapeutic decision-making regarding oral anticoagulant therapy for VTE treatment for individuals with SCD based on patient-specific factors and anticipated ability to adhere to the drug regimen or required monitoring.",
"affiliations": "Samford University McWhorter School of Pharmacy, 800 Lakeshore Drive, Birmingham, AL, 35229, USA. mrober19@samford.edu.;University of Utah Health Care, Salt Lake City, UT, 84132, USA.;Medical University of South Carolina, Charleston, SC, 29425, USA.;Medical University of South Carolina, Charleston, SC, 29425, USA.;Medical University of South Carolina, Charleston, SC, 29425, USA.;Medical University of South Carolina, Charleston, SC, 29425, USA.",
"authors": "Roberts|Megan Z|MZ|http://orcid.org/0000-0002-8662-8557;Gaskill|G Eric|GE|;Kanter-Washko|Julie|J|;Kyle|T Rogers|TR|;Jones|Brittany C|BC|;Bohm|Nicole M|NM|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-018-1637-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "45(4)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Anticoagulants; Factor Xa inhibitors; Sickle cell; Venous thromboembolism; Warfarin",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D000925:Anticoagulants; D006470:Hemorrhage; D006801:Humans; D055118:Medication Adherence; D057285:Precision Medicine; D012189:Retrospective Studies; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D014859:Warfarin",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "512-515",
"pmc": null,
"pmid": "29556958",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "27881693;8470047;27943026;7557864;7647016;27432042;23593937;10861320;21922530;21328441;17000225;23582935;24449213;26867832;28271315;23435703;21128814;22417249;23808982;28595692;26597668;27299806;27189014;18574265;22449293;26238769;26836899;23627575",
"title": "Effectiveness and safety of oral anticoagulants in patients with sickle cell disease and venous thromboembolism: a retrospective cohort study.",
"title_normalized": "effectiveness and safety of oral anticoagulants in patients with sickle cell disease and venous thromboembolism a retrospective cohort study"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP003799",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Familial chylomicronemia syndrome (FCS) is characterized by severe fasting hypertriglyceridemia, abdominal pain, and recurrent acute pancreatitis. Available triglyceride-lowering drugs are insufficient to avoid pancreatitis. Therefore, there is a significant unmet medical need for effective triglyceride-lowering drugs for patients with FCS.\n\n\n\nWe report the second case of a patient with FCS and recurrent pancreatitis treated with lomitapide. Lomitapide treatment resulted in a reduction of fasting TG levels from 2897 mg/dL (32.71 mmol/L) to an average of 954 mg/dL (10.77 mmol/L) on the 30 mg lomitapide equating to a 67% reduction from baseline. After 26 months of lomitapide treatment, histological activity score for hepatic fibrosis was stable although liver biopsy showed a marked increase of liver steatosis and mild perivenular and perisinusoidal fibrosis.\n\n\n\nLomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis. A longer follow-up is necessary to evaluate long-term risk of progression toward severe stages of liver fibrosis. A prospective clinical trial may identify which subgroup of FCS patients would benefit from lomitapide treatment in the absence of significant liver adverse effects.",
"affiliations": "Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy. abaldassare.cefalu@unipa.it.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy.;Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza \"G. D'Alessandro\" (PROMISE), Università degli Studi di Palermo, Via del Vespro 129, 90127, Palermo, Italy. maurizio.averna@unipa.it.",
"authors": "Cefalù|Angelo B|AB|http://orcid.org/0000-0003-1259-8284;Giammanco|Antonina|A|;Noto|Davide|D|;Spina|Rossella|R|;Cabibi|Daniela|D|;Barbagallo|Carlo M|CM|;Averna|Maurizio|M|",
"chemical_list": "C473731:BMS201038; D001562:Benzimidazoles",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-020-02506-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-008X",
"issue": "71(2)",
"journal": "Endocrine",
"keywords": "Acute pancreatitis; Familial chylomicronaemia syndrome; Fatty liver; Lomitapide",
"medline_ta": "Endocrine",
"mesh_terms": "D000208:Acute Disease; D001562:Benzimidazoles; D006801:Humans; D008072:Hyperlipoproteinemia Type I; D010195:Pancreatitis; D011446:Prospective Studies",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "344-350",
"pmc": null,
"pmid": "33006726",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome.",
"title_normalized": "effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1020577",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOCONEXENT"
},
"drugadditional": null,
... |
{
"abstract": "Pseudomyxoma Peritonei, a massive mucinous peritoneal collection due to a rare epithelial neoplasm, can be effectively treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC). A 43-year-old female, previously treated for mucinous ovarian carcinoma with CRS-HIPEC, and total abdominal hysterectomy and bilateral salpingo-oophorectomy, presented with new-onset abdominal distension and early satiety. She was diagnosed with Pseudomyxoma Peritonei. After 48 hours of treatment with CRS-HIPEC, she presented haemodynamically unstable with acute chest pain. Electrocardiogram showed broad complex tachycardia with ST depression in leads V3-6. Severe systolic dysfunction with Ejection Fraction (EF) of 20% along with severe pulmonary hypertension, visualized on Echocardiography. A diagnosis of Stress-induced Cardiomyopathy was established using InterTAK Diagnostic Score. Patients with CRS-HIPEC have presented with Stress-induced Cardiomyopathy. However, no specific relation between the two has been established. This case report discusses Stress-induced Cardiomyopathy as a complication of CRS-HIPEC.",
"affiliations": "Department of Anesthesia, Shifa International Hospital, Islamabad, Pakistan.;Department of Anesthesia, Shifa International Hospital, Islamabad, Pakistan.;MBBS 5th Year Student, Aga Khan University Hospital, Karachi, Pakistan.",
"authors": "Naved|Saad Ahmed|SA|;Parpia|Sadiq Shoukat|SS|;Ali|Huma Shoukat|HS|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.5455/JPMA.05-749",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-9982",
"issue": "71(6)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": " Stress-induced; cardiomyopathy; Cytoreduction; Chemotherapy\n\n",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D000084262:Hyperthermic Intraperitoneal Chemotherapy; D010534:Peritoneal Neoplasms; D011553:Pseudomyxoma Peritonei",
"nlm_unique_id": "7501162",
"other_id": null,
"pages": "1686-1688",
"pmc": null,
"pmid": "34111099",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Development of stress-induced cardiomyopathy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.",
"title_normalized": "development of stress induced cardiomyopathy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy"
} | [
{
"companynumb": "PK-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-316637",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drug... |
{
"abstract": "OBJECTIVE\nAt our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material.\n\n\nMETHODS\nA retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT).\n\n\nRESULTS\nOverall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non-HDT group (98% vs 79%, P < 0.001). Progression-free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non-HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD-treated patients in the entire VRD group (95% vs 89%, P = 0.048).\n\n\nCONCLUSIONS\nUpfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT.",
"affiliations": "Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Hematology Center, Karolinska University Hospital, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Uttervall|Katarina|K|;Borg Bruchfeld|Johanna|J|https://orcid.org/0000-0001-7006-311X;Gran|Charlotte|C|https://orcid.org/0000-0002-6069-6615;Wålinder|Göran|G|;Månsson|Robert|R|;Lund|Johan|J|;Gahrton|Gösta|G|;Alici|Evren|E|;Nahi|Hareth|H|",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide; D013713:Teniposide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13280",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "103(3)",
"journal": "European journal of haematology",
"keywords": "Multiple myeloma; autologous stem cell transplantation; immunomodulatory drugs; proteasome inhibitors",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013713:Teniposide; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "247-254",
"pmc": null,
"pmid": "31231833",
"pubdate": "2019-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Upfront bortezomib, lenalidomide, and dexamethasone compared to bortezomib, cyclophosphamide, and dexamethasone in multiple myeloma.",
"title_normalized": "upfront bortezomib lenalidomide and dexamethasone compared to bortezomib cyclophosphamide and dexamethasone in multiple myeloma"
} | [
{
"companynumb": "SE-CELGENEUS-SWE-20190701836",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The etiology of chronic back pain is often unknown but can include failed spinal surgery. Pain can often be of mixed type and it is important to evaluate pain mechanisms. Comorbid factors often contribute to pain chronicity. Multimodal treatment, including opioid rotation where indicated, may offer a successful management approach. Other rehabilitative procedures such as physiotherapy, exercise therapy, and good sleep hygiene may have a profound impact on patient quality of life. Spinal cord stimulation may be an effective option for some patients with failed spinal surgery syndrome. A case of severe low back pain after surgery in a 45-year-old man is presented to illustrate this.",
"affiliations": null,
"authors": "Rhodin|Annica|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2014.911796",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "28(2)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "back; pain; physical therapy; postlaminectomy syndrome; spinal cord stimulation; surgery",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000701:Analgesics, Opioid; D059350:Chronic Pain; D003131:Combined Modality Therapy; D005081:Exercise Therapy; D055111:Failed Back Surgery Syndrome; D006801:Humans; D017116:Low Back Pain; D008297:Male; D008875:Middle Aged; D026741:Physical Therapy Modalities; D011788:Quality of Life; D012720:Severity of Illness Index; D062187:Spinal Cord Stimulation",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "167-8; discussion 168-9",
"pmc": null,
"pmid": "24801975",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of severe low back pain after surgery.",
"title_normalized": "a case of severe low back pain after surgery"
} | [
{
"companynumb": "SE-MYLANLABS-2020M1020811",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "A case of a 19-year-old female with low-risk acute myeloid leukemia is presented who was diagnosed with idiopathic hyperammonemic encephalopathy following the development of abrupt neurologic decline, respiratory alkalosis, and elevated plasma ammonia levels of unknown etiology. Delayed symptom recognition of this exceedingly rare condition contributes to the often fatal outcomes of idiopathic hyperammonemic encephalopathy. As illustrated by this case, prompt diagnosis and utilization of a variety of ammonia-modulating treatment modalities can result in remarkable clinical recovery. This case provides guidance to clinicians in counseling families about the possibility of neurologic recovery in similar clinical scenarios.",
"affiliations": "Department of Pediatrics, Texas Children's Cancer and Hematology Center.;Department of Molecular and Human Genetics.;Department of Radiology, Baylor College of Medicine.;Department of Pediatrics, Texas Children's Cancer and Hematology Center.",
"authors": "Mangum|Ross|R|;Soler-Alfonso|Claudia|C|;Birchansky|Sherri|S|;Stevens|Alexandra|A|",
"chemical_list": "D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D020160:Sodium Benzoate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001579",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000328:Adult; D001927:Brain Diseases; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D015470:Leukemia, Myeloid, Acute; D020258:Neurotoxicity Syndromes; D010654:Phenylbutyrates; D011379:Prognosis; D020160:Sodium Benzoate; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e452-e455",
"pmc": null,
"pmid": "31415019",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Survival and Neurologic Recovery After Prompt Diagnosis and Aggressive Management of Severe Idiopathic Hyperammonemic Encephalopathy in a Patient with Acute Myeloid Leukemia.",
"title_normalized": "survival and neurologic recovery after prompt diagnosis and aggressive management of severe idiopathic hyperammonemic encephalopathy in a patient with acute myeloid leukemia"
} | [
{
"companynumb": "US-MYLANLABS-2021M1010565",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPARAGINASE ERWINIA CHRYSANTHEMI"
},
"drugad... |
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