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"abstract": "The determination of human insulin or its synthetic analogues in post-mortem specimens represents a challenge for forensic toxicologists due to its proven instability in post-mortem blood. We present two cases of an insulin-induced hypoglycaemia. In the first case, ante-mortem material was available for the detection of an injection with human insulin. Human insulin was detected by immunopurification with magnetic beads and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses at a concentration of 5180 μU/ml. The molar ratio human insulin:C-peptide was 111. The second case describes a suicide by self-injection of Insulin lispro and determination of the drug after pre-extraction with methanol and immunopurification by LC-MS/MS at the injection site, in vitreous humour and organs. Apart from the well-known matrices--femoral blood and urine--the specimen vitreous humour and the injection site promise the best possibilities for a proof of insulin at autopsy. In addition to insulin analyses, the parameters C-peptide, proinsulin, glucose, lactate, and sulfonylureas should be measured in case of suspected fatal hypoglycaemia.",
"affiliations": "Institute of Forensic Medicine, University Hospital Bonn, Stiftsplatz 12, 53111, Bonn, Germany.",
"authors": "Hess|C|C|;Madea|B|B|;Daldrup|T|T|;Musshoff|F|F|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "England",
"delete": false,
"doi": "10.1002/dta.1500",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "5(9-10)",
"journal": "Drug testing and analysis",
"keywords": "LC-MS; hypoglycaemia; insulin; post mortem",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D001344:Autopsy; D002853:Chromatography, Liquid; D017809:Fatal Outcome; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007328:Insulin; D008875:Middle Aged",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "802-7",
"pmc": null,
"pmid": "23847093",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Determination of hypoglycaemia induced by insulin or its synthetic analogues post mortem.",
"title_normalized": "determination of hypoglycaemia induced by insulin or its synthetic analogues post mortem"
} | [
{
"companynumb": "DE-NAPPMUNDI-GBR-2014-0018915",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": nu... |
{
"abstract": "Neuroendocrine differentiation of prostate cancer can result in ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) and Cushing syndrome. The aim of this report is to highlight this unusual mechanism of hypercortisolism and its management.\nWe report a 73-year-old patient with a history of prostate adenocarcinoma who presented with severe weakness, hyperglycemia, and hypokalemia caused by EAS.\nDiagnostic workup showed elevated 24-hour urine cortisol and ACTH levels consistent with EAS. Fluorodeoxyglucose positron emission tomography-computed tomography revealed a hypermetabolic mass in the prostate and metastatic lesions to the liver and bones. Liver biopsy was consistent with small cell carcinoma with positive immunostaining for ACTH. Pleural fluid analysis was consistent with high-grade neuroendocrine carcinoma. The patient underwent chemotherapy with carboplatin and etoposide. Hypercortisolism was treated with ketoconazole, metyrapone, mifepristone, and spironolactone. He suffered complications including opportunistic infections, deep venous thrombosis, and delirium. Given his poor prognosis and clinical decline, the patient opted for comfort measures only in a hospice facility.\nTreatment-related neuroendocrine differentiation of prostate cancer is an emerging entity that may be associated with paraneoplastic syndromes including EAS.",
"affiliations": null,
"authors": "Soundarrajan|Malini|M|;Zelada|Henry|H|;Fischer|Jean Victoria|JV|;Kopp|Peter|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2018-0429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "5(3)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e192-e196",
"pmc": null,
"pmid": "31967032",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11273885;28584167;8530609;20061271;25927031;26222757;24535589;16303835;30279116;16698415;27766686;15914534;6147188;18322802;27170243;18209859;16865726;12242726;15082200",
"title": "ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME DUE TO METASTATIC PROSTATE CANCER WITH NEUROENDOCRINE DIFFERENTIATION.",
"title_normalized": "ectopic adrenocorticotropic hormone syndrome due to metastatic prostate cancer with neuroendocrine differentiation"
} | [
{
"companynumb": "US-ACCORD-171588",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Pediatric use of second-generation antipsychotics, or neuroleptics, has increased over the past decade. Neuroleptic use can have significant and lasting adverse neurologic, metabolic, and cardiovascular effects. In the current literature, neuroleptic prescribing and monitoring is described in outpatient settings, with little description of inpatient pediatric practice. In this study, we are the first to explore prescribing and monitoring in inpatient pediatrics, highlighting similarities and differences in practice between pediatric medicine and psychiatry.\n\n\n\nThis retrospective study included patients <18 years of age who received a neuroleptic during inpatient hospitalization between September 2014 and March 2015, within either the pediatric inpatient medical or psychiatric setting. Data collected included sex, age, race, height, weight, length of stay, service providing care, details involving the neuroleptic(s) administered, comorbidities, lipid and glycemic monitoring, and results, monitoring for extrapyramidal symptoms, and mental health consultation.\n\n\n\nFactors associated with improved neuroleptic monitoring included longer length of stay and evidence of an adverse drug effect. Clearly specified indication for use was associated with improved neuroleptic monitoring. Although neuroleptic initiation during admission had improved indication documentation and monitoring practices compared with initiation before admission, a significant gap exists between inpatient psychiatry and medical settings in adverse drug effect monitoring, particularly extrapyramidal symptom monitoring and lipid collection.\n\n\n\nIn our study, we describe current practice in the use and monitoring of neuroleptics in inpatient pediatric medical and psychiatric settings. In this study, we suggest that the use of neuroleptics in inpatient pediatrics, particularly inpatient medical settings, is conducted with suboptimal monitoring and, at times, without clear documented indication.",
"affiliations": "University of Michigan College of Pharmacy, Department of Clinical Pharmacy, Ann Arbor, Michigan.;University of Michigan College of Pharmacy, Department of Clinical Pharmacy, Ann Arbor, Michigan; jkingsbu@med.umich.edu.;Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan; and.;Department of Psychiatry, and.",
"authors": "Le|Lan|L|;Bostwick|Jolene R|JR|;Andreasen|Arnold|A|;Malas|Nasuh|N|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1542/hpeds.2017-0129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2154-1671",
"issue": "8(7)",
"journal": "Hospital pediatrics",
"keywords": null,
"medline_ta": "Hosp Pediatr",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D002648:Child; D017723:Drug Utilization Review; D005260:Female; D019983:Guideline Adherence; D006801:Humans; D008297:Male; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D011618:Psychotic Disorders; D012189:Retrospective Studies",
"nlm_unique_id": "101585349",
"other_id": null,
"pages": "410-418",
"pmc": null,
"pmid": "29895596",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Neuroleptic Prescribing and Monitoring Practices in Pediatric Inpatient Medical and Psychiatric Settings.",
"title_normalized": "neuroleptic prescribing and monitoring practices in pediatric inpatient medical and psychiatric settings"
} | [
{
"companynumb": "US-HETERO CORPORATE-HET2018US00859",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": null,
... |
{
"abstract": "A 15-year-old boy suffering from a degenerative neurometabolic disorder was treated in a palliative home care unit. Opioid administered by continuous intravenous infusion gave excellent relief from headache, muscle pain and pain from renal calculi. He continued to complain of burning pain in response to tactile stimuli. A prior quantitative sensory test had shown changes in sensation. Intravenous adenosine (ADO) infusions were given weekly. After 5 weeks of infusions, there was no recurrence of pain between treatments. ADO infusions were continued for 7 months without any side effects or signs of tolerance to the drug. There are indications that ADO may play a role as a modulator of neuropathic and nociceptive pain. In this case with pronounced allodynia, our interpretation is that neuropathic mechanisms were responsible and that ADO infusions played an important role in controlling pain.",
"affiliations": "Sollentuna Palliative Home Care Team, PAH, Box 474, S-191 24 Sollentuna, Sweden.",
"authors": "Gyllenhammar|Eva|E|;Nordfors|Lars-Olof|LO|",
"chemical_list": "D000700:Analgesics; D000241:Adenosine",
"country": "United States",
"delete": false,
"doi": "10.1016/S0304-3959(01)00346-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-3959",
"issue": "94(1)",
"journal": "Pain",
"keywords": null,
"medline_ta": "Pain",
"mesh_terms": "D000241:Adenosine; D000293:Adolescent; D000700:Analgesics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008659:Metabolic Diseases; D010146:Pain",
"nlm_unique_id": "7508686",
"other_id": null,
"pages": "121-122",
"pmc": null,
"pmid": "11576751",
"pubdate": "2001-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic adenosine infusions alleviated neuropathic pain.",
"title_normalized": "systemic adenosine infusions alleviated neuropathic pain"
} | [
{
"companynumb": "SE-PFIZER INC-2020193427",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Introduction: Acute generalized exanthematous pustulosis (AGEP) is a rare adverse effect of clindamycin characterized by widespread papules and pustulosis 1 - 3 weeks of its use. Case description: We present a case of a 71-year-old woman diagnosed with AGEP after clindamycin use for a tooth infection. She had been started on empiric prednisone without benefit. She did not have any systemic involvement and had an unremarkable blood work . Her rash resolved completely in a month.",
"affiliations": "Department of Medicine, Reading Hospital, West Reading, PA, USA.;Department of Medicine, Reading Hospital, West Reading, PA, USA.;Department of Medicine, Trumbull Regional Medical Center, Warren, OH, USA.",
"authors": "Basnet|Sijan|S|0000-0002-8324-2827;Dhital|Rashmi|R|;Tharu|Biswaraj|B|0000-0003-4594-741X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2019.1601057",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectZJCHzjch20Journal of Community Hospital Internal Medicine Perspectives2000-9666Taylor & Francis 160105710.1080/20009666.2019.1601057Clinical ImagingAcute generalized exanthematous pustulosis: a rare side effect of clindamycin S. BASNET ET AL.JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVEShttp://orcid.org/0000-0002-8324-2827Basnet Sijan aDhital Rashmi ahttp://orcid.org/0000-0003-4594-741XTharu Biswaraj ba Department of Medicine, Reading Hospital, West Reading, PA, USAb Department of Medicine, Trumbull Regional Medical Center, Warren, OH, USACONTACT Sijan Basnet sijanbasnet@gmail.comDepartment of Internal Medicine, Reading Hospital, West Reading, PA19611, USA2019 19 6 2019 9 3 285 286 27 11 2018 25 3 2019 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.2019The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.ABSTRACT\nIntroduction: Acute generalized exanthematous pustulosis (AGEP) is a rare adverse effect of clindamycin characterized by widespread papules and pustulosis 1 – 3 weeks of its use.\n\nCase description: We present a case of a 71-year-old woman diagnosed with AGEP after clindamycin use for a tooth infection. She had been started on empiric prednisone without benefit. She did not have any systemic involvement and had an unremarkable blood work . Her rash resolved completely in a month.\n\nKEYWORDS\nAcute generalized exanthematous pustulosisclindamycinside effect\n==== Body\n1. Clinical description\nThe patient is a 71-year-old lady seen in primary care physician’s office for non-improvement of diffuse rash that started 2 days prior to completing a 10-day course of clindamycin for a tooth infection. Her rash had been present for 10 days on presentation. She noted erythematous papules and pustules that started on her neck and then quickly spread to her chest and arms over 2 days. They were slightly itchy. She had gone to an urgent care where she was prescribed an 8-day course of prednisone taper. On questioning, she mentioned that she had noted clearing of the rash from the neck region where it had first appeared. She had not noted any mucosal involvement. She did not have any fever or chills. She denied shortness of breath, wheezing or chest tightness. Her past medical history was significant for hypertension and hyperlipidemia. She did not have a known history of psoriasis or any other skin condition. Her home medications included hydrochlorothiazide 12.5 mg daily, meloxicam 15 mg daily, omeprazole 20 mg daily, simvastatin 20 mg nightly, and alprazolam 0.25 mg p.r.n. nightly. None of her home medications were new or had been recently changed and were continued during prednisone use. On examination, her temperature was 98.2 ºF, pulse 96 beats per minute, blood pressure 137/78 mm Hg, and respiratory rate 12 breaths per minute. The patient had a generalized papular rash that coalesced to form plaques on her arms and was studded with non-follicular pustules, along with skin desquamation (Figure 1). Superimposed bacterial skin infection was not noted. She did not have any cervical, axillary or inguinal lymphadenopathy. System examination was unremarkable. Given history of recent clindamycin use and presentation, acute generalized exanthematous pustulosis (AGEP) was suspected. The patient was reassured about the benign nature of the illness and recommended to complete the prednisone taper. She was advised to use fexofenadine as needed for itching. Her complete blood count was within normal range except for an elevated white count of 13.7 10E3/µL (reference range: 4.8–10.8 10E3/µL) with 76.2% (reference range: 37–75%) neutrophils related to prednisone use. Her liver function test was unremarkable. Skin biopsy was not done as it was most likely thought to be related to recent clindamycin use. The patient noted complete resolution of rash in a month on follow up.10.1080/20009666.2019.1601057-F0001Figure 1. Patient’s right arm demonstrating generalized papular rash, pustules along with skin desquamation.\n\n\n\n2. Teaching points\nClindamycin-associated AGEP should in suspected in patients presenting with erythema followed by papules and pustules within 1 −3 weeks of clindamycin use [1,2].\n\nAGEP is self-limited and treatment involves discontinuation of clindamycin and supportive therapy with corticosteroids, antihistamines or antibiotics [2].\n\n\n\nMultiple Choice Question\nA 60-year-old man presents to your clinic for a rash that started 1 week after completing a 7-day course of clindamycin for cellulitis. On examination, the patient has generalized erythematous papules and non-follicular pustules involving his face, hands, and trunk. Patient denies fever or chills. His complete blood count and liver function test are unremarkable. Which of the following is the most likely diagnosis?\n\nA. Contact dermatitis\n\nB. Acute generalized exanthematous pustulosis\n\nC. Fixed drug eruption\n\nD. Drug reaction with eosinophilia and systemic symptoms\n\nAnswer B: Acute generalized exanthematous pustulosis\n\nThe patient has a history of recent antibiotic use and diffuse rash comprising of papules and non-follicular pustules typical for acute generalized exanthematous pustulosis.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n[1] Croy C , Buehrle K , Austin Szwak J. Clindamycin-associated acute generalized exanthematous pustulosis . J Clin Pharm Ther . 2017 ;42 (4 ):499 –501 .28417476 \n[2] Smeets TJL , Jessurun N , Härmark L , et al \nClindamycin-induced acute generalised exanthematous pustulosis: five cases and a review of the literature . Neth J Med . 2016 ;74 (10 ):421 –428 .27966434\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2000-9666",
"issue": "9(3)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Acute generalized exanthematous pustulosis; clindamycin; side effect",
"medline_ta": "J Community Hosp Intern Med Perspect",
"mesh_terms": null,
"nlm_unique_id": "101601396",
"other_id": null,
"pages": "285-286",
"pmc": null,
"pmid": "31258877",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27966434;28417476",
"title": "Acute generalized exanthematous pustulosis: a rare side effect of clindamycin.",
"title_normalized": "acute generalized exanthematous pustulosis a rare side effect of clindamycin"
} | [
{
"companynumb": "US-PFIZER INC-2019290678",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Venlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.",
"affiliations": "Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.;Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan.",
"authors": "Miyahara|Yu|Y|;Funahashi|Hideki|H|;Haruta-Tsukamoto|Ayaka|A|;Hidaka|Hiroto|H|;Fujimoto|Takako|T|;Horinouchi|Akira|A|;Nishimori|Toshikazu|T|;Ishida|Yasushi|Y|https://orcid.org/0000-0002-7601-4906",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.5088",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.5088\nCCR35088\nCase Report\nCase Report\nTime course of effects of venlafaxine on migraine and generalized pruritus in a patient with depression\nMIYAHARA et al.\nMiyahara Yu 1\nFunahashi Hideki 1\nHaruta‐Tsukamoto Ayaka 1\nHidaka Hiroto 1\nFujimoto Takako 1\nHorinouchi Akira 1\nNishimori Toshikazu 1\nIshida Yasushi https://orcid.org/0000-0002-7601-4906\n1 ishiday@med.miyazaki-u.ac.jp\n\n1 Department of Psychiatry Faculty of Medicine University of Miyazaki Miyazaki city Japan\n* Correspondence\nYasushi Ishida, Department of Psychiatry, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki city, Miyazaki 889‐1692, Japan.\nEmail: ishiday@med.miyazaki-u.ac.jp\n\n16 11 2021\n11 2021\n9 11 10.1002/ccr3.v9.11 e0508829 10 2021\n23 8 2021\n31 10 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\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\nVenlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.\n\nVenlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.\n\ndepression\ngeneralized pruritus\nmigraine\nvenlafaxine\nsource-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:16.11.2021\nMiyahara Y , Funahashi H , Haruta‐Tsukamoto A , et al. Time course of effects of venlafaxine on migraine and generalized pruritus in a patient with depression. Clin Case Rep. 2021;9 :e05088. 10.1002/ccr3.5088\n\nFunding information\n\nNone\n==== Body\npmc1 INTRODUCTION\n\nA 37‐year‐old female patient developed with pruritus unresponsive to antihistamines, migraine and depression with insomnia, agitation, and anxiety. The daily administration of 37.5 mg of venlafaxine alleviated pruritus, migraine, and depression. Therefore, venlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.\n\nPain and pruritus are common presenting somatic symptoms, and depression is a common mental disorder. 1 , 2 , 3 Generalized pruritus has been defined as chronic pruritus without skin inflammation and is associated with endocrine diseases, hepatic diseases, renal failure, hematological diseases, and malignancies. 4 Migraine is a disabling paroxysmal neurovascular condition that is characterized by recurrent episodes of moderate to severe headache associated with physiological disruptions to neurological, gastrointestinal, and sensory functions, as well as mood changes. 5 Most cases of depression occur idiopathically, and the limited understanding of its etiology is reflected as a list of risk factors, such as stressful life events, endocrine abnormalities, cancer, and the side effects of drugs, among many others. 6 Pain/pruritus and depression frequently coexist. At least 50% of patients with chronic pain and pruritus are diagnosed with depression and/or anxiety. 2 , 7 Some psychotropic drugs exert their own analgesic and antipruritic effects. 4 , 8 These psychotic disorders affect the quality of life of patients, with disturbances in mood, sleep, and social relationships.\n\nRecommended treatments for generalized pruritus include emollients, systemic antihistamines, topical corticosteroids, phototherapy, nalfurafine, and selective serotonin reuptake inhibitors. 4 Sumatriptan, sodium valproate, topiramate, and antidepressant, such as venlafaxine, are recommended for the treatment of migraine, 9 , 10 and antidepressants are prescribed to treat depression. Therapeutic agents for generalized pruritus are limited because the pharmacological characteristics of drugs for generalized pruritus are poorly understood and limited information is currently available on the relationship between pain and/or pruritus and depression. A previous study reported the differential onset times of mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pruritus and depression. 11 Therefore, we herein investigated differences in the onset time of venlafaxine, an antidepressant belonging to a group of drugs called serotonin and noradrenaline reuptake inhibitors, on generalized pruritus, migraine, and depression.\n\n2 CASE REPORT\n\nA 37‐year‐old female patient developed severe and generalized pruritus without apparent primary lesions on her skin. Pruritus appeared on both forearms at the onset approximately two months ago, and gradually spread to her entire body. Although she had been treated with a conventional antipruritic drug, such as bilastine, and itching was uncontrollable. The patient also had a ten‐year history of migraine with frequent attacks. Previous treatments with two different migraine preventative medications, sumatriptan and sodium valproate, were not successful and the patient rejected new medications. Migraine had been poorly controlled with over‐the‐counter medications, including combinations of caffeine and acetaminophen. The patient had developed more severe and longer lasting headaches in the past several weeks. She developed depression more than two months ago, which was characterized by depressed mood, anxiety, intermediated insomnia, and restlessness associated with irritability. She was diagnosed with a major depressive episode as classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5). 12 Physical examinations and the results of laboratory studies revealed no significant abnormalities. Furthermore, no dermatosis with zoonotic contacts or exposures to chemicals or new cosmetic products prior to pruritus were found. Other than migraine, her medical history was unremarkable. She did not drink alcohol or use recreational drugs.\n\nThe depressive state was assessed using the 17‐item Hamilton Depression Rating Scale (HDRS‐17), 13 in which a total score of “0–7” represents the normal range and “above 23” represents the greatest severity of depression. The HDRS‐17 score before the administration of venlafaxine was 20, indicating severe depression with insomnia and anxiety (Figure 1A, Baseline). The HDRS‐17 score was measured every 7 days until day 28 of the administration of 37.5 mg of venlafaxine. The HDRS‐17 score gradually decreased after the initial dose of venlafaxine and reached a minimum score between days 21 and 28 of its administration (Figure 1A).\n\nFIGURE 1 Effects of venlafaxine on depression, migraine, and pruritus. (A) Time‐dependent changes in depression evaluated by HDRS‐17 after the administration of venlafaxine. (B) Time‐dependent changes in migraine evaluated by VAS after the administration of venlafaxine. (C) Time‐dependent changes in pruritus evaluated by VAS after the administration of venlafaxine\n\nMigraine/pruritus was also assessed using a simple visual analog scale (VAS). 14 The response of migraine to the oral administration of venlafaxine was assessed using VAS on day 0, 7, 14, 21, and 28 of the administration of venlafaxine. She was prescribed 37.5 mg of venlafaxine, the standard initial dose, once daily to minimize adverse events. The VAS score of migraine before the administration of venlafaxine was 80, indicating severe migraine (Figure 1B, Baseline). Following the initiation of venlafaxine, the VAS score gradually decreased until day 14, was less than half that before its administration between days14 and 21, and then remained stable until day 28 (Figure 1B).\n\nA treatment with bilastine, an antihistamine, had no noticeable effects, and the VAS score before the administration of venlafaxine was 70, indicating severe pruritus (Figure 1C, Baseline). The VAS score of pruritus markedly decreased to less than half before the administration of venlafaxine within 7 days, and then remained stable until day 28 (Figure 1C). The administration of venlafaxine for 3 months resulted in the sustained and significant attenuation of pruritus, migraine and depression.\n\n3 DISCUSSION\n\nVenlafaxine, a serotonin noradrenaline reuptake inhibitor (SNRI), has been prescribed as an antidepressant in patients with major depression disorder. It is generally administered at doses of 75–300 mg for the treatment of major depression with an observation period of 6–10 weeks. 15 Therefore, the dose of 37.5 mg used in the present study was markedly lower than that previously reported, suggesting that 37.5 mg of venlafaxine may be sufficient for the treatment of depression. In this case report, venlafaxine mitigated generalized pruritus and migraine in a patient with depression, which is the first evidence for the efficacy of venlafaxine against pruritus. Venlafaxine at a daily dose of 37.5 mg exerted beneficial effects on and attenuated pruritus within 7 days. Therefore, it has potential as a novel drug for the treatment of pruritus.\n\nPrevious studies showed that venlafaxine at a daily dose of 75 mg or higher exerted beneficial effects on migraine. 10 The present case was treated with venlafaxine at a dose of 37.5 mg per day, and migraine was attenuated by day 21. Therefore, 37.5 mg of venlafaxine may be sufficient to exert antinociceptive effects on migraine in patients with depression and pruritus. Since venlafaxine is an SNRI that exerts antipruritic effects, serotonin and noradrenaline receptors appear to be involved in the pruritic process. 16\n\nVenlafaxine exerted antidepressant, antinociceptive, and antipruritic effects in a patient with depression, migraine and chronic pruritus; however, the relationship between the onset times of these effects has not yet been elucidated. In our patient, the treatment with venlafaxine exerted antipruritic effects before the amelioration of migraine and depressive symptoms, indicating that the onset time of antipruritic effects after the treatment with venlafaxine was faster than those of antinociceptive and antidepressant effects. Furthermore, the treatment with venlafaxine exerted antinociceptive effects before the alleviation of depressive symptoms, indicating that the onset time of antinociceptive effects after the treatment with venlafaxine was faster than that of antidepressant effects. Therefore, the attenuation of pruritus and migraine by antidepressants may ameliorate the depressive state because these symptoms generally cause depression in these patients. Alternatively, pruritus and migraine may induce neuronal plasticity in the brain resulting in severe depression. Although the underlying mechanisms remain unclear, Harmer et al. 17 discussed that the repeated administration of antidepressants restored neuronal plasticity to a normal state. Therefore, based on the present results, the repeated administration of venlafaxine normalized the neuronal changes induced in the brain by chronic pruritus, migraine, and depression at differential onset times and via different mechanisms.\n\n4 CONCLUSION\n\nThe present case is novel in that the administration of venlafaxine attenuated depressive disorder, migraine, and severe pruritus, which was not previously documented in the literature. Generalized pruritus and migraine affect the quality of life of patients due to disturbances in mood, sleep, and social relationships. Therapeutic agents for generalized pruritus and migraine are limited because the underlying pathophysiological mechanisms have not yet been elucidated in detail. Furthermore, it remains unclear how pain and/or pruritus and depression influence each other. We herein described a patient with severe pruritus, migraine, and depression who was successfully treated with venlafaxine, indicating its potential as a new therapeutic option for patients with depressive disorder and severe pruritus unresponsive to conventional antipruritic drugs, including antihistamines. The management of the present case provides insights for similar cases in the future.\n\nCONFLICTS OF INTEREST\n\nAll authors declare that they have no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\n\nYM and TN: Wrote the first draft of the article. YM, HF, AH‐T, HH, TF, and AH: Managed the patient. YI: Revised the manuscript. All authors read and approved the final manuscript.\n\nCONSENT\n\nWitten informed consent was obtained from the patient to publish this report in accordance with journal's patient consent policy.\n\nACKNOWLEDGEMENT\n\nNone.\n\nDATA AVAILABILITY STATEMENT\n\nThe authors declare that data supporting the findings of this study are available within the article.\n==== Refs\nREFERENCES\n\n1 Kroenke K , Bair MJ , Damush TM , et al. Optimized antidepressant therapy and pain self‐management in primary care patients with depression and musculoskeletal pain: a randomized controlled trial. JAMA. 2009;301 :2099‐2110.19470987\n2 Ferm I , Sterner M , Wallengren J . Somatic and psychiatric comorbidity in patients with chronic pruritus. Acta Derm Venereol. 2010;90 :395‐400.20574605\n3 Gambassi G . Pain and depression: the egg and the chicken story revisited. Arch Gerontol Geriatr. 2009;49 (Suppl.1 ):103‐112. 10.1016/j.archger.2009.09.018 19836622\n4 Yosipovitch G , Bernhard JD . Chronic pruritus. N Engl J Med. 2013;368 :1625‐1634.23614588\n5 Headache Classification Committee of the International headache Society (IHS) . The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38 :1‐211.\n6 Krishnan V , Nestler EJ . The molecular neurobiology of depression. Nature. 2008;455 (7215 ):894‐902.18923511\n7 Torta R , Ieraci V , Zizzi F . A review of the emotional aspects of neuropathic pain: from comorbidity to co‐pathogenesis. Pain Ther. 2017;6 (Suppl.1 ):11‐17.29178035\n8 Mika J , Zychowska M , Makuch W , Rojewska E , Przewlocka B . Neuronal and immunological basis of action of antidepressants in chronic pain‐clinical and experimental studies. Pharmacol Rep. 2013;65 :1611‐1621.24553009\n9 Silberstein SD . Preventive migraine treatment. Continuum (Minneap Minn). 2015;21 :973‐989.26252585\n10 Ozyalcin SN , Talu GK , Kiziltan E , Yucel B , Ertas M , Disci R . The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45 :144‐152.15705120\n11 Miyahara Y , Haruta‐Tsukamoto A , Funahashi H , et al. Differential onset time of mirtazapine on pruritus and depression in a patient receiving hemodialysis. SAGE Open Med Case Rep. 2021;9 :1‐3.\n12 American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA: American Psychiatric Association; 2013.\n13 Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23 :56‐62.14399272\n14 Reich A , Heisig M , Phan NQ , et al. Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol. 2012;92 :497‐501.22102095\n15 Lyndon GJ , Prieto R , Wajsbrot DB , Allgulander C , Bandelow B . Efficacy of venlafaxine extended release in major depressive disorder patients: effect of baseline anxiety symptom severity. Int Clin Psychopharmacol. 2019;34 :110‐118.30870236\n16 Miyahara Y , Funahashi H , Naono‐Nakayama R , Haruta‐Tsukamoto A , Nishimori T , Ishida Y . Role of serotonin and noradrenaline in the acute itch processing in mice. Eur J Pharmacol. 2019;850 :118‐125.30763572\n17 Harmer CJ , Duman RS , Cowen PJ . How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4 :409‐418.28153641\n\n",
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"issue": "9(11)",
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"keywords": "depression; generalized pruritus; migraine; venlafaxine",
"medline_ta": "Clin Case Rep",
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"title": "Time course of effects of venlafaxine on migraine and generalized pruritus in a patient with depression.",
"title_normalized": "time course of effects of venlafaxine on migraine and generalized pruritus in a patient with depression"
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"abstract": "OBJECTIVE\nDespite several advantages of the novel anticoagulant rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications. The purpose of this study was to analyze the effects of pre-injury treatment with rivaroxaban on patients with mild traumatic brain injury (TBI) and traumatic intracranial haemorrhage (tICH).\n\n\nMETHODS\nA total of 70 patients with tICH after mild TBI were included in this retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality.\n\n\nRESULTS\nNo significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C.\n\n\nCONCLUSIONS\nDespite major limitations of retrospective design and small patient numbers, our results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH.",
"affiliations": "Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: christopher.beynon@med.uni-heidelberg.de.;Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.;Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.;Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.",
"authors": "Beynon|Christopher|C|;Potzy|Anna|A|;Sakowitz|Oliver W|OW|;Unterberg|Andreas W|AW|",
"chemical_list": "D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D000069552:Rivaroxaban",
"country": "Netherlands",
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"journal": "Clinical neurology and neurosurgery",
"keywords": "Anticoagulants, Factor Xa inhibitors, Haemostasis, Intracerebral haemorrhage; Head injury",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001930:Brain Injuries; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D020198:Intracranial Hemorrhage, Traumatic; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D000069552:Rivaroxaban; D016896:Treatment Outcome",
"nlm_unique_id": "7502039",
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"publication_types": "D016428:Journal Article",
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"title": "Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination?",
"title_normalized": "rivaroxaban and intracranial haemorrhage after mild traumatic brain injury a dangerous combination"
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"abstract": "Erythroderma is a rare potentially deadly exfoliative dermatitis characterized by diffuse cutaneous erythema which may be associated with multi-organ dysfunction. Therefore, it is imperative to recognize and treat it promptly. Erythrodermic psoriasis is the most common form of erythroderma. Management of this condition is largely based on aggressive supportive care and the use of anti-inflammatory immunosuppressive and biologic agents. We describe a case of psoriatic erythroderma which was triggered by withdrawal from systemic steroids and successfully treated with apremilast and cyclosporine. Apremilast induced atrial fibrillation limited its continued use after the initial response period.",
"affiliations": "Department of Medicine, Loma Linda University School of Medicine.;Department of Medicine, Loma Linda University School of Medicine.;Department of Medicine, Loma Linda University School of Medicine.;Department of Medicine, Loma Linda University School of Medicine.;Department of Medicine, Loma Linda University School of Medicine.;Department of Medicine, Loma Linda University School of Medicine; Department of Medicine, VA Loma Linda Healthcare System, Loma Linda, CA, USA.",
"authors": "Arcilla|John|J|;Joe|Daniel|D|;Kim|Johnathan|J|;Kim|Yohanan|Y|;Truong|VuAnh N|VN|;Jaipaul|Navin|N|",
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"doi": "10.4081/dr.2016.6599",
"fulltext": "\n==== Front\nDermatol ReportsDermatol ReportsDRDermatology Reports2036-73922036-7406PAGEPress Publications, Pavia, Italy 10.4081/dr.2016.6599Case ReportErythrodermic Psoriasis Treated with Apremilast Arcilla John 1Joe Daniel 1Kim Johnathan 1Kim Yohanan 1Truong VuAnh N. 1Jaipaul Navin 121 Department of Medicine, Loma Linda University School of Medicine2 Department of Medicine, VA Loma Linda Healthcare System, Loma Linda, CA, USAVA Loma Linda Healthcare System, 11201 Benton St. 111N, Loma Linda, CA 92357, USA. +1.909.583.6090 - +1.909.777.3858. Navin.Jaipaul@va.govContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n19 9 2016 15 6 2016 8 1 659913 5 2016 17 8 2016 ©Copyright J. Arcilla et al.2016Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Erythroderma is a rare potentially deadly exfoliative dermatitis characterized by diffuse cutaneous erythema which may be associated with multi-organ dysfunction. Therefore, it is imperative to recognize and treat it promptly. Erythrodermic psoriasis is the most common form of erythroderma. Management of this condition is largely based on aggressive supportive care and the use of anti-inflammatory immunosuppressive and biologic agents. We describe a case of psoriatic erythroderma which was triggered by withdrawal from systemic steroids and successfully treated with apremilast and cyclosporine. Apremilast induced atrial fibrillation limited its continued use after the initial response period.\n\nKey words\nErythrodermaPsoriasisErythrodermic psoriasisApremilast\n==== Body\nIntroduction\nWe report a case of a 79 year old man with erythrodermic psoriasis successfully treated during the initial response phase with the novel oral small-molecule phosphodiesterase-4 inhibitor apremilast.\n\nCase Report\nA 79-year-old man with hypertension and psoriasis was hospitalized for severe sepsis associated with a generalized and painful erythematous rash. He had been diagnosed with psoriasis affecting <1% body surface area (BSA) three months before this presentation and was treated with topical ketoconazole and fluocinolone. Two weeks before hospitalization, he received a five day oral prednisone taper prescribed by a family physician for skin rash. Following this, he developed a confluent, erythematous, scaling rash covering >50% BSA. Methotrexate was started for presumed psoriatic erythroderma; however, his symptoms worsened to include progressive skin involvement, fever, and hypotension which led to hospitalization. Physical exam revealed tender erythematous plaque with scale from head to toe, most prominently involving the head, neck, chest, back, upper arms, abdomen, buttocks, groin, and proximal thighs (Figure 1). Laboratory evaluation was remarkable for leukocytosis of 23.8×103/µL and pre-renalazotemia. Intravenous fluids, empiric antibiotics, topical steroids, and emollient moisturizer were started. Infectious work-up was negative; yet fevers, leukocytosis, and cutaneous pain symptoms persisted. Dermatology performed a punch biopsy which demonstrated evolving pustular psoriasis (Figure 2). Apremilast was started for treatment of erythrodermic psoriasis. The patient’s rash and systemic features began to improve by day 10. Though BSA involvement was essentially unchanged, psoriasis plaques demonstrated reduced erythema and scaling with marked improvement in cutaneous pain symptoms (Figure 3). As a result, Psoriasis Area and Severity Index score improved from 44.0 on admission to 26.4 after initiating apremilast treatment. However, the patient subsequently developed new-onset atrial fibrillation attributed to apremilast which was discontinued and switched to cyclosporine. The patient continued to improve and was discharged on cyclosporine.\n\nDiscussion\nErythroderma is a rare potentially deadly exfoliative dermatitis which may result from systemic infection, drug hypersensitivity, malignancy (e.g. cutaneous T cell lymphoma), and inflammatory conditions such as Stevens Johnson syndrome, pityriasis rubra pilaris, and erythrodermic psoriasis.1 Initial management for severe cases includes fluid resuscitation, empiric antibiotics, and diligent diagnostic evaluation.\n\nErythrodermic psoriasis is the most common form of erythroderma and accounts for 25% of all cases.2 When associated with psoriasis, the erythrodermic variant represents less than 1.5% of cases and manifests with well-defined erythematous plaques and overlying silvery scale.3 It generally affects the entire body and may be associated with life-threatening complications such as sepsis, hypovolemic shock, and acute kidney injury secondary to cutaneous fluid loss.2 Erythrodermic psoriasis may result from uncontrolled dermatosis, abrupt withdrawal of anti-psoriatic drugs such as steroids or methotrexate, drug reaction, systemic infection, ultraviolet burns, alcoholism, and emotional stress.2 Our patient’s withdrawal from oral steroids likely triggered his erythroderma. Skin biopsy may be helpful in diagnosis as erythroderma may develop acutely or gradually from any variant of psoriasis.2 Treatment is largely based on aggressive supportive care and the use of anti-inflammatory immunosuppressive and biologic agents. High quality evidence-based treatment recommendations for erythordermic psoriasis are lacking due to the rarity of the condition. Most randomized clinical trials on psoriasis treatments have excluded less common variants such as the erythrodermic and pustular subtypes.4 In light of this, first-line agents that have been used with variable efficacy include cyclosporine, infliximab, acitretin, and methotrexate.5 Etanercept and combination therapies are second-line alternatives.5 Recently, biologics including ustekinumab and golimumab have also been used with reported efficacy in the treatment of erythrodermic psoriasis.6,7 Systemic corticosteroids and ultraviolet light therapy are not recommended due to risks of disease exacerbation and photosensitivity.5 Choice of therapy should be based on disease severity and patient comorbidities. For example, we chose to treat our patient with apremilast due to the presence of pre-renal acute kidney injury which is a relative contraindication to use of the other aforementioned first-line agents. Apremilast is a novel small-molecule oral medication which selectively inhibits phosphodiesterase 4 and has been shown to downregulate the production of pro-inflammatory cytokines while upregulating anti-inflammatory cytokines.8 It is approved for treatment of psoriatic arthritris and moderate to severe plaque psoriasis. The efficacy of apremilast was demonstrated in a phase III randomized controlled trial that showed a statistically and clinically significant reduction versus placebo in the baseline Psoriasis Area and Severity Index score in patients with moderate to severe plaque psoriasis.9 However, a search of the published literature resulted in no reports describing the use of apremilast in erythrodermic psoriasis. Our patient improved on apremilast; however, he developed new-onset atrial fibrillation which was attributed to the medication so it was discontinued. When compared with placebo, apremilast treatment has been associated with an increased, albeit low, incidence of tachyarrhythmia, most frequently atrial fibrillation.9 Once the patient’s renal function improved, he was started on cyclosporine and his erythroderma eventually resolved.\n\nConclusions\nErythroderma associated with psoriasis may be triggered by withdrawal from systemic steroids. It is a rare and potentially fatal exfoliative dermatitis which needs to be recognized and treated promptly. The mainstay of treatment is founded on aggressive supportive care and use of anti-inflammatory immunosuppressive drugs, including newer biologic agents. We also observed encouraging results in treating erythrodermic psoriasis using the novel oral small-molecule phosphodiesterase-4 inhibitor apremilast. Its continued use in our patient, however, was limited after the initial response period by the development of atrial fibrillation which was attributed to the medication.\n\nFigure 1. Skin findings on day one of hospitalization demonstrating (A) well defined generalized erythema and scaling most prominently involving the head, neck, chest, back, upper arms, abdomen, buttocks, groin, and proximal thighs and (B) magnified view of the erythema and scaling.\n\nFigure 2. Skin biopsy demonstrating mild psoriasiform hyperplasia and rare intracorneal pustules with mild superficial perivascular mixed inflammation consistent with evolving pustular psoriasis.\n\nFigure 3. Skin findings on day ten of hospitalization demonstrating reduced intensity of erythema and scaling in response to apremilast treatment.\n==== Refs\nReferences\n1. Rothe MJ Bernstein ML Grant-Kels JM \nLife-threatening erythroderma: diagnosing and treating the red man . Clin Dermatol \n2005 ;23 :206 -17 .15802214 \n2. Stinco G Errichetti E. \nErythrodermic psoriasis: current and future role of biologicals . Bio Drugs \n2015 ;29 :91 -101 .\n3. Raychaudhuri SK Maverakis E Raychaudhuri SP \nDiagnosis and classification of psoriasis . Autoimmun Rev \n2014 ;13 :490 -5 .24434359 \n4. Menter A Korman NJ Elmets CA \nGuidelines of care for the management of psoriasis and psoriatic arthritis: sections 1,3,4,5. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics . J Am Acad Dermatol \n2008 ;58 :826 -50 .18423260 \n5. Rosenbach M Hsu S Korman NJ \nTreatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation . J Am Acad Dermatol \n2010 ;62 :655 -62 .19665821 \n6. Kim YS Kim JH Lee S \nErythrodermic psoriasis improved by ustekinumab: a report of two cases . Ann Dermatol \n2016 ;28 :121 -2 .26848234 \n7. Lee WK Kim GW Cho HH \nErythrodermic psoriasis treated with golimumab: a case report . Ann Dermatol \n2015 ;27 :446 -9 .26273164 \n8. Kelly JB Foley P Strober BE \nCurrent and future oral systemic therapies for psoriasis . Dermatol Clin \n2015 ;33 :91 -109 .25412786 \n9. Papp K Reich K Leonardi CL \nApremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1) . J Am Acad Dermatol \n2015 ;73 :37 -49 .A)26089047\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7392",
"issue": "8(1)",
"journal": "Dermatology reports",
"keywords": "Apremilast; Erythroderma; Erythrodermic psoriasis; Psoriasis",
"medline_ta": "Dermatol Reports",
"mesh_terms": null,
"nlm_unique_id": "101566470",
"other_id": null,
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"title": "Erythrodermic Psoriasis Treated with Apremilast.",
"title_normalized": "erythrodermic psoriasis treated with apremilast"
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"companynumb": "US-AMNEAL PHARMACEUTICALS-2022-AMRX-01450",
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"abstract": "METHODS\nRecommendations for screening for latent tuberculous infection (LTBI) in patients eligible for anti-tumour necrosis factor (TNF) agents remain unclear in endemic regions.\n\n\nOBJECTIVE\nTo evaluate the long-term efficacy of LTBI screening and treatment in patients with rheumatoid arthritis (RA) receiving TNF blockers.\n\n\nMETHODS\nA total of 202 RA patients were screened for LTBI before receiving anti-TNF treatment using the tuberculin skin test (TST), chest X-ray (CXR) and history of exposure to tuberculosis (TB). All subjects were regularly followed at 1- to 3-month intervals.\n\n\nRESULTS\nEighty-five patients (42%) were treated with a single anti-TNF agent, while 117 patients (58%) changed anti-TNF agents once or twice. LTBI screening was positive in 66 patients, 44 were TST-positive, 23 had a history of TB exposure and 14 had an abnormal CXR. Exposure alone accounted for LTBI diagnosis in 14 patients with a negative TST. LTBI patients were treated with isoniazid (300 mg/day) for 6 months, and none developed TB. During follow-up, TST was repeated in 51 patients. Conversion was observed in 5; 3 were diagnosed with LTBI and 2 with active TB respectively 14 and 36 months after receiving anti-TNF treatment, suggesting new TB exposure.\n\n\nCONCLUSIONS\nLTBI screening and treatment before anti-TNF treatment is effective in endemic areas and reinforces the importance of establishing contact history for diagnosing LTBI in RA patients.",
"affiliations": "Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.",
"authors": "Bonfiglioli|K R|KR|;Ribeiro|A C M|AC|;Moraes|J C B|JC|;Saad|C G S|CG|;Souza|F H C|FH|;Calich|A L|AL|;Bonfa|E|E|;Laurindo|I M M|IM|",
"chemical_list": "D000995:Antitubercular Agents; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D007538:Isoniazid",
"country": "France",
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"issue": "18(8)",
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"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors; D007538:Isoniazid; D055985:Latent Tuberculosis; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D013997:Time Factors; D014374:Tuberculin Test; D014409:Tumor Necrosis Factor-alpha",
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"title": "LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area.",
"title_normalized": "ltbi screening in rheumatoid arthritis patients prior to anti tnf treatment in an endemic area"
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes.\n\n\n\nPatients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%.\n\n\n\nOut of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4-84.5) and 70.5% (66.5-74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2-94.1) and 85.1% (81.7-87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54-0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40-0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59-1.33]; unadjusted HR for OS 0.83 [95% CI 0.45-1.54]).\n\n\n\nNo significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.",
"affiliations": "Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Carrer de Rosselló, 149, 08036, Barcelona, Spain.;Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Medical Oncology Department, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 1632, Genoa, GE, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Viale Benedetto XV, 10, 16132, Genoa, GE, Italy.;Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Breast Unit, Istituto Nazionale Tumori-Fondazione \"G. Pascale\", Via Mariano Semmola, 53, 80131, Naples, NA, Italy.;Department of Medical Oncology, Ospedale Businco, Via Edward Jenner, 1, 09121, Cagliari, CA, Italy.;Department of Clinical and Molecolar Medicine, La Sapienza University, Viale Regina Elena, 324, 00161, Rome, RM, Italy.;Department of Medical Oncology 1, Istituto Nazionale Tumori \"Regina Elena\", Via Elio Chianesi, 53, 00128, Rome, RM, Italy.;Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Sergio Pansini, 5, 80131, Naples, NA, Italy.;Breast Unit, Department of Oncology, Azienda Ospedaliera Santa Croce e Carle, Via Michele Coppino, 26, 12100, Cuneo, CN, Italy.;Department of Medical Oncology, Ospedale Sandro Pertini, Via dei Monti Tiburtini, 385/389, 00157, Rome, RM, Italy; Department of Medical Oncology, Ospedale SS Trinità, Località San Marciano, 03039, Sora, FR, Italy.;Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale, 142, 10060, Turin, TO, Italy.;Department of Medicine, University of Udine, Piazzale Massimiliano Kolbe, 4, 33100, Udine, Italy; Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico Aviano - National Cancer Institute, Via Franco Gallini, 2, 33081, Aviano, PN, Italy.;Breast Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genova, Viale Benedetto XV, 6, 1612, Genoa, GE, Italy; Department of Surgery, IRCCS Policlinico San Martino, Largo Rosanna Benzi 10, 1632, Genoa, GE, Italy.;Medical Oncology Unit 2, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Medical Oncology Department, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 1632, Genoa, GE, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Viale Benedetto XV, 10, 16132, Genoa, GE, Italy.;Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.;Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Viale Benedetto XV, 10, 16132, Genoa, GE, Italy; Breast Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy. Electronic address: lucia.delmastro@hsanmartino.it.",
"authors": "Conte|Benedetta|B|;Bruzzone|Marco|M|;Lambertini|Matteo|M|;Poggio|Francesca|F|;Bighin|Claudia|C|;Blondeaux|Eva|E|;De Laurentiis|Michelino|M|;Valle|Enrichetta|E|;Cognetti|Francesco|F|;Nisticò|Cecilia|C|;De Placido|Sabino|S|;Garrone|Ornella|O|;Gamucci|Teresa|T|;Montemurro|Filippo|F|;Puglisi|Fabio|F|;Cardinali|Barbara|B|;Fregatti|Piero|P|;Miglietta|Loredana|L|;Boccardo|Francesco|F|;Ceppi|Marcello|M|;Del Mastro|Lucia|L|;|||",
"chemical_list": "D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018719:Receptor, ErbB-2",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2020.05.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "136()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Breast cancer; Dose-dense chemotherapy; Hormone receptor-positive; Luminal subtype",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016019:Survival Analysis",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "43-51",
"pmc": null,
"pmid": "32634760",
"pubdate": "2020-09",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial.",
"title_normalized": "effect of dose dense adjuvant chemotherapy in hormone receptor positive her2 negative early breast cancer patients according to immunohistochemically defined luminal subtype an exploratory analysis of the gim2 trial"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020119679",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of disseminated Neosartorya pseudofischeri infection in a bilateral lung transplant patient with cystic fibrosis. The organism was originally misidentified from respiratory specimens as Aspergillus fumigatus using colonial and microscopic morphology. DNA sequencing subsequently identified the organism correctly as N. pseudofischeri.",
"affiliations": "Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, USA.;Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA wengenack.nancy@mayo.edu.",
"authors": "Khare|Reeti|R|;Gupta|Sounak|S|;Arif|Sana|S|;Jentoft|Mark E|ME|;Deziel|Paul J|PJ|;Roden|Anja C|AC|;Wilhelm|Mark P|MP|;Razonable|Raymund R|RR|;Wengenack|Nancy L|NL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.00216-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "52(7)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000328:Adult; D001232:Aspergillus fumigatus; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung; D008172:Lung Diseases, Fungal; D008828:Microbiological Techniques; D008853:Microscopy; D055326:Neosartorya; D017422:Sequence Analysis, DNA; D066027:Transplant Recipients",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "2722-5",
"pmc": null,
"pmid": "24829237",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7747958;18212093;14766893;19675215;21067321;18490953;17030996;21510879;11956874;16333088;7747954;7852580;19369533",
"title": "Misidentification of Neosartorya pseudofischeri as Aspergillus fumigatus in a lung transplant patient.",
"title_normalized": "misidentification of neosartorya pseudofischeri as aspergillus fumigatus in a lung transplant patient"
} | [
{
"companynumb": "US-009507513-1407USA010294",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Human bite wounds are more prone to infection than animal bites, which may cause necrotizing soft tissue infections such as myositis, fasciitis. Both aerobic and anaerobic microorganisms may be responsible, including Streptococcus spp., Staphylococcus aureus, Peptostreptococcus spp. Necrotizing fasciitis is characterized by serious tissue destruction and systemic toxicity with high morbidity and mortality. We report a patient with Streptococcus mitis associated necrotizing fasciitis on the upper extremity resulting from an accidental human bite, which caused nearly fatal infection. Prophylactic antibiotic treatment should be given after a human bite to prevent infection. If the infection signs and symptoms develop, rapid diagnosis, appropriate antibiotic and surgical therapy should be administered immediately. Streptococcus mitis is a viridans streptococcus, usually known as a relatively benign oral streptococcus. To our knowledge, this is the first necrotizing fasciitis case due to Streptococcus mitis after human bite.",
"affiliations": "Ankara Numune Training and Research Hospital, Ankara, Turkey. dr.aliye@yahoo.com.",
"authors": "Bastug|Aliye|A|;Kislak|Sumeyye|S|;Mutlu|Nevzat Mehmet|NM|;Akcaboy|Zeynep Nur|ZN|;Koksal|Asude|A|;Sertcelik|Ahmet|A|;Ünlü|Ramazan Erkin|RE|;Akinci|Esragul|E|;Bodur|Hurrem|H|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Italy",
"delete": false,
"doi": "10.3855/jidc.7040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1972-2680",
"issue": "10(1)",
"journal": "Journal of infection in developing countries",
"keywords": null,
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001132:Arm; D001734:Bites, Human; D003646:Debridement; D019115:Fasciitis, Necrotizing; D006801:Humans; D008297:Male; D008875:Middle Aged; D013290:Streptococcal Infections; D034361:Streptococcus mitis",
"nlm_unique_id": "101305410",
"other_id": null,
"pages": "100-2",
"pmc": null,
"pmid": "26829544",
"pubdate": "2016-01-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotizing fasciitis due to Streptococcus mitis caused by accidental human bite.",
"title_normalized": "necrotizing fasciitis due to streptococcus mitis caused by accidental human bite"
} | [
{
"companynumb": "TR-BAYER-2016-045576",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Monoclonal gammopathies are frequently seen in B-cell malignancies. Monoclonal proteins are seen in a significant proportion of patients with chronic lymphocytic leukemia (CLL), which is a clonal disorder of mature B cells. The use of more sensitive laboratory methods has enabled the detection of monoclonal proteins or light chains in the serum and/or urine in the majority of these patients. The presence of some of these monoclonal proteins may explain the different autoimmune phenomena that are associated with this disease. Some reports indicate that the finding of monoclonal proteins has a negative impact on patients' survival. The presence of two different monoclonal proteins (i.e. biclonal gammopathy) is on the other hand rare. Most of the reported cases in the literature are of patients with plasma cell disorders. In this report, we describe a rare occurrence of biclonal gammopathy in a patient with CLL. Serum protein electrophoresis and immunofixation, which were negative at the time of initial diagnosis, showed biclonal immunoglobin A (IgA) kappa and IgA lambda during the course of the disease. The patient's disease showed steady progression, despite multiple treatments. Although this could just be the result of using more sensitive laboratory techniques, biclonal gammopathy in this patient likely reflects the evolution of another clone, which would explain the encountered resistance to therapy. Because of paucity of reports, the impact of biclonal gammopathies in such patients is not known and an effort to collectively report the presentation and outcome of these patients is needed to further understand the pathophysiology and clinical significance of such a finding.",
"affiliations": "Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.;Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.;Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.;Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.;Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.;Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman.",
"authors": "Al-Riyami|Nafila|N|;Al-Farsi|Khalil|K|;Al-Amrani|Khalfan|K|;Al-Harrasi|Sameera|S|;Al-Huneini|Mohammed|M|;Al-Kindi|Salam|S|",
"chemical_list": null,
"country": "Oman",
"delete": false,
"doi": "10.5001/omj.2015.45",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1999-768X",
"issue": "30(3)",
"journal": "Oman medical journal",
"keywords": "Leukemia, B-Cell; Leukemia, Chronic Lymphocytic; Paraproteinemias",
"medline_ta": "Oman Med J",
"mesh_terms": null,
"nlm_unique_id": "101526350",
"other_id": null,
"pages": "216-8",
"pmc": null,
"pmid": "26171130",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports",
"references": "21141443;3103417;3122707;1453768;3082535;6797297;2948384;19828698;6401889;6312923;8049436;3952462;21765023;16616070;6437461",
"title": "Biclonal Gammopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature.",
"title_normalized": "biclonal gammopathy in chronic lymphocytic leukemia case report and review of the literature"
} | [
{
"companynumb": "OM-SA-2019SA059207",
"fulfillexpeditecriteria": "1",
"occurcountry": "OM",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "A 61-year-old woman was diagnosed in June 2011 as having immunoglobulin G (IgG) ĸ-type multiple myeloma (MM), stage II, according to the International Staging System (ISS). Chromosome analysis showed a complex karyotype, including t(11;14) and del 13q. Analysis of the cell surface markers revealed that the cells were positive for mature plasma cell-1 (MPC-1), and negative for cluster of differentiation (CD) 45 and CD49e, suggestive of an intermediate level of maturity of the cells. The disease was refractory to bortezomib-dexamethasone (BD) therapy and progressed to plasma cell leukemia despite the treatment. Treatment was therefore switched to lenalidomide-dexamethasone (RD) therapy, however, the condition again proved to be refractory to this therapy. A partial response (PR) was achieved with vincristine-doxorubicin-dexamethasone (VAD) therapy. The residual plasma cells became CD45-positive, suggesting a change of the cells from an intermediate level of maturity to mature cells. In December, autologous peripheral blood stem cell transplantation (Auto-PBSCT) was performed after high-dose melphalan therapy (melphalan 200 mg/m(2)) as pretreatment. PR was observed and a second Auto-PBSCT was performed in July 2012. Stringent complete remission (sCR) has been maintained for 2 years since, without any further treatment. This is the first reported case of secondary plasma cell leukemia (sPCL) resistant to new drugs that was successfully treated by high-dose melphalan in combination with VAD therapy and Auto-PBSCT.",
"affiliations": "Department of Hematology, Juntendo University Urayasu Hospital Japan.;Department of Hematology, Juntendo University Urayasu Hospital Japan ; Department of Hematology, Juntendo University Hospital Japan.;Department of Hematology, Juntendo University Urayasu Hospital Japan.;Department of Hematology, Juntendo University Urayasu Hospital Japan.;Department of Pathology, Juntendo University Urayasu Hospital Japan.;Department of Pathology, Juntendo University Urayasu Hospital Japan.;Department of Clinical Laboratory, Juntendo University Urayasu Hospital Japan.;Department of Clinical Laboratory, Juntendo University Urayasu Hospital Japan.;Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo Japan.;Department of Hematology, Juntendo University Hospital Japan.;Department of Hematology, Juntendo University Urayasu Hospital Japan.",
"authors": "Sekiguchi|Yasunobu|Y|;Shimada|Asami|A|;Wakabayashi|Mutsumi|M|;Sugimoto|Keiji|K|;Tomita|Shigeki|S|;Izumi|Hiroshi|H|;Nakamura|Noriko|N|;Sawada|Tomohiro|T|;Ohta|Yasunori|Y|;Komatsu|Norio|N|;Noguchi|Masaaki|M|",
"chemical_list": "D014408:Biomarkers, Tumor; D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-2625",
"issue": "7(9)",
"journal": "International journal of clinical and experimental pathology",
"keywords": "Bortezomib; VAD therapy; high-dose chemotherapy in combination with autologous peripheral blood stem cell transplantation; lenalidomide",
"medline_ta": "Int J Clin Exp Pathol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001856:Bone Marrow Examination; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077269:Lenalidomide; D007952:Leukemia, Plasma Cell; D017493:Leukocyte Common Antigens; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D010950:Plasma Cells; D011719:Pyrazines; D012074:Remission Induction; D013792:Thalidomide; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101480565",
"other_id": null,
"pages": "6313-22",
"pmc": null,
"pmid": "25337285",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3503574;12780789;16311736;16416115;16888783;17325863;17469169;17613775;17613776;17934254;17975015;18216867;18720213;18676019;19339770;20701603;20553988;21813352;22837533;24123068;11999568;12060146;15609327",
"title": "A case of secondary plasma cell leukemia resistant to novel agents, in which stringent complete remission was achieved and maintained for a long period of time after VAD therapy and tandem autologous transplantation.",
"title_normalized": "a case of secondary plasma cell leukemia resistant to novel agents in which stringent complete remission was achieved and maintained for a long period of time after vad therapy and tandem autologous transplantation"
} | [
{
"companynumb": "JP-TAKEDA-2015MPI004587",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Anagrelide is a cytoreductive agent for essential thrombocythemia and its common side effects are anemia, headache, palpitation, diarrhea, and fluid retention. However, severe pulmonary adverse effects are rare. A 66-year-old Japanese man with essential thrombocythemia presented with hemoptysis 2 months after starting anagrelide treatment. Interstitial pneumonia was diagnosed based on physical and radiographic findings. Discontinuation of anagrelide and institution of corticosteroids resulted in the improvement of interstitial pneumonia. Severe lung injury associated with anagrelide is a rare but an important adverse event that must be addressed when treating interstitial pneumonia.",
"affiliations": "1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.;1Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507 Japan.",
"authors": "Tamaru|Satoshi|S|0000-0002-2959-6077;Tono|Yasutaka|Y|;Matsumoto|Takeshi|T|;Oda|Hiroyasu|H|;Sugimoto|Yuka|Y|;Mizuno|Toshiro|T|;Katayama|Naoyuki|N|;Nishikawa|Masakatsu|M|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-016-0265-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "6(1)",
"journal": "International cancer conference journal",
"keywords": "Anagrelide; Corticosteroids; Essential thrombocythemia; Hypersensitivity pneumonitis; Interstitial pneumonia",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "31149463",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports",
"references": "12921504;16000354;16430463;23315161;25160063",
"title": "Successful treatment by prednisolone for interstitial pneumonia associated with anagrelide in a patient with essential thrombocythemia.",
"title_normalized": "successful treatment by prednisolone for interstitial pneumonia associated with anagrelide in a patient with essential thrombocythemia"
} | [
{
"companynumb": "GB-IMPAX LABORATORIES, INC-2017-IPXL-00523",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANAGRELIDE HYDROCHLORIDE"
},
... |
{
"abstract": "A case study demonstrating the association between aripiprazole and impulse-control disorders and a call for caution when prescribing aripiprazole to high-risk patients.",
"affiliations": "Flinders Medical Centre, Bedford Park, SA 5042, Australia. Electronic address: titus.mohan@sa.gov.au.;Flinders University, Bedford Park, SA 5042, Australia. Electronic address: dola0034@flinders.edu.au.;Flinders University, Bedford Park, SA 5042, Australia. Electronic address: moha0302@flinders.edu.au.;Flinders Medical Centre, Bedford Park, SA 5042, Australia. Electronic address: jessica.dawson@sa.gov.au.",
"authors": "Mohan|Titus|T|;Dolan|Sarah|S|;Mohan|Riche|R|;Dawson|Jessica|J|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2017.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "27()",
"journal": "Asian journal of psychiatry",
"keywords": "Aripiprazole; Impulse-control",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D007174:Disruptive, Impulse Control, and Conduct Disorders; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D012559:Schizophrenia",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "67-68",
"pmc": null,
"pmid": "28558898",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aripiprazole and impulse-control disorders in high-risk patients.",
"title_normalized": "aripiprazole and impulse control disorders in high risk patients"
} | [
{
"companynumb": "AU-MYLANLABS-2017M1029748",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Oritavancin is a lipoglycopeptide antibiotic approved for use in acute bacterial skin and skin structure infections as a single 1200-mg parenteral dose. Because of oritavancin's long half-life and broad gram-positive activity, interest in its use for other infections is high.\n\n\n\nThis study is a retrospective cohort evaluation of patients receiving oritavancin at a single academic medical center. All patients receiving more than one dose of oritavancin were included. Patients were excluded if therapy was interrupted by more than 14 days. Efficacy, defined a priori as clinical success, improvement, or failure, and adverse drug effect outcomes were collected.\n\n\n\nSeventeen patients received multiple oritavancin doses (range 2-18 doses) for the treatment of complicated infections including osteomyelitis, surgical site infection, intravascular infections, and pneumonia. All patients achieved clinical success or improvement with oritavancin. Four patients (24%) had an adverse event requiring oritavancin discontinuation that reversed rapidly.\n\n\n\nOff-label oritavancin use may be a safe and effective alternative to daily antibiotic infusions to treat complicated infectious disease processes. This study is limited by small sample size and retrospective design, but it provides information on using oritavancin in these complex gram-positive infections.",
"affiliations": "University of Wisconsin Health, Madison, Wisconsin.;Massachusetts General Hospital, Boston, Massachusetts.;Ohio State University Wexner Medical Center, Columbus, Ohio.;University of Wisconsin School of Pharmacy, Madison, Wisconsin.",
"authors": "Schulz|Lucas T|LT|;Dworkin|Emily|E|;Dela-Pena|Jennifer|J|;Rose|Warren E|WE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; C100708:oritavancin",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "38(1)",
"journal": "Pharmacotherapy",
"keywords": "Oritavancin; case series; osteomyelitis; pneumonia; surgical site infection",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077427:Lipoglycopeptides; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "152-159",
"pmc": null,
"pmid": "29121395",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multiple-Dose Oritavancin Evaluation in a Retrospective Cohort of Patients with Complicated Infections.",
"title_normalized": "multiple dose oritavancin evaluation in a retrospective cohort of patients with complicated infections"
} | [
{
"companynumb": "US-009507513-1802USA001162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly \"biological drugs.\" One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.",
"affiliations": "Hematology Unit, Bnai Zion Medical Center, Haifa, Israel.;Pathology Department, Bnai Zion Medical Center, Haifa, Israel.;Hematology Department, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.;Hematology Unit, Bnai Zion Medical Center, Haifa, Israel.",
"authors": "Kreiniz|Natalia|N|;Bejar|Jacob|J|;Polliack|Aaron|A|;Tadmor|Tamar|T|http://orcid.org/0000-0002-3435-8612",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "36(1)",
"journal": "Hematological oncology",
"keywords": "CLL; chronic lymphocytic leukemia; ibrutinib; immunosuppression; infection; pneumonia",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000225:Adenine; D000368:Aged; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D016393:Lymphoma, B-Cell; D010880:Piperidines; D011014:Pneumonia; D011720:Pyrazoles; D011743:Pyrimidines",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "349-354",
"pmc": null,
"pmid": "28156016",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma.",
"title_normalized": "severe pneumonia associated with ibrutinib monotherapy for cll and lymphoma"
} | [
{
"companynumb": "IL-ROCHE-2225073",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Chronic hepatitis E virus (HEV) infection in hematopoietic stem cell transplantation (HSCT) recipients is an emerging threat. The aim of this study was to provide data on the HEV burden in an Italian cohort of HSCT recipients and analyze risk factors for HEV seropositivity. This retrospective study reports data from 596 HSCT recipients compiled between 2010 and 2019. It included patients who underwent transplantation between 2010 and 2015 for whom pretransplantation (n = 419) and post-transplantation (n = 161) serum samples were available and tested retrospectively, as well as patients in whom prospective HEV testing was performed during the standard care: pre-HSCT IgG screening in 144, pre-HSCT HEV-RNA screening in addition to IgG screening in 60, and HEV-RNA testing in case of clinical suspicion of HEV infection in 59 (26 of whom were also included in the IgG screening cohorts). The rate of pre-HSCT HEV-IgG positivity was 6.0% (34 of 563). Older age was an independent risk factor for seropositivity (P = .039). None of the 34 HEV-IgG-positive patients had detectable HEV-RNA. One case of transient HEV-RNA positivity pre-HSCT was identified through screening. Two patients were diagnosed with chronic HEV hepatitis, and 1 patient was successfully treated with ribavirin. The burden of HEV infection in HSCT recipients in Italy is limited, and pre-HSCT screening appears to be of no benefit. Timely diagnosis of HEV infection with HEV-RNA is mandatory in cases of clinical suspicion.",
"affiliations": "Division of Infectious Diseases, Department of Health Sciences, University of Genoa, Genoa, Italy.;Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Infectious Diseases, Department of Health Sciences, University of Genoa, Genoa, Italy; Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Hematology and Bone Marrow Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Hematology and Bone Marrow Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Hematology and Bone Marrow Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Internal Medicine and Oncology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Division of Infectious Diseases, Department of Health Sciences, University of Genoa, Genoa, Italy.;Hygiene Unit, Hospital Policlinico San Martino, Genova, Italy.;Division of Hematology and Bone Marrow Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Infectious Diseases, Department of Health Sciences, University of Genoa, Genoa, Italy; Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Division of Infectious Diseases, Department of Health Sciences, University of Genoa, Genoa, Italy; Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: m.mikulska@unige.it.",
"authors": "Furfaro|Elisa|E|;Nicolini|Laura|L|;Della Vecchia|Andrea|A|;Di Grazia|Carmen|C|;Raiola|Anna Maria|AM|;Varaldo|Riccardo|R|;Ferrando|Fabio|F|;Barisione|Gaia|G|;Bruzzone|Bianca|B|;Angelucci|Emanuele|E|;Viscoli|Claudio|C|;Mikulska|Malgorzata|M|",
"chemical_list": "D012367:RNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.03.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Hematopoietic stem cell transplantation; Hepatitis E; Prevalence; Ribavirin; Seroepidemiologic studies",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000368:Aged; D018380:Hematopoietic Stem Cell Transplantation; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D007558:Italy; D011446:Prospective Studies; D012367:RNA, Viral; D012189:Retrospective Studies; D016036:Seroepidemiologic Studies",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1355-1362",
"pmc": null,
"pmid": "32200124",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis E Virus Infection in an Italian Cohort of Hematopoietic Stem Cell Transplantation Recipients: Seroprevalence and Infection.",
"title_normalized": "hepatitis e virus infection in an italian cohort of hematopoietic stem cell transplantation recipients seroprevalence and infection"
} | [
{
"companynumb": "IT-PFIZER INC-2020395839",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Intractable hiccups are a relatively uncommon condition characterized by involuntary, spasmodic contractions of the diaphragm. This type of hiccups generally has a duration of more than 1 month. We describe a 59-year-old kidney transplant recipient with a complicated medical history (atrial fibrillation, chronic renal failure, type 2 diabetes mellitus, gastroesophageal reflux, gout, hypertension, hyperlipidemia, and obstructive sleep apnea) who developed intractable hiccups that significantly affected his quality of life. Despite an extensive gastrointestinal and pulmonary evaluation, and treatment failures with several different drug regimens--metoclopramide, desipramine, amantadine, cyclobenzaprine, phenytoin, and lorazepam--his hiccups were eventually controlled with a combination of baclofen and low-dose olanzapine therapy. Baclofen is a c-aminobutyric acid (GABA) analog that contains a phenylethylamine moiety. It is hypothesized that having both GABA and phenylethylamine properties activates inhibitory neurotransmitters, most notably GABA, which may in turn block the hiccup stimulus. The exact mechanism through which olanzapine is effective in patients with hiccups is not fully understood. It is thought that the effect is, in part, due to serotonin augmenting phrenic motoneuronal activity on the reflex arcs involved in the generation of hiccups within the spinal cord. In addition, since olanazapine is a dopamine antagonist, particularly a dopamine D₂-receptor antagonist, this could also have played a role in its effectiveness in treating our patient. Strong evidence for a specific treatment regimen for intractable hiccups is lacking in the primary literature. Our case report adds to the available literature, as there are currently no published data on the use of combination therapy for the treatment of intractable hiccups, and the combination of baclofen and olanzapine significantly improved our patient's quality of life.",
"affiliations": null,
"authors": "Thompson|Amy N|AN|;Ehret Leal|Julie|J|;Brzezinski|Walter A|WA|",
"chemical_list": "D001569:Benzodiazepines; D001418:Baclofen; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(1)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D001418:Baclofen; D001569:Benzodiazepines; D004359:Drug Therapy, Combination; D006606:Hiccup; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D016896:Treatment Outcome",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e4-8",
"pmc": null,
"pmid": "24551889",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine and baclofen for the treatment of intractable hiccups.",
"title_normalized": "olanzapine and baclofen for the treatment of intractable hiccups"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0040388",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE SODIUM"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo study efficiency and tolerance of Structum in gonarthrosis patients as well as duration of its effect after discontinuation.\n\n\nMETHODS\n100 patients with femorotibial gonarthrosis aged 45 years and older entered an open randomised trial. They had knee joint arthrosis satisfying diagnostic criteria OA ACR at stage II-III according to Kellgren-Lawrence with pain syndrome. Walking pain intensity was > or = 30 mm by the visual analogue scale (VAS), Leken total functional index > or = 4 and < or = 11. Antiinflammatory drugs (AI) were regularly taken for 30 days for the 3 pretreatment months. 50 patients of the study group received Structum and ibuprofen (1200 mg/day) for 6 months. 50 patients of the control group received ibuprofen only. The two groups were followed up for 3 months. Clinical examination was made monthly.\n\n\nRESULTS\nThere were significant differences between the groups by the Leken's index (p < 0.005), VAS, pain, daily AI drug requirement. Structum proved more effective. Tolerance was good. Side effects were observed only in two patients (diarrhea and nausea). In the control group, side effects made 15 patients to discontinue the treatment.\n\n\nCONCLUSIONS\nStructum is a new effective drug against gonarthrosis which reduces pain, improves joint function. It is well tolerated and allows to diminish the dose of AI drugs. The response to Structum persisted for 3 months after the treatment.",
"affiliations": null,
"authors": "Alekseeva|L I|LI|;Benevolenskaia|L I|LI|;Nasonov|E L|EL|;Chichasova|N V|NV|;Kariakin|A N|AN|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D002809:Chondroitin Sulfates; D007052:Ibuprofen",
"country": "Russia (Federation)",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3660",
"issue": "71(5)",
"journal": "Terapevticheskii arkhiv",
"keywords": null,
"medline_ta": "Ter Arkh",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002809:Chondroitin Sulfates; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis",
"nlm_unique_id": "2984818R",
"other_id": null,
"pages": "51-3",
"pmc": null,
"pmid": "10399232",
"pubdate": "1999",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D004740:English Abstract; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Structum (chondroitin sulfate)--a new agent for the treatment of osteoarthrosis.",
"title_normalized": "structum chondroitin sulfate a new agent for the treatment of osteoarthrosis"
} | [
{
"companynumb": "RU-PFIZER INC-2017487483",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Background Transdermal opioids are widely used among elderly adults with chronic pain. However, transdermal patches may be involved in a significant proportion of opioid-related patient safety incidents, as the application process includes several subprocesses, each associated with an individual risk of error. Objective The aim was to obtain specific knowledge on patient safety incidents related to transdermal opioid treatment within both the primary care sector and the hospital sector in Denmark. Setting The study is descriptive with data provided by the Danish Patient Safety Database. Methods We manually retrieved all patient safety incidents concerning transdermal opioids reported for 2018 from (1) the hospital sector and (2) the primary care sector. Study data were collected and managed using REDCap electronic data capture tools. Main outcome measure The available information for each incident was sorted into the following categories: location, medication process, type of problem, outcome at time of reporting, and outcome classification. Results A total of 866 patient safety incidents involving transdermal opioids were reported to the Danish Patient Safety Database in 2018. No fatal incidents were present in the database. In 386 cases, the incidents were reported as harmful, and these 386 cases were analysed. Most reports came from the primary care sector (nursing home, home care or social housing). The majority of incidents were related to the administration of the patch in the medication process, and the most prevalent problem was the omission of doses. Conclusion This study has demonstrated that the administration of transdermal opioids is challenging and may cause harm, particularly in the primary care sector. To improve patient safety, optimized systems, including guidelines on drug management and the continuing education of healthcare personnel in transdermal opioid management, are necessary. These guidelines should preferably incorporate reminders and checklists, since the omission of doses was the most reported problem.",
"affiliations": "Department of Clinical Pharmacology, Aalborg University Hospital, Gartnerboligen, ground floor Mølleparkvej 8a, 9000, Aalborg, Denmark. aneso@rn.dk.;Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.;Department of Clinical Pharmacology, Aalborg University Hospital, Gartnerboligen, ground floor Mølleparkvej 8a, 9000, Aalborg, Denmark.;Division of Knowledge and Learning, The Danish Patient Safety Authority, Copenhagen, Denmark.;Department of Clinical Pharmacology, Aalborg University Hospital, Gartnerboligen, ground floor Mølleparkvej 8a, 9000, Aalborg, Denmark.",
"authors": "Olesen|A E|AE|http://orcid.org/0000-0001-9365-1918;Henriksen|J N|JN|;Nielsen|L P|LP|;Knudsen|P|P|;Poulsen|B K|BK|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-020-01057-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "43(2)",
"journal": "International journal of clinical pharmacy",
"keywords": "Incidents; Medication error; Opioids; Safety; Transdermal application",
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D016208:Databases, Factual; D003718:Denmark; D006761:Hospitals; D006801:Humans; D061214:Patient Safety",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "351-357",
"pmc": null,
"pmid": "32430881",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patient safety incidents involving transdermal opioids: data from the Danish Patient Safety Database.",
"title_normalized": "patient safety incidents involving transdermal opioids data from the danish patient safety database"
} | [
{
"companynumb": "DK-TEVA-2021-DK-1919824",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional": "3",
... |
{
"abstract": "The adverse drug reactions (ADRs) related to clonazepam are mild, and only two cases of myotoxicity induced by clonazepam have been reported, with both patients recovering well. We present a unique case of a serious ADR outcome after taking clonazepam.\n\n\n\nA 24-year-old woman with a long-standing history of polio and a 2-year history of epilepsy developed a serious ADR after repeated exposure to oral clonazepam combined with sodium valproate that manifested as myotoxicity and elevated levels of creatine phosphokinase. The patient is currently bedridden and unable to take care of herself.\n\n\n\nClinicians should be vigilant of the possibility of myotoxicity induced by clonazepam, especially in specific populations such as polio patients or when clonazepam is used in combination therapies.",
"affiliations": "Department of Pharmacy, Xi'an Central Hospital, Houzaimen No.185, North Street, Xi'an, 710003, Shaanxi, China.;Department of Pharmacy, Xi'an Central Hospital, Houzaimen No.185, North Street, Xi'an, 710003, Shaanxi, China. 184232699@qq.com.",
"authors": "Han|Xiaonian|X|;Wang|Jinping|J|0000-0003-4325-9939",
"chemical_list": "D000927:Anticonvulsants; D002998:Clonazepam; D014635:Valproic Acid",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-019-0366-y",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 36610.1186/s40360-019-0366-yCase ReportA serious adverse drug reaction probably induced by clonazepam: a case report of myotoxicity Han Xiaonian xjtuhxn@126.com http://orcid.org/0000-0003-4325-9939Wang Jinping 184232699@qq.com grid.478124.cDepartment of Pharmacy, Xi’an Central Hospital, Houzaimen No.185, North Street, Xi’an, 710003 Shaanxi China 5 11 2019 5 11 2019 2019 20 6418 7 2019 23 10 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\nThe adverse drug reactions (ADRs) related to clonazepam are mild, and only two cases of myotoxicity induced by clonazepam have been reported, with both patients recovering well. We present a unique case of a serious ADR outcome after taking clonazepam.\n\nCase presentation\nA 24-year-old woman with a long-standing history of polio and a 2-year history of epilepsy developed a serious ADR after repeated exposure to oral clonazepam combined with sodium valproate that manifested as myotoxicity and elevated levels of creatine phosphokinase. The patient is currently bedridden and unable to take care of herself.\n\nConclusion\nClinicians should be vigilant of the possibility of myotoxicity induced by clonazepam, especially in specific populations such as polio patients or when clonazepam is used in combination therapies.\n\nKeywords\nMyotoxicityCreatine phosphokinaseClonazepamPolioissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nEpilepsy is one of the most common serious disorders of the brain, affecting about 50 million people worldwide. Nearly a quarter of these patients have drug-refractory epilepsy [1]. Clonazepam is one of the 1,4-benzodiazepine drugs commonly used in epilepsy management, and it is recommended as a second-line adjunctive treatment for various types of seizure [2]. Studies have shown that clonazepam should be used primarily as an adjunctive therapy in patients with different types of drug-resistant primarily and secondarily generalized seizures [3]. The main adverse events are depression, somnolence, dizziness, nervousness, ataxia and reduced intellectual ability [4], and reports of myotoxicity induced by clonazepam are rare. Gupta [5] reported a 15-year-old boy who developed myotoxicity and elevated levels of creatine phosphokinase (CPK) after three doses of oral clonazepam, while Chen [6] reported another 63-year-old woman who suffered from mitochondrial myopathy after the long-term oral administration of clonazepam. All symptoms of these two patients gradually resolved, with the CPK level decreasing to the normal reference range after drug withdrawal.\n\nThere has been no previous report on serious adverse drug reactions (ADR) associated with clonazepam. Here we describe a patient who developed myotoxicity and became bedridden after repeated exposure to clonazepam combined with sodium valproate.\n\nCase presentation\nA 24-year-old woman had experienced non-progressive polio from 1 year of age despite having been inoculated with polio vaccine on time. She could walk with a limp but could not control her right hand sufficiently well to write, and so had not received the usual schooling. However, she could take care of herself and help her parents with a small amount of housework. About 2 years previously she had suffered from epilepsy in the form of bilateral tonic-clonic seizures, but she had not received regular treatment due to financial reasons. The epilepsy had not resulted in any deterioration of her polio symptoms.\n\nThe patient had been taken to the hospital to receive regular treatment for epilepsy for the first time 6 months previously, at which time her antiepileptic regimen was sustained-release sodium valproate (500 mg p.o.) plus clonazepam (2 mg p.o.) every 12 h. The patient developed drowsiness after the first combined dose of sodium valproate and clonazepam, and slept from 3 p.m. on the first day to 10 a.m. on the following day. She could not walk unaided and felt very tired, but she did not contact her doctor, instead continuing on this antiepileptic regimen regularly for 21 days until she ran out of clonazepam tablets. Her epilepsy symptoms were well controlled during this 21-day treatment period, but she developed muscle weakness and muscle pain, and remained in bed since she could not take care of herself.\n\nThe patient continued taking the sustained-release sodium valproate tablets (500 mg p.o. every 12 h), during which her epilepsy symptoms remained well controlled. Her muscle weakness symptoms started to improve gradually over the following 2 weeks, allowing her to stand but not walk. At this time she was taken to hospital for the second time. The patient and her family unfortunately refused electromyography, a muscle biopsy and other tests with the exception of some simple blood tests due to financial reasons. The findings of preliminary blood examinations including the complete blood count, urine test, liver and kidney function test, electrolytes, and plasma ammonia were within clinically acceptable limits, but her serum CPK was markedly raised at 4261 U/L (38–174 U/L), while her serum sodium valproate concentration was 101.89 μg/mL (50–100 μg/mL) and her serum globulin concentration was 36.4 g/L (25–35 g/L). There had been no preceding illness, infection or trauma, the patient did not have a history of statins or other drugs, and there was no family history of any neuromuscular disorder. Based on the relationship between medication times and symptoms, we attributed the myotoxicity to clonazepam, and assigned the patient to an antiepileptic regimen of sodium valproate monotherapy, with clonazepam remaining discontinued.\n\nA 2-month telephone-based follow-up revealed that the patient had started taking clonazepam irregularly because of insomnia, and suffered from muscle weakness and muscle pain again. Her clinical condition had deteriorated to the point that she was unable to stand or walk, and was unable to take care of herself. The patient and her family refused further physical examinations and treatment because they had lost confidence in curing the disease and also for financial reasons. We recommended that the patient discontinued clonazepam immediately and never take it again. At another follow-up 3 months later, the frequency and severity of epileptic seizures were significantly reduced in the patient, but her myotoxicity condition had not improved, she still could not stand or walk, and she was now bedridden.\n\nDiscussion and conclusion\nOur patient developed muscle weakness after taking sodium valproate and clonazepam at the same time, and the myopathy caused by sodium valproate and by clonazepam had been reported [5–9]. However, the clinical symptoms in the present patient gradually improved when clonazepam was stopped while continuing sodium valproate, and the patient experienced muscle weakness again after restarting clonazepam. There had been no preceding known illness, infection or trauma, the patient denied taking any other medications or substances, and there was no family history of any neuromuscular disorder. Although the patient had a long-standing history of polio and a 2-year history of epilepsy, these conditions had been non-progressive. We decided to substantiate the diagnosis further by using the Naranjo ADR Probability Scale, which is used to determine the likelihood of an ADR being due to the implicated drug or other factors [10] (Table 1). Our patient scored 6 on this scale, which indicates a probable ADR, and so her myotoxicity was probably related to the taking of clonazepam.\nTable 1 Naranjo adverse drug reaction probability score\n\nNo.\tItem\tYes\tNo\tDo not know\tScore\t\n1\tAre there previous conclusive reports of this reaction?\t+ 1\t0\t0\t+ 1\t\n2\tDid the adverse reaction event appear after the suspected drug was administered?\t+ 2\t−1\t0\t+ 2\t\n3\tDid the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\t+ 1\t0\t0\t+ 1\t\n4\tDid the adverse reaction reappear when the drug was readministered?\t+ 2\t−1\t0\t+ 2\t\n5\tAre there alternative cause (other than the drug) that could on their own have caused the reaction?\t−1\t+ 2\t0\t−1\t\n6\tDid the reaction reappear when a placebo was given?\t−1\t+ 1\t0\t0\t\n7\tWas the drug detected in the blood (or other fluids) in concentrations knows to be toxic?\t+ 1\t0\t0\t0\t\n8\tWas the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+ 1\t0\t0\t0\t\n9\tDid the patient have a similar reaction to the same or similar drugs at any previous exposure?\t+ 1\t0\t0\t0\t\n10\tWas the adverse event confimed by any objective evidence?\t+ 1\t0\t0\t+ 1\t\n\t\t\t\tTotal\t6\t\nDefinite:≥9; Probable: 5–8; Possible: 1–4; Doubtful: ≤0\n\n\n\nThe patient and her family declared that her polio and epilepsy were non-progressive. However, the dearth of neurological examinations meant that the woman might have actually had a slowly progressive early-onset type of muscle-wasting disease of neurological or myopathic origin, whose acceleration by the epilepsy treatment could have caused her clinical manifestations. Moreover, the probable myopathy varied with her clonazepam intake, representing further evidence that clonazepam was related to the myotoxicity. Numerous agents exhibit well-documented myocytoxicity, including anticholesterol statins, antirheumatic/inflammatory/immunosuppressive drugs, antinucleoside analogues, contaminated products, and dietary agents, and they result in symptomatologies ranging from mild discomfort and inconvenience to permanent damage and disability [11, 12]. The toxic myopathies can be classified according to the type of injury induced in the muscle fibre or specific organelle as follows: necrotizing myopathy, inflammatory myopathy, thick-filament loss myopathy, type II fibre atrophy, mitochondrial myopathies, lysosomal storage myopathies, antimicrotubular myopathies, myofibrillar myopathies, and fasciitis [11]. Cases of myotoxicity induced by clonazepam have probably been classified as mitochondrial myopathies, as confirmed by COX, NADH and SDH staining of the muscle biopsy samples of a 63-year-old woman [6]. Performing a muscle biopsy is essential to document myotoxicity, but regrettably we were only able to perform blood and urine tests in our patient, and so the lack of EMG and muscle biopsy results represent limitations of this study. We could therefore only speculate that the myotoxicity in our patient was mitochondrial myopathy.\n\nBecause our patient was taking sodium valproate at the same time as clonazepam, drug interactions might have been present. Jeavons et al. [13] reported the development of absence status in 5 of 11 patients taking both sodium valproate and clonazepam. Sodium valproate is an enzyme inhibitor and clonazepam is metabolized by cytochrome P450 in vivo [14, 15], which could explain why the patient experienced prolonged sedation. Baruzzi et al. [16] measured the serum levels of sodium valproate and clonazepam in epileptic patients treated with multiple antiepileptic drugs, and found only a weak correlation between the dose of clonazepam and its plasma level, which contrasts with other reports on clonazepam as a monotherapy [17, 18]. This observation was attributed to drug interactions, and so a pharmacodynamic drug interaction between sodium valproate and clonazepam cannot be completely excluded as a cause of an ADR in the present patient.\n\nThe reported myocytoxicity symptoms including ataxia, fatigue and weakness induced by clonazepam were resolved and the CPK level reduced to the normal reference range after stopping clonazepam in our patient [5, 6]. The disability experienced by our patient might have resulted from immobility and prolonged sedation, or an interaction between sodium valproate and clonazepam, but it could also have been related to the history of polio, despite the lack of evidence for clonazepam being forbidden in polio. Furthermore, the recognition of ADR and the lack of medical knowledge were also contributing factors to this serious ADR. It was a great pity that our patient refused to receive further physical examinations and treatment due to losing confidence in curing the disease and also for financial reasons.\n\nWe have described a case of the serious ADR of myotoxicity that was probably induced by clonazepam. Our findings suggest that clinicians should be vigilant of the possibility of myotoxicity induced by clonazepam, especially in specific populations such as polio patients or when clonazepam is used in combination therapies.\n\nAbbreviations\nADRAdverse drug reaction\n\nAZTAzidothymidine\n\nCPKCreatine phosphokinase\n\nEMGElectromyogram\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nWe would like to thank our patient and her families for their patience in replying our questions during the follow-up.\n\nAuthors’ contributions\nJW completed the literature review and the case presentation, XH wrote the article. Both authors read and approved the final manuscript and its submission for the BMC pharmacology & toxicology journal.\n\nFunding\nNo funding was provided.\n\nAvailability of data and materials\nThe data used in this case report is available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nBefore writing the report, we obtained the consent of the Medical Ethics Committee approval of Xi’an Central Hospital.\n\nConsent for publication\nThe patient gave her informed consent for a case report publication. A copy of the written consent is available in annex.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Kwan P Schachter SC Brodie MJ Drug-resistant epilepsy N Engl J Med 2011 365 919 926 10.1056/NEJMra1004418 21899452 \n2. National Institute for Health and Clinical Excellence The epilepsies: the diagnosis and management ofthe epilepsies in adults and children in primary and secondary care. Pharmacological update of clinical guideline 2012 London Royal College of Physicians (UK) NBK247130 \n3. Riss J Cloyd J Gates J Collins S Benzodiazepines in epilepsy: pharmacology and pharmacokinetics Acta Neurol Scand 2008 118 69 86 10.1111/j.1600-0404.2008.01004.x 18384456 \n4. US Food, Drug Administration. Klonopin tablets (clonazepam) Klonopin wafers (clonazepam orally disintegrating tablets). FDA. 2010. www.accessdata.fda.gov/drugsatfda_docs/label/2010/017533s046s048,020813s006s007lbl.pdf. Accessed 14 July 2015.\n5. Gupta R Myotoxicity induced by clonazepam_ a case report.pdf Paediatr Perinat Drug Ther 2003 5 4 214 216 10.1185/146300903774115838 \n6. Yang C Luo S Qiao K Wang Y Jiahong LU Myotoxicity induced by clonazepam: a case report and literature review Chin J Clin Neurosci 2014 22 1 98 102 \n7. Kasturi L Sawant SP Sodium valproate — induced skeletal myopathy Indian J Pediatr 2005 72 3 243 244 10.1007/BF02859266 \n8. Papadimitriou A Servidei S Late onset lipid storage myopathy due to multiple acyl CoA dehydrogenase deficiency triggered by valproate Neuromuscul Disord 1991 1 4 247 252 10.1016/0960-8966(91)90097-C 1822802 \n9. Reiche I Tröger U Postel SC Valproic acid-induced myopathy in a patient with schizoaffective disorder J Clin Psychopharmacol 2009 29 4 402 403 10.1097/JCP.0b013e3181ad2256 19593189 \n10. Naranjo CA Busto U Sellers EM Sandor P Ruiz I A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n11. Dalakas MC Toxic and drug-induced myopathies J Neurol Neurosurg Psychiatry 2009 80 832 838 10.1136/jnnp.2008.168294 19608783 \n12. Guis S Mattei JP Cozzone PJ Bendahan D Pathophysiology and clinical presentations of rhabdomyolysis Joint Bone Spine 2005 72 382 391 10.1016/j.jbspin.2004.04.010 16214072 \n13. Jeavons PM Clark JE Maheshwari MC Treatment of generalized epilepsies of childhood and adolescence with sodium valproate (‘Epilim’) Dev Med Child Neurol 1977 19 9 25 10.1111/j.1469-8749.1977.tb08015.x 403104 \n14. Seree EJ Pisano PJ Placidi M. Rahmani R. Barra YA Identification of the human and animal hepatic cytochromes P450 involved in clonazepam metabolism Fundamental & Clinical Pharmacology 1993 7 2 69 75 10.1111/j.1472-8206.1993.tb00219.x 8486332 \n15. Raymond WN Russell AP Collins RJ Diana LS Konstantin HD In vivo induction and in vitro inhibition of hepatic cytochrome P450 activity by the benzodiazepine anticonvulsants clonazepam and diazepam Drug Metab Dispos 1997 25 6 750 756 9193878 \n16. Baruzzi A Bordo B Bossi L Plasma levels of di-N-propylacetate and clonazepam in epileptic patients Int J Clin Pharmacol Biopharm 1977 15 403 408 334679 \n17. Dreifuss FE Penny JK Rose SW Serum clonazepam concentrations in children with absence seizures Neurology 1975 25 255 258 10.1212/WNL.25.3.255 1089913 \n18. Naestoft J Lund M Larsen N-E Assay and pharmacokinetics of clonazepam in humans Acta Neruol Scand Suppl 1973 53 103 108\n\n",
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"keywords": "Clonazepam; Creatine phosphokinase; Myotoxicity; Polio",
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"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002998:Clonazepam; D004359:Drug Therapy, Combination; D004827:Epilepsy; D005260:Female; D006801:Humans; D000081030:Myotoxicity; D014635:Valproic Acid; D055815:Young Adult",
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"title": "A serious adverse drug reaction probably induced by clonazepam: a case report of myotoxicity.",
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"abstract": "BACKGROUND\nDescending necrotizing mediastinitis is a common and progressive polymicrobial infection involving the neck and chest with a high death rate (10 to 40%). From a microbiological point of view, descending necrotizing mediastinitis is sustained by Gram-positive bacteria (43-62%), anaerobes (46-78%), and, rarely, Gram-negative bacteria. Data collected during the Antibiotic Resistance-Istituto Superiore di Sanità project confirmed that Italy is positioned among the countries with the highest levels of resistance in most pathogenic species under surveillance. In particular, 32.9% of Klebsiella pneumoniae isolates were resistant to carbapenem, 33.6% of Staphylococcus aureus to methicillin, and 28.7% and 43.9% of Escherichia coli isolates to third-generation cephalosporins and fluoroquinolones, respectively.\n\n\nMETHODS\nWe describe the case of a 38-year-old white man with septic shock due to descending necrotizing mediastinitis sustained by multidrug-resistant Gram-negative and Gram-positive bacteria treated after surgery with an IgM-enriched immunoglobulin preparation and polymyxin B hemoperfusion therapy.\n\n\nCONCLUSIONS\nDespite the contrasting data on the use of immunoglobulins and polymyxin B hemoperfusion in septic shock and the lack of literature in cases of acute mediastinitis caused by both Gram-negative and Gram-positive multidrug-resistant bacteria, we obtained an improvement in clinical conditions and the survival of our patient, against all odds.",
"affiliations": "Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy. Vincenzo.pota@unicampania.it.;Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy.;Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy.;Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy.;Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy.;Thoracic Surgery Unit, University of Campania \"L. Vanvitelli\", Naples, Italy.;Department of Women, Infant and Surgical and Specialist Surgery, University of Campania \"L. Vanvitelli\", Piazza Miraglia 2, 80138, Naples, Italy.",
"authors": "Pota|Vincenzo|V|;Passavanti|Maria Beatrice|MB|;Sansone|Pasquale|P|;Pace|Maria Caterina|MC|;Peluso|Filomena|F|;Fiorelli|Alfonso|A|;Aurilio|Caterina|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007075:Immunoglobulin M; D011112:Polymyxin B",
"country": "England",
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"doi": "10.1186/s13256-018-1611-5",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 161110.1186/s13256-018-1611-5Case ReportSeptic shock from descending necrotizing mediastinitis – combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report Pota Vincenzo 00390815665215Vincenzo.pota@unicampania.it 1Passavanti Maria Beatrice Beatrice.passavanti@libero.it 1Sansone Pasquale Pasquale.sansone@unicampania.it 1Pace Maria Caterina Caterina.pace@libero.it 1Peluso Filomena Filemona.peluso@gmail.com 1Fiorelli Alfonso Alfonso.fiorelli@unicampania.it 2Aurilio Caterina Caterina.aurilio@unicampania.it 11 Department of Women, Infant and Surgical and Specialist Surgery, University of Campania “L. Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy 2 Thoracic Surgery Unit, University of Campania “L. Vanvitelli”, Naples, Italy 3 3 2018 3 3 2018 2018 12 5513 4 2017 8 2 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\nDescending necrotizing mediastinitis is a common and progressive polymicrobial infection involving the neck and chest with a high death rate (10 to 40%). From a microbiological point of view, descending necrotizing mediastinitis is sustained by Gram-positive bacteria (43–62%), anaerobes (46–78%), and, rarely, Gram-negative bacteria. Data collected during the Antibiotic Resistance-Istituto Superiore di Sanità project confirmed that Italy is positioned among the countries with the highest levels of resistance in most pathogenic species under surveillance. In particular, 32.9% of Klebsiella pneumoniae isolates were resistant to carbapenem, 33.6% of Staphylococcus aureus to methicillin, and 28.7% and 43.9% of Escherichia coli isolates to third-generation cephalosporins and fluoroquinolones, respectively.\n\nCase presentation\nWe describe the case of a 38-year-old white man with septic shock due to descending necrotizing mediastinitis sustained by multidrug-resistant Gram-negative and Gram-positive bacteria treated after surgery with an IgM-enriched immunoglobulin preparation and polymyxin B hemoperfusion therapy.\n\nConclusion\nDespite the contrasting data on the use of immunoglobulins and polymyxin B hemoperfusion in septic shock and the lack of literature in cases of acute mediastinitis caused by both Gram-negative and Gram-positive multidrug-resistant bacteria, we obtained an improvement in clinical conditions and the survival of our patient, against all odds.\n\nKeywords\nSeptic shockIgM-enriched immunoglobulin preparationPolymyxin B hemoperfusionMediastinitisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAcute mediastinitis (AM), because of its high mortality rate, is one of the most dangerous forms of infection in the human organism. It is a severe acute inflammation of the connective tissues located in the middle thoracic cavity. Descending necrotizing mediastinitis (DNM) represents 20% of cases of AM [1, 2]. DNM is a common and progressive polymicrobial infection involving the neck and chest and it is associated with a high death rate (10 to 40%).\n\nThere are no guidelines or published articles with high level of evidence (above level III) on the treatment of DNM. Currently, the best evidence is available from four meta-analyses [3–6] of published case series of DNM, covering the period from 1960 to 2008, and a review of cervical necrotizing fasciitis and DNM [7]. The primary treatment of DNM is surgical eradication of the pharyngeal or odontogenic focus and a concomitant extensive drainage of the neck and the mediastinum. The thoracic surgical treatment could be a median sternotomy, or standard right posterolateral thoracotomy, or anterolateral thoracotomy, or subxiphoid approach, or clamshell incision, or video-assisted mediastinoscopy (VAM) drainage, and/or video-assisted thoracic surgery (VATS) drainage. Unfortunately, the literature did not offer a consensus on the optimal treatment modalities [6]. Surely, the surgical treatment has to be combined with an intravenously administered wide-spectrum antibiotic therapy and other intensive care treatment. From a microbiological point of view, DMD is sustained by Gram-positive bacteria (43–62%), anaerobes (46–78%), and, rarely, Gram-negative bacteria.\n\nWe describe a case of AM caused by an odontogenic infection due to methicillin-resistant Enterococcus raffinosus, carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Klebsiella pneumoniae (CR-Kp) unresponsive to conventional surgical and medical therapy complicated with high levels of procalcitonin (PCT), endotoxin, and septic shock.\n\nCase presentation\nA 38-year-old white man, 100 kg weight, with a diagnosis of DNM, was transferred to the intensive care of University of Campania “L. Vanvitelli” because of the necessity of a chest surgery-dedicated intensive care unit (ICU). He came from an ICU of a peripheral hospital with the incorrect diagnosis of pneumonia, based on a chest X-ray. He was treated with tazobactam (2 g/day)/piperacillin (16 g/day) and meropenem (6 g/day) for approximately 10 days and percutaneous tracheostomy. When he arrived at our ICU he presented respiratory failure with the necessity of mechanical ventilation with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) < 90. He was in septic shock with severe hypotension with necessity of norepinephrine > 0.3 μg/kg per minute. His mean arterial pressure (MAP) was 50 mmHg, heart rate 130 beats per minute (bpm), and body temperature 40 °C.\n\nHis medical history was: amoxycillin (2 g/day) had been used to treat his severe toothache for 2 weeks and then he presented to the emergency room of a peripheral hospital with dyspnea. He was obese (body mass index > 39) but was not affected by any other comorbidities. He was single and he worked as a truck driver. He did not smoke tobacco or drink alcohol and he did not have any other risk factor for mediastinitis.\n\nAll his skin was pallid except for the left side of his neck. He had a large warm mass on the left side of his neck, which extended from his mouth to his left supraclavicular region. At thoracic auscultation there were no lung sounds at the left side and some wheezes at the right side. He also presented peripheral edema. A neurological examination was not done because he was deeply sedated (Ramsay Sedation Scale 6 and Glasgow Coma Scale 3). Chest and neck computed tomography with contrast medium showed: a wide abscess in left parotid-masseter region that extended from the floor of his mouth up to the ipsilateral inferior parapharyngeal compartment, this lesion appeared to be liquefied with areas of air pockets; severe bilateral pleural effusion; and an abscess in his anterior mediastinum that extended from median to left paramedian area (Figs. 1 and 2). He immediately underwent bilateral thoracotomy and left cervicotomy with abscess drainage and left superior and inferior third molars (2.8 and 3.8 tooth), whose dental roots were necrotic, and then he was admitted to our ICU because of septic shock: qSequential Organ Failure Assessment (qSOFA) 3; SOFA score 12. All cultural examinations were done (chest drain samples, blood cultures, bronchial aspirate culture, and urine sample); in particular, the blood sample culture (VersaTREK REDOX® 1 and 2) revealed the presence of methicillin-resistant Enterococcus raffinosus, CRAB, and CR-Kp. In addition, the culture from the abscess drainage also revealed CRAB and CR-Kp. The cultures were identified with standard methods (we did not have rapid test) and minimal inhibitory concentration (MIC) susceptibility test. The stains of pus collected were both Gram positive and Gram negative. The blood samples also revealed: white blood cells (WBC) 17,500/mL (neutrophils 85%, lymphocytes 8%), red blood cell (RBC) 2.79 × 106/ml, hemoglobin 7.2 g/dl, hematocrit 22.8%, platelet 118 × 103/ml, C-reactive protein (CRP) 12.3 mg/L (normal range 0–10 mg/L), PCT 12 ng/mL (normal 0.15 ng/mL), endotoxin activity assay (EAA) 0.72 (EAA in the low range < 0.4) with a negative predictive value of 95.1% from risk of culture-proven Gram-negative infection, aspartate transaminase 21 U/L, alanine transaminase 24 U/L, total bilirubin 0.46 mg/dl, unconjugated bilirubin 0.11 mg/dl, conjugated bilirubin 0.35 mg/dl, serum creatinine 1.4 mg/dl, urea 53 mg/dl, and body temperature 40 °C. Hemodynamic parameters monitored with Vigileo (specific monitor that analyzes arterial blood pressure waveform and its changes) were: cardiac output (CO) 2.1 L/minute (normal range 4.0–8.0 L/minute), systemic vascular resistance (SVR) 400 dynes · second/cm5 (normal range 800–1200 dynes · second/cm5), MAP 50 mmHg (with dobutamine 8 μg/kg per minute and norepinephrine 0.3 μg/kg per minute), and urinary output > 0.5 mL/kg per hour with Acute Kidney Injury (AKI) scale 1. The blood gases showed PaO2/FiO2 171 and lactate 2.5 mMol/L (normal range up to 1.9 mMol/L). He started an antibiotic therapy with: linezolid 1200 mg/day, colistin 9,000,000 UI/day, rifampicin 600 mg/day, and tigecycline 100 mg/day. At 36 hours after the surgical and antibiotics therapy we did not notice a significant improvement so we decided to start a combined therapy with 250 ml/kg per day IgM-enriched immunoglobulin preparation for 3 consecutive days, together with direct hemoperfusion therapy with immobilized polymyxin B cartridges for 2 hours a day for 2 consecutive days (blood flow 100 ml/minute). Toraymyxin (PMX 20-R; Toray Industries, Tokyo, Japan) is a selective blood endotoxin removal cartridge. PMX 20-R is a cartridge composed of polymyxin B covalently bonded to polystyrene-derivative fibers. Blood flow direction is well controlled by adopting a radial flow system. PMX 20-R treatment occurs by hemoperfusion at a blood flow rate of approximately 80–120 mL/minute. Heparin is preferably used as an anticoagulant. Pentaglobin (IgM-enriched immunoglobulin; Biotest) is a plasma-derived solution with the sequent composition: 12% IgM – 76% IgG – 12% IgA. Several mechanisms of action have been postulated for Pentaglobin: direct activity of antibodies, neutralization of endotoxin, enhanced clearance of lipopolysaccharide (LPS), and reduction of classical complement pathway. Approximately 3 days after the beginning of this multimodal intensive and progressive treatment, gradual improvements in hemodynamics (MAP 85 mmHg without norepinephrine, CO 5.2 L/minute, urinary output > 0.5 ml/kg per hour), blood gases, and inflammatory markers (CRP 2.3 mg/dl, PCT 1 ng/ml, EAA < 0.6, body temperature 36.5 °C, and lactate 0.3 mMol/L) were achieved (Table 1). We noted a fluid overload of our patient during the first 36 hours before starting the therapy with Toraymyxin and Pentaglobin but there was a rapid and immediate recovery of a normal urine output after the beginning of that therapy, following on from increasing MAP.Fig. 1 Cervical computed tomography scan\n\nFig. 2 Thoracic computed tomography scan\n\nTable 1 Hemodynamic and septic parameters\n\n\tT0\tT1\tT2\t\nCRP (mg/dl)\t12.3\t12\t2.3\t\nPCT (ng/ml)\t3.2\t3\t1\t\nEAA\t0.71\t0.6\t0.5\t\nFEVER (°C)\t40\t38\t36.5\t\nSVR (dynes second/cm5)\t400\t600\t1200\t\nCO\t2.1\t3.0\t5.2\t\nMAP\t50\t70\t85\t\nT0: Before the beginning of IgM-enriched immunoglobulin preparation (Pentaglobin) and direct hemoperfusion therapy with polymyxin B immobilized fiber cartridges\n\nT1: 24 hours after the beginning of IgM-enriched immunoglobulin preparation (Pentaglobin) and direct hemoperfusion therapy with polymyxin B immobilized fiber cartridge\n\nT2: 72 hours after the beginning of IgM-enriched immunoglobulin preparation (Pentaglobin) and direct hemoperfusion therapy with polymyxin B immobilized fiber cartridge\n\nCO cardiac output, CRP C-reactive protein, EAA endotoxin activity assay, MAP mean arterial pressure, PCT procalcitonin, SVR systemic vascular resistance\n\n\n\nSo the weaning from mechanical ventilation started. Approximately 3 weeks after his admission to ICU, he was successfully weaned from mechanical ventilation. His ICU course was complicated also by polyneuropathy, myopathy, and hyperthyroidism. Finally, after 5 weeks, he was transferred to a rehabilitation institute. He was discharged home 3 weeks later (Fig. 3). At 6 months follow-up he was discharged to home without tracheostomy and was starting to work again.Fig. 3 Case report timeline. ICU intensive care unit\n\n\n\nDiscussion\nIn this case report we describe a rare case of DNM due to Gram-negative and Gram-positive multidrug-resistant bacteria. We obtained the resolution of DNM by assembling conventional surgical therapy and a novel treatment with IgM-enriched immunoglobulin preparation and direct hemoperfusion therapy with immobilized polymyxin B cartridges, even though there was no recommendation for this treatment in this case and there was a lack of literature.\n\nAM is a severe, life-threatening infection of the mediastinal connective tissues, interpleural spaces, and surrounding thoracic organs. DNM is a rare complication of odontogenic infection [8] arising generally from the second or third molar. Other less common infections include acute tonsillitis, and retropharyngeal and peritonsillar abscess. This abscess can rupture into the submandibular and parapharyngeal spaces and reach the mediastinum mainly along the retropharyngeal space or along the perivascular and pretracheal spaces [9, 10]. The effect of gravity and the negative intrathoracic and pleural pressure during inspiration, and the absence of barriers in the facial planes are important pathophysiological factors in the extension of deep neck infections of the mediastinum [10]. In a systematic review published in April 2016 by Prado-Callero et al., the authors analyzed 26 studies with a total of 480 patients. DNM was reported to be limited to the upper mediastinum in 189 patients (39%) and extended to the inferior mediastinum in 249 patients (51%) [1]. The origin of DNM was pharyngeal (acute tonsillitis, retropharyngeal and peritonsillar abscess) in 204 patients (45%), odontogenic abscess in 163 patients (36%), from other causes in 83 patients (18%), and not reported in 30 patients [1].\n\nIn addition the presence of coexisting morbidities, such as diabetes mellitus (DM), alcoholism, tobacco smoking, chronic renal failure, and liver cirrhosis, can facilitate this rapid extension and increase the occurrence of complications including bilateral empyema, purulent pericarditis, AKI requiring hemodialysis, prolonged mechanical ventilation, and septic shock. Endo et al. [11] classified DNM according to the anatomic extent: type I infection above the carina (localized form); and type II infection below the tracheal bifurcation (diffuse form), which is subdivided into type IIA (lower anterior mediastinum) and type IIB (lower posterior mediastinum).\n\nThe mortality under current “standard treatment” is reported to be between 20 and 40% [12, 13] mostly as a consequence of multiorgan failure (MOF).\n\nThe etiological organisms of DNM are mostly mixed, aerobic and anaerobic [5, 14]. Although the main microorganisms implicated are Gram-positive bacteria (e.g. staphylococci), Gram-negative pathogens can also be a relevant cause of DNM [15].\n\nA European network of national surveillance systems on antimicrobial resistance (EARS-Net), coordinated and financed by European Centre for Disease Prevention and Control (ECDC), has been created to collect data from 29 European countries to analyze temporal and spatial trends of the phenomenon. European data confirm an increase in resistance to third-generation cephalosporins, fluoroquinolones, and aminoglycosides especially in Escherichia coli and in K. pneumoniae, responsible for urinary tract infections, sepsis, and other health care-related infections. These resistances are often combined, generating multi-resistant bacteria. In recent years, resistance to carbapenem has appeared, making some infections untreatable. Data collected during the Antibiotic Resistance-Istituto Superiore di Sanità (AR-ISS) project have confirmed that Italy is among the countries with the highest levels of resistance in most pathogenic species under surveillance, namely 32.9% of K. pneumoniae isolates were resistant to carbapenem, 33.6% of Staphylococcus aureus to methicillin, and 28.7% and 43.9% of E. coli isolates to third-generation cephalosporins and fluoroquinolones, respectively [16].\n\nCompared with other microorganisms, DNM associated with Gram-negative pathogens has higher rates of in-hospital death [16]. Invasive infections associated with carbapenem-resistant Enterobacteriaceae (CRE) pose a serious challenge to clinicians. CRAB has increasingly emerged as an important nosocomial pathogen [17, 18], and the postoperative mediastinitis caused by CRAB is rare. It has severe complications associated with high morbidity and mortality. Treatments with polymyxin (polymyxin b or colistin), carbapenem, or their combinations are basically supported by observational studies [19, 20].\n\nThe significance of interplay between immune system-related substances and bacterial toxins in the pathogenesis of sepsis and the subsequent deleterious effects on organ function is well known. Apparently, endotoxins/LPS and lipoteichoic acid are the key toxins produced by Gram-negative and Gram-positive bacteria, respectively, playing an important role in inducing a systemic inflammatory response [21, 22] and it was found that removing them from circulation can have beneficial effects. Polymyxin B is a well-known antibiotic with high affinity for endotoxin and it is able to neutralize it, although it is associated with neurotoxicity and nephrotoxicity, which precludes its systemic use. In 1994, the Japanese company Toray (Tokyo, Japan) designed Toraymyxin (PMX-20R device) in order to adsorb and neutralize endotoxins from the circulation by using polymyxin B in extracorporeal modality, fixing it covalently on polystyrene fiber matrix. It has been shown in meta-analyses and many experimental studies [24, 25] that extracorporeal endotoxin adsorption using this method is beneficial in the management of patients with sepsis [23], especially in managing the septic shock and in the reversal of organ dysfunction. Some researchers [24, 25] reported that selective removal of endotoxins/LPS can specifically improve hemodynamic and respiratory functions, and this was explored in a systematic review by Cruz et al. [26] concluding that it is associated with an improved MAP, inotrope use, levels of PaO2/FiO2 ratio, and decreased mortality.\n\nSeveral studies reported improvement in SVR [27–31], CO, or cardiac index [29, 31]. However, pooled data seem to indicate that polymyxin B hemoperfusion should be able to increase blood pressure with the reduction of vasoactive agents [29, 32–35] compared with conventional treatments [36, 37]. Polymyxin B hemoperfusion might improve the oxygenation index and oxygenating lung functions [33, 34] possibly because of a reduction in pulmonary epithelium injury, permeability, and endothelial damage. Polymyxin B hemoperfusion improves gas exchange (PaO2/FiO2 ratio), but there was only a single randomized controlled trial (RCT) that reported this outcome and it showed only a non-significant positive trend [37]. After polymyxin B hemoperfusion, reduced levels of other mediators, such as interleukin (IL)-6 [38, 39], IL-10 [38, 39], IL-18 [40], tumor necrosis factor (TNF)-α [39, 41], metalloproteinase-9 [27], plasminogen activator inhibitor-1 [39, 41], neutrophil elastase [42, 43], platelet factor-4 [40], β-thromboglobulin [40], soluble P selectin [40], and endogenous cannabinoids, were also observed [44].\n\nHowever, there are currently no recommendations supporting (nor against) the routine use of blood purification techniques in sepsis in International Guidelines for Management of Sepsis and Septic Shock [45]. Moreover, a recent meta-analysis demonstrated a favorable effect on overall mortality with this technique [46]. However, these findings must be interpreted with caution because of the suboptimal quality of studies. The other treatment used in these patients was IgM-enriched polyclonal immunoglobulin (IVIgGM). Immunoglobulins constitute an innovative product with a wide range of clinical use.\n\nIn the 2016 Surviving Sepsis Campaign, there is a weak recommendation with low quality of evidence concerning the use of immunoglobulins [45]. One larger multicenter RCT [47] in adult patients found no benefit for intravenously administered immunoglobulin (IVIg). The Cochrane meta-analysis [48] differentiates between standard polyclonal intravenously administered immunoglobulins (IVIgG) and IVIgGM. In ten studies with IVIgG, mortality between 28 and 180 days was 29.6% in the IVIgG group and 36.5% in the placebo-group, and for the seven studies with IVIgGM, mortality between 28 and 60 days was 24.7% in the IVIgGM group and 37.5% in the placebo-group. The certainty of the studies was rated as low for the IVIgG trials, based on the risk of bias and heterogeneity, and as moderate for the IVIgGM trials, based on risk of bias. However, the recent Cochrane analysis revealed no survival benefits. These findings are similar to those of an older meta-analysis [49] from other Cochrane authors. One systematic review [50] showed a reduction in death with immunoglobulin treatment; however, the results of only high quality trials did not show a statistically significant difference. Finally, Laupland et al. [49] found a significant reduction in mortality with the use of IVIg treatment.\n\nRecently, two meta-analyses, using less strict criteria to identify sources of bias found significant improvement in patient mortality with IVIg treatment [51, 52]. Finally, there are no cut-offs for plasma IVIg levels in patients with sepsis, for which substitution with IVIg improves outcome data [52]. Subgroup effects between IgM-enriched and non-enriched formulations reveal significant heterogeneity. The low certainty of evidence led to the grading as a weak recommendation. The statistical information that comes from the high quality trials does not support a beneficial effect of polyclonal IVIg.\n\nConclusions\nIn our case we decided to start the treatment with immunoglobulins and polymyxin B hemoperfusion after the failure of conventional surgical and medical therapy and in light of elevated endotoxin level. This case of DNM was difficult to treat because of the presence of multidrug-resistant bacteria probably related to the delay in diagnosis and the use of first-line antibiotics for treatment of incorrectly assumed pneumonia. After the surgical source control, only with the combined use of IgM-enriched immunoglobulin preparation and polymyxin B hemoperfusion as integration antibiotic therapy, did we obtain an improvement of hemodynamic and respiratory parameters. CO, cardiac index, SVRs, central venous saturation of oxygen (ScVO2), and oxygen delivery (DO2I) improved. PaO2/FiO2 ratio improved, endotoxemia and PCT decreased, and vasoactive agents were interrupted. Despite the contrasting data on the use of immunoglobulins and polymyxin B hemoperfusion in septic shock and AM caused by either Gram-negative or Gram-positive multidrug-resistant bacteria, we obtained an improvement of clinical conditions and the survival of our patient against all odds.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThere is no funding to declare.\n\nAvailability of data and materials\nThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nVP pooled the data, analyzed the literature about mediastinitis and septic shock, and wrote the manuscript. MBP analyzed the literature about mediastinitis and septic shock. PS analyzed the literature about mediastinitis and septic shock. MCP analyzed the literature about mediastinitis and septic shock. FP analyzed the literature about mediastinitis and septic shock. AF analyzed the literature about mediastinitis and septic shock. CA pooled the data, analyzed the literature about mediastinitis and septic shock, and wrote the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe authors obtained ethics approval and written informed consent. We obtained Ethical Approval for the data publication from ethical Committee (EC).\n\nThe authors obtained consent for publication from the patient.\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-in-Chief 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. Prado-Calleros HM Jiménez-Fuentes E Jiménez-Escobar Descending necrotizing mediastinitis: Systematic review on its treatment in the last 6 years, 75 years after its description Head Neck. 2016 38 1 E2275 E2283 10.1002/hed.24183 26829352 \n2. Kocher GJ Hoksch B Caversaccio M Wiegand J Schmid RA Diffuse descending necrotizing mediastinitis: surgical therapy and outcome in a single-centre series Eur J Cardiothorac Surg. 2012 42 e66 e72 10.1093/ejcts/ezs385 22761501 \n3. 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"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "IgM-enriched immunoglobulin preparation; Mediastinitis; Polymyxin B hemoperfusion; Septic shock",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003131:Combined Modality Therapy; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria; D006094:Gram-Positive Bacteria; D006464:Hemoperfusion; D006801:Humans; D007075:Immunoglobulin M; D007362:Intensive Care Units; D008297:Male; D008480:Mediastinitis; D009333:Neck; D009336:Necrosis; D011112:Polymyxin B; D012121:Respiration, Artificial; D012772:Shock, Septic; D013908:Thoracotomy; D016896:Treatment Outcome; D015300:Ventilator Weaning",
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"pmid": "29499757",
"pubdate": "2018-03-03",
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"title": "Septic shock from descending necrotizing mediastinitis - combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report.",
"title_normalized": "septic shock from descending necrotizing mediastinitis combined treatment with igm enriched immunoglobulin preparation and direct polymyxin b hemoperfusion a case report"
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"abstract": "We report on a Subsaharian patient with HIV infection and disseminated tuberculosis who developed acute, severe hypersensitivity reaction to efavirenz including acute renal failure in addition to liver and lung involvement, in the absence of skin changes or blood eosinophilia.",
"affiliations": "Infectious Diseases and Tropical Medicine Unit, Department of Clinical and Surgical Sciences, University of Las Palmas de Gran Canaria, Plaza Dr Pasteur s/n, 35080 Las Palmas, Spain.",
"authors": "Angel-Moreno-Maroto|Alfonso|A|;Suárez-Castellano|Laura|L|;Hernández-Cabrera|Michele|M|;Pérez-Arellano|Jose-Luis|JL|",
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"title": "Severe efavirenz-induced hypersensitivity syndrome (not-DRESS) with acute renal failure.",
"title_normalized": "severe efavirenz induced hypersensitivity syndrome not dress with acute renal failure"
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"abstract": "BACKGROUND\nThe use of warfarin in patients undergoing hemodialysis is associated with decreased bone mineral density and an increased incidence of bone fracture. However, no studies to date have directly estimated bone quality with bone histomorphometry in patients with bone abnormalities who are taking warfarin and undergoing hemodialysis.\nA 47-year-old female with Noonan syndrome presented with progressive bilateral lower extremity pain on walking, and skin sclerosis. She had been undergoing maintenance hemodialysis for 25 years following 2 years of peritoneal dialysis for chronic glomerulonephritis. She had been taking warfarin as an anticoagulant agent for 13 years after she underwent an aortic valve replacement.\n\n\nMETHODS\nWarfarin-induced impairment of bone material quality.\n\n\nRESULTS\nHistomorphometric analysis of the bone biopsy specimens showed impairment in bone calcification processes, a high turnover of bone remodeling, low bone volume, and mild fibrosis. The bone abnormality could not be categorized into any type of representative bone disease classification such as osteitis fibrosa, osteomalacia, adynamic bone disease, uremic osteodystrophy, or hyperparathyroidism, but was consistent with warfarin-induced impairment of bone material quality.\n\n\nCONCLUSIONS\nWarfarin can induce impairment of bone material quality in a patient undergoing hemodialysis.",
"affiliations": "Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University.;Saitama Tsukinomori Clinic, Saitama, Japan.;Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University.;Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University.;Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University.;Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University.",
"authors": "Ishii|Hiroki|H|;Kurihara|Satoshi|S|;Hirai|Keiji|K|;Yanai|Katsunori|K|;Ookawara|Susumu|S|;Morishita|Yoshiyuki|Y|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
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"doi": "10.1097/MD.0000000000020724",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32569210\nMD-D-19-09664\n10.1097/MD.0000000000020724\n20724\n5200\nResearch Article\nClinical Case Report\nWarfarin-induced impairment of bone material quality in a patient undergoing maintenance hemodialysis\nA case reportIshii Hiroki MDa Kurihara Satoshi MD, PhDb Hirai Keiji MD, PhDa Yanai Katsunori MDa Ookawara Susumu MD, PhDa Morishita Yoshiyuki MD, PhDa∗ Saranathan. Maya a Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University\nb Saitama Tsukinomori Clinic, Saitama, Japan.\n∗ Correspondence: Yoshiyuki Morishita, Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan (e-mail: ymori@jichi.ac.jp).\n19 6 2020 \n19 6 2020 \n99 25 e207249 12 2019 31 3 2020 11 5 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nThe use of warfarin in patients undergoing hemodialysis is associated with decreased bone mineral density and an increased incidence of bone fracture. However, no studies to date have directly estimated bone quality with bone histomorphometry in patients with bone abnormalities who are taking warfarin and undergoing hemodialysis.\n\nPatient concerns:\nA 47-year-old female with Noonan syndrome presented with progressive bilateral lower extremity pain on walking, and skin sclerosis. She had been undergoing maintenance hemodialysis for 25 years following 2 years of peritoneal dialysis for chronic glomerulonephritis. She had been taking warfarin as an anticoagulant agent for 13 years after she underwent an aortic valve replacement.\n\nDiagnosis:\nWarfarin-induced impairment of bone material quality.\n\nInterventions and outcomes:\nHistomorphometric analysis of the bone biopsy specimens showed impairment in bone calcification processes, a high turnover of bone remodeling, low bone volume, and mild fibrosis. The bone abnormality could not be categorized into any type of representative bone disease classification such as osteitis fibrosa, osteomalacia, adynamic bone disease, uremic osteodystrophy, or hyperparathyroidism, but was consistent with warfarin-induced impairment of bone material quality.\n\nConclusion:\nWarfarin can induce impairment of bone material quality in a patient undergoing hemodialysis.\n\nKeywords\nbone material quality impairmentdialysishistomorphometric analysiswarfarinOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPatients undergoing hemodialysis have a higher risk of bone fracture due to impairment of bone material quality.[1] Several factors in this population contribute to impairment of bone material quality, including uremic osteodystrophy and secondary hyperparathyroidism.[2] Additionally, several drugs including glucocorticoids, loop diuretics, and warfarin have been shown to impair bone material quality.[3–5] Warfarin is an antagonist of vitamin K that can impair bone mineralization by inhibiting γ-carboxylation of osteocalcin, which is a vitamin K-dependent protein.[6] Vitamin K deficiency is frequently observed in patients undergoing hemodialysis.[7] Thus, in these patients, taking warfarin is considered to increase the impairment of bone material quality resulting in an increased risk of bone fracture. Previous studies have reported that the use of warfarin in patients undergoing hemodialysis is associated with decreased bone mineral density and an increased incidence of bone fracture.[8,9] However, no studies to date have directly estimated bone quality with bone histomorphometry in patients with bone abnormalities who are taking warfarin and undergoing hemodialysis. We herein report a case of warfarin-induced impairment of bone material quality that was evaluated by bone histomorphometry in a patient who was undergoing hemodialysis.\n\n2 Case\nA 47-year-old female with Noonan syndrome had been undergoing maintenance hemodialysis for 25 years following 2 years of peritoneal dialysis for chronic glomerulonephritis. She had been taking warfarin as an anticoagulant agent for 13 years after she underwent an aortic valve replacement. Her warfarin dose was 2 to 3 mg/d with a prothrombin time-international normalized ratio range from 1 to 2. For 3 years before admission, she experienced pain on walking, skin sclerosis, and a restricted range of joint motion in the bilateral lower extremities, and these symptoms were gradually progressing. Computed tomography showed extensive fascia and tendon calcification of the bilateral lower extremities (Fig. 1A and 1B, white arrows). Additionally, dual-energy X-ray absorptiometry showed low bone mineral density at -4.5 standard deviations compared with the standard value of bone mineral density of a younger age group (20–29 years old) in her radial bone. The patient's chronic kidney disease–mineral and bone disorder (CKD-MBD) was well controlled by taking calcium carbonate, vitamin D and calcimimetics; however, she had mild parathyroid swelling (4.8 mm × 9.0 mm × 7.5 mm). These results suggested a severe impairment of bone material quality apart from CKD-MBD. Thus, to investigate the cause of her bone abnormality and skin sclerosis, iliac bone and femoral skin biopsies were planned on admission. Upon admission, characteristic findings of Noonan syndrome including facial feature abnormalities, short stature, and a broad/webbed neck were found. Her mental development was normal. Skin findings including edema and painful sclerosis were detected, but no redness or ulceration of the skin were observed. The patient was taking calcium carbonate (500 mg/d), calcitriol (2.5 μg/d) and cinacalcet hydrochloride (25 mg/d). Laboratory data showed normal levels of serum calcium (10.1 mg/dL) and serum phosphate (3.0 mg/dL). Other laboratory data including bone metabolism markers are shown in Table 1.\n\nFigure 1 Computed tomography images of lower extremities. The images show calcification of the fascia in the lower extremities (A and B, white arrows).\n\nTable 1 Laboratory data on admission.\n\nA skin biopsy specimen from the right lower extremity showed severe calcification in the subcutaneous tissue (Fig. 2, black arrow). A bone biopsy was undertaken for bone histomorphometry analysis using the tetracycline double-labeling method.[10] Briefly, 14 days before the bone biopsy, tetracycline (600 mg/d) was administered for 2 days following a drug-free interval of 5 days. This course was repeated twice. Then, a biopsy of the iliac crest was performed. The bone histomorphometry analysis showed increased erosion (Fig. 3A, black broken line) and a number of osteoclasts (Fig. 3A, white arrow) on the bone surface. A large volume of osteoid (Fig. 3B, black broken line), and only 1 tetracycline-labeled band (Fig. 3B, white broken line) were observed in most areas, suggesting impairment of bone calcification processes; normal bone calcification is indicated by the presence of 2 tetracycline-labeled bands. Some mild fibrosis was observed. The results for other histomorphometric parameters are shown in Table 2. These bone biopsy findings led to a diagnosis of high bone turnover, low mineralization, and low bone volume (Table 3). The patient's bone disease could not be categorized into any type of representative bone disease classification such as osteitis fibrosa, osteomalacia, adynamic bone disease, uremic osteodystrophy or hyperparathyroidism in accordance with turnover, mineralization, and volume classifications (Table 3)[11,12], but was consistent with warfarin-induced impairment of bone material quality (Table 3).[13] These results led to a diagnosis of bone material quality impairment induced by warfarin. However, warfarin could not be suspended because of the increased risk of blood clots caused by the implanted mechanical aortic valve. Hence, treatment with a bisphosphonate (monthly intravenous ibandronate 1 mg), which binds to the bone mineral surface and inhibits osteoclasts, was started after diagnosis. Her skin sclerosis and clinical symptoms, such as lower extremity pain and limited range of joint motion, improved after 1 year of treatment with bisphosphonates. Furthermore, bone density was maintained and calcification in the subcutaneous tissue did not progress.\n\nFigure 2 Skin biopsy findings. Skin biopsy specimens show calcification of the subcutaneous tissue.\n\nFigure 3 Bone biopsy findings. (A) Increased erosion (Figure 3A, black broken line) and numerous osteoclasts (Figure 3A, white arrow) on the bone surface. The volume of osteoid is greatly increased (Figure 3B, black broken line), and only 1 tetracycline-labeled band is present (Figure 3B, white broken line).\n\nTable 2 Bone histomorphometry analysis.\n\nTable 3 Bone disease classification by turnover, mineralization, and volume.\n\n3 Discussion\nWe report a case of warfarin-induced impairment of bone material quality evaluated by bone histomorphometry in a patient who was undergoing hemodialysis.\n\nPrevious studies have reported that the use of warfarin is associated with an increased incidence of bone fractures in patients undergoing hemodialysis[14]; however, no studies have directly estimated bone quality by bone histomorphometry in patients with bone abnormalities who are taking warfarin. To our knowledge, this is the first report of warfarin-induced bone material quality impairment evaluated by bone histomorphometry in a patient undergoing hemodialysis.\n\nIn this case study, the bone histomorphometry analysis showed increases in erosion, the number of osteoclasts on the bone surface, and the osteoid volume. A significant reduction in the double-labeled surface was observed without diffuse fibrosis; this patient exhibited only one tetracycline-labeled band in most areas of bone. This bone abnormality was not representative of any type of bone disease in the turnover, mineralization, and volume classification.[11,12] A previous study reported that warfarin-treated animals showed increases in erosion and the number of osteoclasts on the bone surface without fibrosis.[13] Furthermore, long-term warfarin administration was shown to impair bone material quality in a rat experimental study.[15] These reported effects of warfarin led us to conclude that the patient's bone disease was induced by warfarin. However, because our patient had end-stage renal disease and was undergoing hemodialysis, it was necessary to consider the effects of CKD-MBD including secondary hyperparathyroidism as a possible cause of bone disease in this case. Secondary hyperparathyroidism is characterized by an increased level of serum parathyroid hormone. The serum parathyroid hormone level is positively correlated with bone turnover in CKD-MBD.[16] Additionally, an increased level of parathyroid hormone results in bone fibrosis and deficient bone mineralization.[17] In this case, the parathyroid hormone level was not high, and the bone fibrosis was quite mild; hence, it was unlikely that secondary hyperparathyroidism significantly contributed to the development of her bone disease. We observed an increase in the osteoid volume and a decrease in the double tetracycline labeling surface area in this patient. These observations indicated a deficiency in bone mineralization. Although deficient bone mineralization occurs in osteomalacia[11], the bone histomorphometry analysis of this patient showed no evidence of osteomalacia. Furthermore, this patient did not have any predisposing factors for osteomalacia such as vitamin D deficiency or iron overload.[18]\n\nIn this case, the ratio of undercarboxylated osteocalcin to carboxylated osteocalcin (undercarboxylated osteocalcin/carboxylated osteocalcin) in the serum was markedly elevated at 0.96 (normal range: <0.15–0.57). This ratio is regarded as a metabolic marker of vitamin K status in bone.[19] In this patient, undercarboxylated osteocalcin was elevated by negative feedback; its conversion to carboxylated osteocalcin may have been blocked by warfarin.[6] Additionally, X-ray and skin biopsy specimens of this patient showed severe calcification of the fascia, tendons and subcutaneous tissue. Such calcification can be explained by warfarin-mediated inhibition of vitamin K-dependent gla-protein which acts as a strong inhibitor of tissue calcification.[20] Noonan syndrome is not characterized by poor bone material quality. Taking all these factors into consideration, we concluded that the impaired bone material quality in this case was induced by warfarin. We administered a bisphosphonate (monthly intravenous ibandronate 1 mg) to inhibit osteoclast activity and suppress bone remodeling because the high turnover of bone was considered to be one of the factors accelerating the patient's bone disease.[21] Her skin sclerosis and clinical symptoms, such as lower extremity pain and limited range of joint motion, improved after 1 year of treatment with bisphosphonates. Furthermore, her bone density was maintained and calcification in the subcutaneous tissue did not progress. These results suggest that bisphosphonates may be effective at least partially in reducing warfarin-induced impairment of bone material quality in a patient undergoing maintenance hemodialysis. However, these effects of bisphosphonates need to be investigated carefully over a longer period.\n\nRecently, warfarin has been replaced in many cases with direct-acting oral anticoagulants for several reasons including drug interactions, a lower risk of major bleeding, and possible improvement in stroke prevention rates.[22] However, some concerns have been raised regarding the safety of direct-acting oral anticoagulants in patients undergoing dialysis. The development of direct-acting oral anticoagulants that can be safely used even in patients undergoing hemodialysis are yet to be developed.\n\nIn conclusion, we report a case of a patient undergoing hemodialysis who was diagnosed with warfarin-induced impairment of bone material quality. The analysis of bone histomorphometry was useful in the diagnosis of this bone disease.\n\nAcknowledgments\nWe thank Helen Jeays, BDSc AE, from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.\n\nAuthor contributions\nConceptualization: Satoshi Kurihara.\n\nData curation: Hiroki Ishii.\n\nInvestigation: Keiji Hirai, Katsunori Yanai.\n\nMethodology: Satoshi Kurihara, Susumu Ookawara.\n\nWriting – original draft: Hiroki Ishii.\n\nWriting – review & editing: Satoshi Kurihara, Yoshiyuki Morishita.\n\nAbbreviation: CKD-MBD = chronic kidney disease–mineral and bone disorder.\n\nHow to cite this article: Ishii H, Kurihara S, Hirai K, Yanai K, Ookawara S, Morishita Y. Warfarin-induced impairment of bone material quality in a patient undergoing maintenance hemodialysis: a case report. Medicine. 2020;99:25(e20724).\n\nPatient has provided informed consent for publication of the case.\n\nThere is no funding for this article.\n\nThe authors have no conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Pimentel A Urena-Torres P Zillikens MC \nFractures in patients with CKD-diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation\n. Kidney Int \n2017 ;92 :1343 –55\n.28964571 \n[2] Malluche HH Porter DS Pienkowski D \nEvaluating bone quality in patients with chronic kidney disease\n. Nat Rev Nephrol \n2013 ;9 :671 –80\n.24100399 \n[3] Compston J \nManagement of glucocorticoid-induced osteoporosis\n. Nat Rev Rheumatol \n2010 ;6 :82 –8\n.20125175 \n[4] Lim LS Fink HA Kuskowski MA \nLoop diuretic use and increased rates of hip bone loss in older men: the Osteoporotic Fractures in Men Study\n. Arch Intern Med \n2008 ;168 :735 –40\n.18413556 \n[5] Philip WJ Martin JC Richardson JM \nDecreased axial and peripheral bone density in patients taking long-term warfarin\n. QJM \n1995 ;88 :635 –40\n.7583077 \n[6] Sugiyama T Kugimiya F Kono S \nWarfarin use and fracture risk: an evidence-based mechanistic insight\n. Osteoporos Int \n2015 ;26 :1231 –2\n.25300528 \n[7] Fusaro M Plebani M Iervasi G \nVitamin K deficiency in chronic kidney disease: evidence is building up\n. Am J Nephrol \n2017 ;45 :1 –3\n.27842304 \n[8] Rezaieyazdi Z Falsoleiman H Khajehdaluee M \nReduced bone density in patients on long-term warfarin\n. Int J Rheum Dis \n2009 ;12 :130 –5\n.20374330 \n[9] Palermo A Tuccinardi D D’Onofrio L \nVitamin K and osteoporosis: myth or reality?\n\nMetabolism: clinical and experimental \n2017 ;70 :57 –71\n.28403946 \n[10] Melsen F Mosekilde L \nTetracycline double-labeling of iliac trabecular bone in 41 normal adults\n. Calcified tissue research \n1978 ;26 :99 –102\n.737565 \n[11] Moe S Drueke T Cunningham J \nDefinition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO)\n. Kidney Int \n2006 ;69 :1945 –53\n.16641930 \n[12] Dousdampanis P Trigka K \nThe importance of bone biopsy in chronic kidney disease-Mineral bone disorders\n. Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia \n2017 ;28 :992 –6\n.\n[13] Fusaro M Dalle Carbonare L Dusso A \nDifferential effects of dabigatran and warfarin on bone volume and structure in rats with normal renal function\n. PloS One \n2015 ;10 :e0133847 .26241483 \n[14] Fusaro M Tripepi G Noale M \nPrevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients\n. Curr Vasc Pharmacol \n2015 ;13 :248 –58\n.23927679 \n[15] Sugiyama T Takaki T Sakanaka K \nWarfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli\n. J Endocrinol \n2007 ;194 :213 –22\n.17592035 \n[16] Sprague SM Bellorin-Font E Jorgetti V \nDiagnostic accuracy of bone turnover markers and bone histology in patients with ckd treated by dialysis\n. Am J Kidney Dis \n2016 ;67 :559 –66\n.26321176 \n[17] Urena P Hruby M Ferreira A \nPlasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients\n. J Am Soc Nephrol \n1996 ;7 :506 –12\n.8704118 \n[18] Reginster JY \nThe high prevalence of inadequate serum vitamin D levels and implications for bone health\n. Curr Med Res Opin \n2005 ;21 :579 –86\n.15899107 \n[19] Nimptsch K Hailer S Rohrmann S \nDeterminants and correlates of serum undercarboxylated osteocalcin\n. Ann Nutr Metab \n2007 ;51 :563 –70\n.18227625 \n[20] Epstein M \nMatrix Gla-protein (MGP) not only inhibits calcification in large arteries but also may be renoprotective: connecting the dots\n. EBioMedicine \n2016 ;4 :16 –7\n.26981564 \n[21] Drake MT Clarke BL Khosla S \nBisphosphonates: mechanism of action and role in clinical practice\n. Mayo Clin Proc \n2008 ;83 :1032 –45\n.18775204 \n[22] Liew A O’Donnell M Douketis J \nComparing mortality in patients with atrial fibrillation who are receiving a direct-acting oral anticoagulant or warfarin: a meta-analysis of randomized trials\n. J Thromb Haemost \n2014 ;12 :1419 –24\n.24986568\n\n",
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"mesh_terms": "D000925:Anticoagulants; D015519:Bone Density; D012080:Chronic Kidney Disease-Mineral and Bone Disorder; D005260:Female; D006801:Humans; D008875:Middle Aged; D009634:Noonan Syndrome; D006435:Renal Dialysis; D014859:Warfarin",
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"title": "Warfarin-induced impairment of bone material quality in a patient undergoing maintenance hemodialysis: A case report.",
"title_normalized": "warfarin induced impairment of bone material quality in a patient undergoing maintenance hemodialysis a case report"
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"abstract": "BACKGROUND\nImmune checkpoint inhibitors are monoclonal antibodies which target immune \"checkpoints\" enhancing T cell-mediated cytotoxic and antitumor responses. Together to the amazing results, these drugs are associated with some peculiar adverse events called immune-related adverse events. Alopecia is one of these. It is usually reported to be clinically and histologically similar to alopecia areata.\n\n\nOBJECTIVE\nWe report a case of eosinophilic folliculitis of the scalp occurred during nivolumab therapy, its management and some pathogenetic hypotheses.\n\n\nMETHODS\nHerein, we report the first case of eosinophilic folliculitis of the scalp occurred during nivolumab therapy, firstly appeared as a lichen planopilaris. Topical steroids and fusidic acid cream were applied with partial benefit and a scaring outcome. No discontinuation of nivolumab was required.\n\n\nCONCLUSIONS\nImmune checkpoint inhibitors induced inflammatory response leads to the exposure of hair follicle antigens and a consequent loss of Immuno Privilege. We hypothesize a role of steroids in deviating a primarily lichenoid reaction toward a folliculitis.",
"affiliations": "Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.;Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.;Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.;Department of Ematology, Oncology and Dermatology, \"Sapienza\" University of Rome, Rome, Italy.",
"authors": "Rossi|Alfredo|A|https://orcid.org/0000-0002-7442-3423;Magri|Francesca|F|https://orcid.org/0000-0002-6365-7291;Caro|Gemma|G|https://orcid.org/0000-0002-6568-3389;Federico|Alessandro|A|;Fortuna|Maria Caterina|MC|;Soda|Giuseppe|G|;De Vincentiis|Ludovica|L|;Carlesimo|Marta|M|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D061026:Programmed Cell Death 1 Receptor",
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"journal": "Journal of cosmetic dermatology",
"keywords": "folliculitis; hair; immune checkpoint; nivolumab; scaring alopecia",
"medline_ta": "J Cosmet Dermatol",
"mesh_terms": "D000505:Alopecia; D005499:Folliculitis; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008010:Lichen Planus; D061026:Programmed Cell Death 1 Receptor; D012535:Scalp",
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"title": "Eosinophilic folliculitis of the scalp associated with PD-1/PDL1 inhibitors.",
"title_normalized": "eosinophilic folliculitis of the scalp associated with pd 1 pdl1 inhibitors"
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"abstract": "The present report describes a case of diffuse panbronchiolitis (DPB) in a child from Western China and the favorable outcome associated with early diagnosis. DPB is an uncommon presentation in pediatric patients. A 13-year-old Chinese boy was admitted to the respiratory outpatient department due to recurrent cough and progressive exertional dyspnea that had persisted for 1 year. An initial diagnosis of bronchial asthma was made, and the patient was prescribed inhaled fluticasone combined with salmeterol (50/250 µg, twice daily), and montelukast (4 mg daily). However, 2 months later no clinical improvement was observed. The disease was re-diagnosed as DPB following the identification of features such as centrilobular small nodular opacities, a 'tree-in-bud appearance' and thickening of the bronchial walls meeting the diagnostic criteria for DPB. Complete resolution of the disease and sustained alleviation of the patient's respiratory symptoms were achieved following the early institution of erythromycin therapy, and the exacerbation of chronic bronchitis was reduced. In conclusion, it is essential to consider that successful treatment for DPB lies in early diagnosis and early treatment. DPB may be treated well by use of erythromycin.",
"affiliations": "Department of Respiratory Medicine, Institute of Surgery Research, The Third Affiliated Hospital, The Third Military Medical University, Chongqing 400042, P.R. China.;Department of Radiology, Institute of Surgery Research, The Third Affiliated Hospital, The Third Military Medical University, Chongqing 400042, P.R. China.;Department of Respiratory Medicine, Institute of Surgery Research, The Third Affiliated Hospital, The Third Military Medical University, Chongqing 400042, P.R. China.;Department of Respiratory Medicine, Institute of Surgery Research, The Third Affiliated Hospital, The Third Military Medical University, Chongqing 400042, P.R. China.",
"authors": "Zhao|Na-Na|NN|;Cao|Hui|H|;Zhang|Shi-Si|SS|;Cao|Guo-Qiang|GQ|",
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"issue": "13(5)",
"journal": "Experimental and therapeutic medicine",
"keywords": "Western China; child; diffuse panbronchiolitis",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "2094-2096",
"pmc": null,
"pmid": "28565813",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": "22640847;25824890;8313679;17953806;16082696;26705139;26888742",
"title": "Successful treatment of diffuse panbronchiolitis in a child from Western China: A case report.",
"title_normalized": "successful treatment of diffuse panbronchiolitis in a child from western china a case report"
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"abstract": "Palbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor that is indicated in combination with an aromatase inhibitor for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2 -negative advanced or metastatic breast cancer. The commonly described side effects of palbociclib are neutropenia, anaemia, thrombocytopenia, fatigue, nausea, stomatitis, alopecia, diarrhoea, decreased appetite, vomiting, asthenia, peripheral neuropathy and epistaxis. However, post approval, increasing use of this drug has revealed another potentially fatal complication, in the form of pneumonitis, especially in the Asian population. The PALOMA 3 trial showed that rates of grade 3 and grade 4 adverse events were modestly higher in Asians than non-Asians, though palbociclib exposure was similar in both races. From this, we could infer that adverse effects of this drug must be monitored more specifically in individual racial populations. We report a patient who developed pneumonitis while on palbociclib and discuss the possible mechanisms and management of CDK 4/6 inhibitor-related lung injury.",
"affiliations": "Department of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India.;Department of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India.;Department of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India.;Department of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India.;Department of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India.",
"authors": "Mathew|Namrata|N|;Joel|Anjana|A|;Andrews|Anand George|AG|;John|Ajoy Oommen|AO|;Singh|Ashish|A|",
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"doi": "10.3332/ecancer.2021.1245",
"fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605\nCancer Intelligence\n\n10.3332/ecancer.2021.1245\ncan-15-1245\nCase Report\nCDK 4/6 inhibitor induced lung injury: a case report and review of literature\nMathew Namrata\nJoel Anjana\nAndrews Anand George\nJohn Ajoy Oommen\nSingh Ashish\nDepartment of Medical Oncology, Christian Medical College and Hospital, Ida Scudder Road, Vellore 632004, Tamilnadu, India\nCorrespondence to: Dr Anjana Joel anjanajoel@gmail.com\n2021\n07 6 2021\n15 124526 11 2020\n© the authors; licensee ecancermedicalscience.\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nPalbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor that is indicated in combination with an aromatase inhibitor for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2 -negative advanced or metastatic breast cancer. The commonly described side effects of palbociclib are neutropenia, anaemia, thrombocytopenia, fatigue, nausea, stomatitis, alopecia, diarrhoea, decreased appetite, vomiting, asthenia, peripheral neuropathy and epistaxis. However, post approval, increasing use of this drug has revealed another potentially fatal complication, in the form of pneumonitis, especially in the Asian population. The PALOMA 3 trial showed that rates of grade 3 and grade 4 adverse events were modestly higher in Asians than non-Asians, though palbociclib exposure was similar in both races. From this, we could infer that adverse effects of this drug must be monitored more specifically in individual racial populations. We report a patient who developed pneumonitis while on palbociclib and discuss the possible mechanisms and management of CDK 4/6 inhibitor-related lung injury.\n\ndrug induced pneumonitis\nCDK 4/6 inhibitors\npalbociclib\n==== Body\nIntroduction\n\nCyclin dependent kinase (CDK) 4/6 inhibitors are the backbone of the treatment of metastatic oestrogen receptor positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The haematological adverse events (neutropenia, leukopenia, thrombocytopenia) and non-haematological adverse events (fatigue, diarrhoea, nausea) are well described. We describe a patient who developed pneumonitis while on palbociclib, review the literature and discuss the possible mechanisms and management of CDK 4/6 inhibitor related lung injury.\n\nCase presentation\n\nA 67-year-old post-menopausal lady was diagnosed to have metastatic hormone positive breast cancer in February 2019. Her imaging showed multiple bony metastases with few bilateral subpleural metastases (<1 cm). She underwent open reduction and internal fixation for a pathological fracture of her right neck of femur. Biopsy of the breast lump showed an infiltrating ductal carcinoma grade 1, Estrogen receptor (ER) + (Allred 8/8), progesterone receptor+ (PR+) and HER2 negative. She was a well-controlled hypertensive and had a background of bronchiectasis (Figure 1) for which she was asymptomatic. Her bronchiectasis was first diagnosed in 2 years prior to the current diagnosis of breast cancer, when she presented to another hospital was a probable infective exacerbation of underlying lung disease. She had no prior history of necrotising pneumonia in childhood or tuberculosis or features of ciliary dyskinesias/cystic fibrosis. There was no clinical or serological evidence of autoimmune disease (acute inflammatory markers were, however, elevated due to inflammatory, fumigating breast carcinoma). Acute infective aetiologies were also ruled out, with multiple blood and sputum cultures for bacteria, mycobacteria and fungi yielding no growth. Polymerase chain reaction (PCR) for viruses and mycobacteria was also negative. There was no evidence of immunocompromise other than underlying malignancy which was diagnosed subsequently in Feb 2019.\n\nShe was started on 3-monthly Zoledronic acid and palbociclib with Letrozole. There was significant reduction in size of the breast lesion, with healing of the breast ulcer and clinical improvement in terms of her bone pains. Four months later, she developed dry nonproductive cough and worsening breathlessness on exertion with no history of fever or prodromal illness. She was non-neutropenic with no renal or hepatic dysfunction. Arterial blood gas showed hypoxaemia and type 1 respiratory failure. Her high-resolution computed tomography (CT) thorax (Figure 2) was compared with her baseline imaging (Figure 1) and showed multiple new patchy and confluent ground glass opacities (GGOs) in bilateral lung fields, suggestive of acute interstitial lung disease (ILD).\n\nA comprehensive workup including blood and sputum cultures was negative for bacterial, mycobacterial, fungal infections, influenza and pneumocystis carinii. Serological workup for underlying connective tissue disorder including anti-nuclear antibody, double-stranded DNA, Rheumatoid factor and anti-cyclic citrullinated peptide (CCP) was also negative. She was started on noninvasive ventilation and broad-spectrum intravenous (IV) antibiotics as she was unfit for a bronchoscopy/bronchoalveolar lavage (BAL) in view of her rapid deterioration. After a detailed discussion with the patient, she was started on IV methylprednisolone with an empirical diagnosis of drug induced pneumonitis. She refused aggressive treatment including ICU care, invasive ventilation and continued non-invasive ventilation. She was weaned off the noninvasive ventilation and was discharged on home oxygen therapy and letrozole. A follow-up CT was not performed as the patient clinically improved on systemic corticosteroids and antibiotics and she refused subsequent scans and opted for comfort care. Thus, after initiation of palbociclib in March 2019, palbociclib was discontinued in June 2019; after she developed the pneumonitis. She had also expressed her wishes against further imaging or invasive procedures. Therefore, bronchoscopy, trans-bronchial lung biopsy and/or BAL were not performed. She succumbed to her illness a month later at home.\n\nDiscussion\n\nDrug induced pneumonitis related to conventional chemotherapeutic agents like bleomycin, methotrexate, gemcitabine and taxanes and oral agents like epidermal growth factor receptor tyrosine kinase inhibitors and everolimus is well described [1, 2]. Pneumonitis as an immune related adverse event, especially following anti-cytotoxic T lymphocyte associated protein (CTLA) 4 agents is managed with the help of an algorithmic approach [3]. Improvement in our understanding of the mechanisms and patterns of pulmonary toxicity related to these agents has reflected in our capacity to suspect and recognise this toxicity early. Delayed recognition of this entity leads to a more severe grade of pneumonitis at diagnosis which leads to higher morbidity and mortality.\n\nCDK 4/6 inhibitors are known for their efficacy and favourable adverse event profile which allows patients to maintain their quality of life. Severe and adverse non-haematological toxicities associated with these drugs are rare and sporadic and have been only been described in case reports or case series. [4–6].\n\nThe incidence of pulmonary toxicity (pneumonitis/respiratory failure/embolism) ranges around 1% [7–14]. There are few prior publications reporting CDK 4/6 inhibitor associated ILD (Table 1). It is a diagnosis of exclusion, in the setting of patients on CDK 4/6 inhibitors presenting with respiratory distress without any infective or auto immune aetiology. All patients were managed with steroids, ventilatory support and supportive measures. The first report of CDK 4/6i related pneumonitis in Asia was from Japan among 14 patients, with the use of Abemaciclib [15].\n\nMechanisms for CDK 4/6 inhibitor related lung injury are largely unclear and are still under investigation. In a study done on mouse models in 2020, palbociclib (CDK 4/6 inhibitor) was evaluated as a means to ameliorate pulmonary fibrosis in mice treated with intra-tracheal bleomycin. It was postulated that as CDK 4/6 inhibitors were essentially cell cycle inhibitors, they could attenuate the development of bleomycin induced pulmonary fibrosis. However, though palbociclib in this study was found to reduce collagen deposition in the lung, it did not translate into improvement in pulmonary function and also led to significant weight loss and deterioration of general health in the treated mice. BAL showed recruitment of large number of inflammatory cells, including significantly increased levels of monocyte-derived and interstitial macrophages, dendritic cells, neutrophils, γδTCR+ and CD8+ effector T-cells.\n\nIt was further proposed that this altered inflammatory cell milieu, in the presence of a cell cycle inhibitor like palbociclib, led to cell senescence and a consequent ‘senescence associated secretory phenotype’ (SASP). The SASP is in essence an increase in inflammatory cytokines, growth factors and extracellular matrix modulating proteins that promote pulmonary fibrosis [2]. The role of cellular SASP has been elucidated in other studies as well [3, 4]. However, the possible synergy of palbociclib and Bleomycin, and the exact role of each of the above-mentioned inflammatory cell types in CDK 4/6 inhibitor mediated lung injury has to be addressed in future studies.\n\nOur patient and those described in prior literature have developed these side effect months into their treatment, implying that this is not an immediate side effect following initiation of CDK 4/6i. There are no patient or disease related factors that point to a predisposition for CDK 4/6i related pneumonitis. The diagnosis of CDK 4/5 inhibitor related ILD in majority of these patients was arrived at after extensive workup (including a bronchoscopy with BAL fluid cultures and transbronchial lung biopsy) to rule out infections, autoimmune aetiologies and disease progression. As with any other drug induced pneumonitis, removal of the offending agent along with oxygen and ventilatory support with IV steroids and broad-spectrum antibiotic cover, while allowing recovery of pulmonary function is the common therapeutic approach.\n\nConclusion\n\nThe use of CDK 4/6 inhibitors in the first- and second-line setting in metastatic hormone positive breast cancer is the new standard of care and has led to the more widespread use of these agents. CDK 4/6i related pneumonitis requires early diagnosis and prompt discontinuation of the offending agent in order to improve outcomes.\n\nConflicts of interest\n\nThe authors declare that they have no conflicts of interest.\n\nFunding statement\n\nThe authors received no financial support for the research, authorship and publication of this article.\n\nFigure 1. High-resolution CT thorax of the patient prior to initiation of CDK 4/6 inhibitor (Palbociclib).\n\nFigure 2. High-resolution CT thorax of the patient, taken at timepoint of clinical deterioration, three months after initiation of CDK 4/6 inhibitor (Palbociclib) therapy.\n\nTable 1. Comparison of our patient with those described a priori.\n\n\t\tCDK 4/6 inhibitor\tAge\tCT appearance\tCompanion drug\tBronchoscopy/transbronchial lung biopsy\tOutcome\t\nPatient 1\tJazieh et al [4]\tPalbociclib\t74\tBilateral ground glassing\tFulvestrant\tNonspecific lung injury\tRecovered after 8 months of home oxygen\t\nPatient 2\tJazieh et al [4]\tAbemaciclib\t60\tPatchy multifocal alveolar ground-glass densities within the upperlobes\tFulvestrant\tBAL showed inflammatory cells\tDead\t\nPatient 3\tAhsan et al [5]\tPalbociclib\t52\tBilateral ground glassing\tNA\tNot done\tHospice\t\nPatient 4\tGong et al [6]\tPalbociclib\t72\tBilateral ground glassing\tFulvestrant\tNot done\tResolution after 3 months of home oxygen\t\nPatient 5\tOfer et al [16]\tPalbociclib\t71\tPeripheral sub-pleural consolidations with air bronchogram and scattered GGO\tLetrozole\tTransbronchial lung biopsy showed subacute lung injury/organising diffuse alveolar damage\tDead\t\nPatient 6\tOur patient\tPalbociclib\t67\tBilateral ground glassing\tLetrozole\tNot done\tDead\n==== Refs\nReferences\n\n1. Leger P Limper AH Maldonado F Pulmonary toxicities from conventional chemotherapy Clin Chest Med 2017 38 2 209 222 10.1016/j.ccm.2017.01.002 28477634\n2. Shah RR Shah DR Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology Drug Saf 2019 42 2 181 198 10.1007/s40264-018-0772-x 30649743\n3. Jain A Shannon VR Sheshadri A Naing A Hajjar J Immune-related adverse events: pneumonitis Immunotherapy 2018 18/10/19 Cham Springer International Publishing 131 149 [Internet] [http://link.springer.com/10.1007/978-3-030-02505-2_6] 10.1007/978-3-030-02505-2_6\n4. Jazieh KA Budd GT Dalpiaz N Can CDK4/6 inhibitors cause fatal lung injury? Expert Rev Anticancer Ther 2019 19 11 917 919 10.1080/14737140.2019.1674651 31566017\n5. Ahsan I Malik F Jafri SI Palbociclib related pnemotoxicity: a rare side effect C43 Drug Induced Lung Disease: Case Reports 2017 18/10/19 American Thoracic Society A5546 A5546 [Internet] [https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A5546]\n6. Gong J Cho M Yu KW A single institution experience with palbociclib toxicity requiring dose modifications Breast Cancer Res Treat 2018 168 2 381 387 10.1007/s10549-017-4606-9 29218462\n7. Hortobagyi GN Stemmer SM Burris HA Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer Ann Oncol 2018 29 7 1541 1547 10.1093/annonc/mdy155 29718092\n8. Johnston S Martin M Di Leo A MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer NPJ Breast Cancer 2019 5 1 1 8 10.1038/s41523-018-0097-z 30675511\n9. Johnston S Martin M Leo AD MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer NPJ Breast Cancer 2019 24/10/19 5 5 Available from: https://www.nature.com/articles/s41523-018-0097-z 10.1038/s41523-018-0097-z 30675515\n10. Slamon DJ Neven P Chia S Phase III randomized study of ribociclib and fulvestrant in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3 J Clin Oncol 2018 36 24 2465 2472 10.1200/JCO.2018.78.9909 29860922\n11. Tripathy D Im SA Colleoni M Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial Lancet Oncol 2018 19 7 904 915 10.1016/S1470-2045(18)30292-4 29804902\n12. Cristofanilli M Turner NC Bondarenko I Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 2016 18/10/19 17 4 425 439 Available from: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00613-0/fulltext 10.1016/S1470-2045(15)00613-0 26947331\n13. Tripathy D Im S Colleoni M Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial Lancet Oncol 2018 18/10/19 19 7 904 915 [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30292-4/fulltext] 10.1016/S1470-2045(18)30292-4 29804902\n14. Cristofanilli M Turner NC Bondarenko I Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 2016 17 4 425 439 10.1016/S1470-2045(15)00613-0 26947331\n15. Breast cancer drug Verzenio could have serious side effects on lungs, Japan’s health ministry warns | The Japan Times [Internet] 18/10/19 [https://www.japantimes.co.jp/news/2019/05/17/national/science-health/breast-cancer-drug-verzenio-serious-side-effects-lungs-japans-health-ministry-warns/#.Xam5k-gzY2w]\n16. Fatal palbociclib-related interstitial pneumonitis [Internet] 04/12/19 [http://www.fortunejournals.com/articles/fatal-palbocyclibrelated-interstitial-pneumonitis.html]\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "15()",
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"keywords": "CDK 4/6 inhibitors; drug induced pneumonitis; palbociclib",
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"title": "CDK 4/6 inhibitor induced lung injury: a case report and review of literature.",
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"abstract": "Background: Dynamic lung hyperinflation (DLH) following metronome-paced incremental hyperventilation (MPIH) was reported to be useful for assessment of pathophysiological impairment in patients with chronic obstructive pulmonary disease (COPD), and the effects of tiotropium and olodaterol on DLH following MPIH have not been reported. Methods: Treatment consisted of administration of tiotropium/olodaterol 5/5 μg inhalation solution (2.5/2.5 μg per actuation) using a soft-mist inhaler once a day. We compared outcomes before and after 8 weeks of treatment. The primary outcome was defined as a decrease in inspiratory capacity (IC) from rest by MPIH, which is an index of DLH. The secondary outcomes were COPD assessment test (CAT), forced expiratory volume in 1 s (FEV1), and 6-min walking distance (6MWD). In addition, we investigated whether there were correlations between changes with treatment in DLH and FEV1, 6MWD, and dyspnea. Results: Thirty-three of the 38 registered patients completed this study. Most of these 33 patients had mild to moderate COPD. Decreasing IC by MPIH was significantly reduced by treatment for 8 weeks, with a mean change of about -0.11 to -0.13 mL (P <0.05). In addition, CAT score, FEV1, and 6MWD improved with treatment (P <0.05). There were no significant correlations between changes in DLH, FEV1, 6MWD, or dyspnea with treatment. Conclusions: The results of this study showed that the combination of tiotropium and olodaterol is effective for improvement of DLH following hyperventilation.",
"affiliations": "Department of Biomedical Laboratory Science, Graduate School of Medicine, Shinshu University, Nagano 390-8621, Japan.;Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences, Matsumoto 390-8621, Japan.",
"authors": "Kawachi|Shohei|S|;Fujimoto|Keisaku|K|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D004338:Drug Combinations; D018727:Muscarinic Antagonists; C000611386:tiotropium-olodaterol; D000069447:Tiotropium Bromide",
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"fulltext": "\n==== Front\nInt J Chron Obstruct Pulmon DisInt J Chron Obstruct Pulmon DisCOPDcopdInternational Journal of Chronic Obstructive Pulmonary Disease1176-91061178-2005Dove 20110610.2147/COPD.S201106Original ResearchEfficacy of tiotropium and olodaterol combination therapy on dynamic lung hyperinflation evaluated by hyperventilation in COPD: an open-label, comparative before and after treatment study Kawachi and FujimotoKawachi and FujimotoKawachi Shohei 1Fujimoto Keisaku 21 Department of Biomedical Laboratory Science, Graduate School of Medicine, Shinshu University, Nagano\n390-8621, Japan2 Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences, Matsumoto\n390-8621, JapanCorrespondence: Keisaku Fujimoto Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences, 3-1-1, Asahi, Matsumoto390-8621, JapanTel +81 26 337 2393Fax +81 26 337 2393Email keisaku@shinshu-u.ac.jp27 5 2019 2019 14 1167 1176 10 1 2019 10 4 2019 © 2019 Kawachi and Fujimoto.2019Kawachi and Fujimoto.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background: Dynamic lung hyperinflation (DLH) following metronome-paced incremental hyperventilation (MPIH) was reported to be useful for assessment of pathophysiological impairment in patients with chronic obstructive pulmonary disease (COPD), and the effects of tiotropium and olodaterol on DLH following MPIH have not been reported.\n\nMethods: Treatment consisted of administration of tiotropium/olodaterol 5/5 μg inhalation solution (2.5/2.5 μg per actuation) using a soft-mist inhaler once a day. We compared outcomes before and after 8 weeks of treatment. The primary outcome was defined as a decrease in inspiratory capacity (IC) from rest by MPIH, which is an index of DLH. The secondary outcomes were COPD assessment test (CAT), forced expiratory volume in 1 s (FEV1), and 6-min walking distance (6MWD). In addition, we investigated whether there were correlations between changes with treatment in DLH and FEV1, 6MWD, and dyspnea.\n\nResults: Thirty-three of the 38 registered patients completed this study. Most of these 33 patients had mild to moderate COPD. Decreasing IC by MPIH was significantly reduced by treatment for 8 weeks, with a mean change of about −0.11 to −0.13 mL (P <0.05). In addition, CAT score, FEV1, and 6MWD improved with treatment (P <0.05). There were no significant correlations between changes in DLH, FEV1, 6MWD, or dyspnea with treatment.\n\nConclusions: The results of this study showed that the combination of tiotropium and olodaterol is effective for improvement of DLH following hyperventilation.\n\nVideo abstract\n\n\nPoint your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:\n\nhttps://youtu.be/j1pN5vQuhyc\n\nKeywords\nbronchodilator agentstiotropiumolodateroldynamic lung hyperinflationhyperventilation\n==== Body\nIntroduction\nDynamic lung hyperinflation (DLH) is an important factor involved in dyspnea on exertion and exercise limitation in chronic obstructive pulmonary disease (COPD).1 Therefore, it is important to improve DLH by treatment. DLH involves hyperinflation of the lung, which progresses by hyperventilation with exertion. In patients with COPD, the decrease in lung elastic recoil pressure and narrowing of the peripheral bronchial lumen have been considered to induce lung hyperinflation. Therefore, exhalation may not be completed prior to the onset of the next breath, causing progressive hyperinflation.2 DLH refers to the variable increase in end-expiratory lung volume (EELV) above the relaxation volume of the respiratory system.3 As total lung capacity (TLC) remains essentially unchanged during exercise, changes in EELV during exercise can be reliably tracked by serial inspiratory capacity (IC) measurements.4\n\nThere is evidence that combined administration of a long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) in patients with COPD provides increases forced expiratory volume in 1 s (FEV1) and reduces symptoms compared to monotherapy. Therefore, combination therapy with LAMA and LABA is recommended in patients with more severe symptoms, especially those suffering from dyspnea and exercise limitation.5 Previous clinical trials have demonstrated the efficacy of combined treatment with tiotropium and olodaterol on FEV1, health-related quality of life, and exacerbation in patients with COPD.6,7,8 In addition, the MORACTO trial demonstrated improvements of IC at rest and during exercise associated with tiotropium and olodaterol treatment.9 However, the effects of tiotropium and olodaterol on DLH following metronome-paced incremental hyperventilation (MPIH) have not been reported. Gelb et al, reported that the non-invasive simplicity of hyperventilation provides a clinically useful screening surrogate for monitoring changes in IC following exercise.10 Then, we reported DLH following MPIH using a spirometer. DLH is dependent on the increase in respiration rate, and we measured the decrease in IC with stepwise increases in respiration rate (Figure 1). IC is significantly reduced in patients with COPD, resulting in DLH. Therefore, we showed that DLH following MPIH is useful for assessment of pathophysiological impairment in patients with COPD.11 Using this method, we investigated the effects of single and combined use of LAMA and LABA in DLH.12,13 However, the effects of tiotropium and olodaterol on DLH following MPIH have not been reported. This study was performed to elucidate the effects of combined treatment with tiotropium and olodaterol on DLH following MPIH in patients with COPD.Figure 1 Method for measuring dynamic lung hyperinflation by hyperventilation.\n\nAbbreviations: IC, inspiratory capacity; bpm, breaths/min; DLH, dynamic lung hyperinflation.\n\n\n\nMaterials and methods\nSubjects\nThe study population consisted of patients with stable COPD who visited Shinshu University Hospital (Matsumoto, Nagano, Japan) or Shinsei Hospital (Obuse, Nagano, Japan) between March 1, 2017, and December 1, 2018. Diagnosis was made according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.5 Patients were diagnosed based on medical history and respiratory function characterized by clinical symptoms and irreversible airflow obstruction.\n\nAll patients suffered from smoking-related COPD without α1 antitrypsin deficiency, and those with a smoking history of ≥10 pack-years, including current smokers, were selected for this study. In addition, as a substitute for LAMA and LABA during the washout period, patients whose symptoms responded to short-acting treatment were selected as eligible for inclusion. After receiving a thorough explanation of the study, patients who provided written consent were enrolled in the study. Patients with dysuria due to prostate hypertrophy, glaucoma, severe heart failure, symptom exacerbation and/or respiratory infection within 3 months, prior history of lung surgery, severe heart disease, or impairment or difficulty in walking due to motor or cognitive dysfunction were excluded. A history of exacerbation was defined as acute worsening of respiratory symptoms that resulted in additional therapy.5 Registration in this study was suspended for patients who declined to participate or withdrew their consent or if it was found after registration that the subject did not satisfy the eligibility criteria.\n\nEthical considerations\nThis study was conducted in accordance with the tenets of the Declaration of Helsinki, received approval from Shinshu University Medical Ethics Committee (approval number: 3654), and has been registered in the University Hospital Medical Information Network Clinical Trials Registry system (trial ID: UMIN000027521). Individual de-identified participant data for all outcomes were used in the analysis and shared on the University Hospital Medical Information Network Clinical Trials Registry system (UMIN). The data can be accessed by registering with UMIN, and then contacting the author to receive the appropriate URL. As the number of people that can view the data is limited, this requires approval from the author. The data have already been registered on UMIN, and there is no restriction on the period of publication. Documents related to other available study are research plan on the internet.\n\nStudy design\nThis study had an open-label, prospective, comparative before and after treatment design. Patients visiting the hospital for diagnosis and treatment of COPD who provided informed consent were included in the study. The combination of LAMA and LABA used consisted of Spiolto™ and Respimat®, respectively (Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan), which contained 2.5 μg of tiotropium and 2.5 μg of olodaterol per puff, respectively. We set a washout period of 3 days before the baseline examination in patients who had already been prescribed LAMA, LABA, and/or inhaled corticosteroid (ICS) based on their half-lives.14,15 In an emergency during the washout period, short-acting treatment was used to respond to symptoms. Patients first underwent baseline examination after washout consisting of COPD questionnaire followed by lung function testing. Then, we performed DLH measurement by MPIH followed by 6-min walking test (6MWT). Treatment was performed on the day after completion of the baseline examination, and consisted of administration of tiotropium/olodaterol 5/5 μg inhalation solution (2.5/2.5 μg per actuation) using a soft-mist inhaler. Patients were instructed to inhale two puffs from the inhaler, once a day, in the morning. After 8 weeks, the same test was repeated for before and after comparison following inhalation as usual. The primary outcome was defined as a decrease in IC from rest by MPIH, which is an index of DLH. The secondary outcomes were the COPD assessment test (CAT), FEV1, and 6-min walking distance (6MWD). As in previous studies, we also investigated whether there were correlations between changes in DLH and exercise tolerance or dyspnea on exercise associated with treatment.\n\nEfficacy outcomes\nDLH\nIn this study, DLH was measured using a spirometer (Fukuda Denshi Co., Ltd., Tokyo, Japan). The subjects regulated their breathing rate and timing in accordance with a light-emitting diode lamp for inspiration and expiration using a buzzer sound in place of a metronome. Each subject was asked to take several breaths at rest and then perform maximum inspiration followed by maximum expiration. Figure 2 shows the measurement of DLH based on MPIH using a spirometer. The resting IC and vital capacity (VC) was then measured. Next, the subjects breathed in synchronization with a pulsing sound and light for 30 s at a respiratory rate of 20 breaths/min (bpm). Finally, the subjects performed maximum inspiration. After a 1–2 mins pause, the respiratory rate was increased in steps to 30 bpm for 30 s and then to 40 bpm for 30 s. At the end of each period of hyperventilation, the subjects performed maximum inspiration, and the IC was measured. The average of the valleys of three breaths just before maximum inspiration was set as the EELV, and the IC was measured from the EELV. IC measurement by each hyperventilation was repeated three times, and the machine automatically calculated the average. The ICs at rest and at hyperventilation rates of 20, 30, and 40 bpm were expressed as the ICrest, IC20, IC30, and IC40, respectively. DLH was evaluated from the decreases in IC from ICrest to IC20 (−IC20; IC20−ICrest), to IC30 (−IC30; IC30−ICrest), and to IC40 (−IC40; IC40−ICrest). The ratios of −IC20, −IC30, and −IC40 to resting IC were expressed as ΔIC20, ΔIC30, and ΔIC40, respectively.Figure 2 Details of dynamic lung hyperinflation measurement method using spirometer.\n\nAbbreviations: IC, inspiratory capacity; bpm, breaths/min; ICrest, IC at rest; IC20, IC at 20 bpm; IC30, IC at 30 bpm; IC40, IC at 40 bpm.\n\n\n\nQuestionnaire\nCAT was used to comprehensively evaluate the symptoms of COPD, and the Modified Medical Research Council dyspnea scale was used to evaluate subjective dyspnea.\n\nLung function\nSpirometry, FRC lung volume, and lung diffusion capacity for carbon monoxide (DLCO) were measured using a spirometer (Chestac 8900; Nihon Kohden Co., Ltd., Tokyo, Japan). FRC and DLCO were evaluated only at the first examination. FRC was measured using a body box, after which the subject immediately inspired to TLC and expired maximally to RV, allowing calculation of lung volume and RV/TLC. For predicted values of FEV1 and VC, Japanese local reference data developed by the Japanese Respiratory Society were adopted,16 and predicted values for DLCO and lung volumes (FRC, RV, and TLC) measured by body plethysmography were determined using the formulae of Nishida et al,17 and Boren et al,18, respectively. As Shinsei Hospital only has a spirometer, FRC and DLCO were not measured in patients at this hospital.\n\n6-Minute walking test\nThe 6MWT was performed using a method that complied with the ATS Guidelines.19 Percutaneous oxygen saturation (SpO2) and pulse rate were recorded using a wrist-worn pulse oximeter capable of automatic remote monitoring (WristOX2™, Model 3150; Philips Electronics Japan Co., Ltd., Tokyo, Japan). All patients were instructed to walk as far as possible over a 6-min period. The walking distance (m), SpO2, heart rate, and modified Borg scale (BS) rating before and immediately after the walking test were analyzed.\n\nStatistical analysis\nTo compare the decreases in IC from ICrest before and after treatment as indexes of DLH, we set conditions for statistical analyses with an examination power of 80%, an effect size of 0.4, and significance probability of 5%. The effect size was calculated in a previous study of the effects of bronchodilators on DLH by MPIH.13 The required sample size was calculated to be 38. The classification of COPD severity was based on airflow obstruction classification according to the GOLD criteria.5 The values in the text, tables, and figures are expressed as means ± SEM. Wilcoxon’s signed rank test was used for comparison of each outcome before and after treatment. Spearman’s rank correlation coefficient was used for a single regression analysis between IC change due to treatment and FEV1, 6MWD, or BS change. In all analyses, P <0.05 was taken to indicate statistical significance. SPSS ver. 22 software was used for statistical analyses (SPS Inc., Chicago, IL).\n\nResults\nFive of the 38 registered patients dropped out of the study for hospitalization due to gastrointestinal disorder, discontinuation of hospital visits for unknown reasons, refusal to undergo examination after treatment, hospitalization due to exacerbation of respiratory diseases, and not meeting the criteria of COPD after registration into the study in one patient each. The results were not trough values, as the after treatment examination was conducted following inhalation as usual.\n\nCharacteristics of patients and comparison of lung functions before and after treatment\nTable 1 shows the basic physical findings, smoking history, medication history, and the results before and after treatment for each lung function along with the questionnaire responses. The study population included patients with mild to severe COPD as determined by the classification of airflow limitation severity using %FEV1,5 with 60% of all subjects showing moderate disease status. FEV1, %FEV1, and FEV1/FVC (forced vital capacity) ratio were significantly higher after treatment compared with before treatment (mean differences: FEV1, 161±4 mL; %FEV1, 5.4±1.4%; FEV1/FVC, 1.7±0.5%), while CAT was lower after treatment (mean differences: CAT, −2.1±0.8, MRC, −0.2±0.2).Table 1 Characteristics of patients and comparison of lung function before and after treatment\n\n\tBefore\tAfter\t\nn\t33\t33\t\nAge, years\t76.2±1.2\t\t\nSex (male/female)\t32/1\t32/1\t\nSmoking history, pack × year\t53.3±5.8\t\t\n Past smoker, n\t30\t\t\n Current smoker, n\t3\t\t\nBMI, kg/m2\t22.7±0.4\t\t\nCAT\t13.7±1.4\t10.8±1.2*\t\nmMRC\t1.3±0.2\t1.0±0.2\t\n%VC, %\t101.1±2.8\t105.1±2.2*\t\nIC, L\t2.32±0.09\t2.32±0.06\t\nFEV1, L\t1.58±0.10\t1.67±0.08 **\t\nFEV1, %\t61.1±3.2\t63.9±2.6 **\t\nFEV1/FVC, %\t51.4±1.9\t51.6±1.8 **\t\n%FRC, %\t99.7±3.9\t\t\n%RV, %\t158.8±8.3\t\t\n%TLC, %\t125.6±3.4\t\t\nRV/TLC, %\t42.4±1.8\t\t\n%DLCO, %\t67.4±3.5\t\t\nGOLD stage (1, 2, 3, 4)\t4/21/7/1\t\t\nTreatment with inhaled agents at before including study\t\t\t\n No drug, n\t5\t\t\n LAMA, n\t13\t\t\n LABA, n\t2\t\t\n LAMA+LABA, n\t4\t\t\n LABA+ICS, n\t2\t\t\n LAMA±LABA±ICS, n\t7\t\t\nNotes: Values represent mean ± standard error of the mean; *p<0.05 and **p<0.01 vs before treatment.\n\nAbbreviations: BMI, body mass index; CAT, COPD assessment test; mMRC, Modified Medical Research Council dyspnea scale, VC, vital capacity; IC, inspiratory capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity; DLCO, lung-diffusion capacity for carbon monoxide; LAMA, long-acting muscarinic antagonist; LABA, long-acting beta 2 agonist; ICS, inhaled corticosteroid.\n\n\n\n\nComparison of DLH following MPIH and 6MWT before and after treatment\nTable 2 shows the results of comparing DLH by MPIH and exercise tolerance before and after treatment. −IC20, −IC30, and −IC40 were significantly decreased after treatment (mean differences: −IC20, −0.12±0.06 L; −IC30, −0.11±0.05 L; −IC40, −0.13±0.06 L) (Figure 3). IC20, IC30, and IC40 were significantly increased after treatment (mean differences: ICrest, 0.04±0.06 L; IC20, 0.15±0.06 L; IC30, 0.15±0.04 L; IC40, 0.17±0.05 L). In addition, ΔIC was significantly decreased after treatment. The 6MWD was significantly increased after treatment compared with the value before treatment (mean difference: 14.6±8.4 m).Table 2 Comparison of dynamic lung hyperinflation following hyperventilation and 6-min walking test (6MWT) before and after treatment\n\n\tBefore\tAfter\t\nn\t33\t33\t\nICrest, L\t2.39±0.08\t2.42±0.09\t\nIC20, L\t2.25±0.09\t2.41±0.09 *\t\nIC30, L\t2.12±0.09\t2.27±0.09 **\t\nIC40, L\t1.99±0.10\t2.15±0.10 **\t\n–IC20, L\t–0.13±0.05\t−0.02±0.05 *\t\n–IC30, L\t–0.27±0.05 ††\t−0.16±0.06 *†\t\n–IC40, L\t–0.40±0.06 ††\t−0.27±0.06 *††\t\nΔIC20, %\t–5.6±2.2\t0.5±2.5 *\t\nΔIC30, %\t–11.6±2.3 ††\t−5.5±2.8 *†\t\nΔIC40, %\t–16.9±2.7 ††\t−10.8±2.7 **††\t\n6MWD, m\t460.2±19.4\t477.1±18.4 *\t\nPre SpO2, %\t95.3±0.3\t95.2±0.4\t\nLowest SpO2, %\t87.3±0.9\t87.9±0.9\t\nPRmin, bpm\t73.4±2.3\t72.4±2.6\t\nPRmax, bpm\t115.0±2.4\t113.5±3.1\t\nBSmin,\t0.4±0.2\t0.3±0.2\t\nBSmax,\t5.2±0.5\t4.6±0.4\t\nNotes: Values represent mean ± standard error of the mean; *p<0.05 and **p<0.01 vs before treatment; †p<0.05 and ††p<0.01 vs –IC20 or ΔIC20.\n\nAbbreviations: IC, inspiratory capacity; bpm, breaths/min; ICrest, IC at rest; IC20, IC at 20 bpm; –IC20, decrease in IC from ICrest to IC20; ΔIC20, change in IC from ICrest to IC20; IC30, IC at 30 bpm; –IC30, decrease in IC from ICrest to IC30; ΔIC30, change in IC from ICrest to IC30; IC40, IC at 40 bpm; –IC40, decrease in IC from ICrest to IC40; ΔIC40, change in IC from ICrest to IC40; 6MWD, 6-min walking distance; SpO2, percutaneous oxygen saturation; PRmin, minimum pulse rate; PRmax, maximum pulse rate; BSmin, minimum modified Borg scale; BSmax, maximum modified Borg scale.\n\n\nFigure 3 Comparison of dynamic lung hyperinflation following hyperventilation before and after treatment. *P<0.05 vs before combined treatment with tiotropium and olodaterol.\n\nAbbreviations: Tio, Tiotropium; Olo, Olodaterol; IC, inspiratory capacity; bpm, breaths/min; ICrest, IC at rest; −IC20, decrease in IC from ICrest to IC at 20 bpm; −IC30, decrease in IC from ICrest to IC at 30 bpm; −IC40, decrease in IC from ICrest to IC at 40 bpm.\n\n\n\nCorrelation of changes in DLH, FEV1, exercise tolerance, and dyspnea with treatment\nTable 3 shows the correlations between change in DLH after treatment and the changes in FEV1, 6MWD, and maximum BS. There were no significant correlations between changes in IC, FEV1, 6MWD, or BSmax with treatment. The scatter plot in Figure 4 shows the correlations of changes in values with treatment between 6MWD and FEV1, IC40, or −IC40 and between −IC40 and FEV1.Table 3 Correlation of changes in DLH, FEV1, exercise tolerance, and dyspnea with treatment\n\n\tFEV1 (L)\t6MWD (m)\tBSmax\t\nICrest\t0.30\t0.25\t0.28\t\nIC20\t0.06\t0.05\t0.06\t\nIC30\t0.22\t0.15\t0.18\t\nIC40\t0.13\t0.18\t0.06\t\n–IC20\t−0.23\t−0.20\t–0.17\t\n–IC30\t−0.06\t−0.14\t–0.13\t\n–IC40\t−0.17\t−0.12\t–0.14\t\nΔIC20\t−0.24\t−0.18\t–0.09\t\nΔIC30\t−0.01\t−0.05\t–0.10\t\nΔIC40\t−0.03\t−0.02\t−0.17\t\nNotes: Values represent the means. The value of change associated with treatment was calculated as the post-value minus the pre-value.\n\nAbbreviations: IC, inspiratory capacity; ICrest, IC at rest; IC20, IC at 20 bpm; –IC20, decrease in IC from ICrest to IC20; ΔIC20, change in IC from ICrest to IC20; IC30, IC at 30 bpm; –IC30, decrease in IC from ICrest to IC30; ΔIC30, change in IC from ICrest to IC30; IC40, IC at 40 bpm; –IC40, decrease in IC from ICrest to IC40; ΔIC40, change in IC from ICrest to IC40. FEV1, forced expiratory volume in 1 s; 6MWD, 6-min walking distance; BSmax, maximum modified Borg scale.\n\n\nFigure 4 Correlations of changes in value associated with treatment between 6MWD and FEV1 (A), IC40 (B) or −IC40 (C) and between IC40 and FEV1 (D). IC40, inspiratory capacity (IC) following 30-s hyperventilation at 40 breaths/min; −IC40, change in IC at rest to IC40.The value of change associated with treatment was calculated as the post-value minus the pre-value.\n\nAbbreviations: Ch, change in value by treatment; FEV1, forced expiratory volume in 1 s; 6MWD, 6-min walking distance; IC, inspiratory capacity; IC40, IC at 40 breaths/min; −IC40, decrease in IC from IC at rest to IC40.\n\n\n\nDiscussion\nThe present study was performed to elucidate the effects of combined treatment with tiotropium and olodaterol on DLH following MPIH. Thirty-three patients completed the study and five dropped out. Most of the 33 patients had mild to moderate COPD. −IC and ΔIC decreased significantly and IC after each hyperventilation increased after treatment. In addition, lung functions, subjective symptoms, and exercise tolerance improved significantly with treatment for 8 weeks. There were no correlations between the changes in DLH and exercise tolerance, FEV1, or dyspnea. The results of this study revealed the effects of combined treatment with tiotropium and olodaterol on DLH following MPIH.\n\nDynamic lung hyperinflation\nPrevious studies demonstrated improvements in DLH using combinations of LAMA and LABA for DLH evaluated by MPIH methods and exercise loading. In a previous study using MPIH, the treatment groups receiving tiotropium/indacaterol (5/150 μg), showed significant increases in IC20, IC30, and IC40 from resting IC of 0.10, 0.15, and 0.19 L in, respectively.13 The results of the present study were similar to those reported previously as olodaterol and indacaterol have similar efficacy in patients with COPD.20 However, we newly elucidated the effects of combined treatment with tiotropium and olodaterol on DLH following MPIH. As IC measurements were substituted for EELV,10 the changes in IC were due to the improvement of EELV. The DLH associated with increased EELV was improved by the increase in the exhalation flow rate by LAMA.21 Fujimoto et al, reported that EELV and IC were improved by bronchodilators based on measurements by MPIH.22 Therefore, improvement of DLH was suspected to have been due to increased expiratory flow by tiotropium and olodaterol in the present study.\n\nIn a study using exercise loading, O’Donnell et al, compared a combination of tiotropium and olodaterol (2.5/5 and 5/5 μg) with placebo or each agent administered alone as monotherapy.9 They measured periodical IC during exercise loading and IC decrease during exercise to evaluate DLH, and reported that resting IC increased significantly by 0.245 L after treatment compared to placebo. Furthermore, IC during exercise increased by about 0.1–0.15 L after treatment compared to each monotherapy. In the present study, however, the resting IC was increased by 0.04±0.06 L, and IC by MPIH showed a mean increase of 0.17±0.05 L after treatment. In contrast to the previous study, only the resting IC did not show a significant improvement in the present study. Resting IC did not improve in a study of the effects of combined LAMA and LABA treatment in the study of Fujimoto et al13, but improvement was observed in another study by Ichinose et al23. Further studies of the effects on resting IC are required because the results were not consistent with previous studies of bronchodilators in Japanese subjects with the same characteristics.\n\nLung function\nPrevious studies have mainly reported the effects of combined treatment with tiotropium and olodaterol on lung function and subjective symptoms. Beeh et al, compared the effects between five groups, ie, tiotropium/olodaterol combination (2.5/5 and 5/5 μg), each monotherapy, and placebo.7 They reported that the group receiving combined tiotropium/olodaterol treatment showed significantly improved FEV1 compared to the other groups. In the present study, the combination treatment with tiotropium and olodaterol showed improvements in subjective symptoms and FEV1, consistent with previous studies. However, these improvements were milder in the present study compared with previous reports. For example, Beeh et al, reported that Peak0-3 FEV1 was increased by 0.411 L compared to baseline by 6 weeks of combined treatment with tiotropium/olodaterol (5/5 μg),7 while an improvement of 0.161±0.004 L compared to baseline was observed after 8 weeks in the present study. Dave et al, reported a transition dyspnea index of 1.67–1.85 as a subjective symptom compared to baseline, representing an improvement of >1 in meaningful Minimal Clinical Important Difference (MCID) for dyspnea by treatment with tiotropium/olodaterol (5/5 μg),24 while CAT showed improvement of 2.1±0.8 compared to baseline, representing an improvement of <3 in MCID of CAT in the present study. Therefore, improvements in subjective symptoms and lung function were milder in the present study compared to previous reports. This was probably because the subjects in the present study were older than those in these previous studies. Tashkin et al, reported that advanced age was one of the baseline characteristics associated with poor response to bronchodilators in the UPLIFT study, which investigated the long-term effects of tiotropium for mild to moderate disease.25 While the average age of subjects in the previous clinical studies of tiotropium and olodaterol was 60 years, the subjects in the present study had an average age of 70 years.6,9 In addition, the mean age of subjects in a study of the same treatment regimen in Japanese subjects by Ichinose et al, was 72 years.23 Ichinose et al, reported that FEV1 showed mild improvement from a baseline of 1.228 –1.275 L after the same treatment as applied in the present study. Therefore, it was considered that the mild improvements of subjective symptoms and lung function in the present study were because of the advanced age of the subjects.\n\nExercise tolerance\nImprovement of exercise tolerance was also observed in the present study, because 6MWD showed a significant increase after treatment. However, 6MWD showed an improvement of <25–30 m in MCID of 6MWD in the present study.26 This was considered to have been due to the milder severity of disease in our patients. O’Donnell et al, reported that LAMA and LABA maintenance therapy in patients with COPD provide sustained lung volume reduction as a result of improved tidal expiratory flow rates and lung emptying, with reduced resting and exercise lung hyperinflation, and a delay in the mechanical limitation to ventilation, with consequent alleviation of exertional dyspnea and exercise capacity.21 In addition, combined tiotropium and olodaterol treatment were reported to affect exercise capacity.9 Therefore, the reduction in DLH was considered to have improved exercise tolerance in the present study. However, Ichinose et al, reported improvement in a subgroup with only severe COPD in a study with administration of the same treatment regimen in Japanese subjects.23 Although Ichinose demonstrated improvements only in severe COPD, the patients in the present study had mild to moderate COPD. Several studies indicated that exercise capacity is improved in the subgroup with more severe COPD,23,27 while the results of the present study in patients with mild to moderate COPD were consistent with similar studies of tiotropium/olodaterol in patients with less severe disease. Ferguson et al, reported greater improvements compared to baseline after 24 weeks of tiotropium/olodaterol combination treatment in the subgroup with less severe COPD.28 Therefore, further studies are required to examine the improvement of exercise capacity in relation to severity, and the results reported to date have been inconsistent.\n\nCorrelations of changes in DLH, FEV1, exercise tolerance, and dyspnea with treatment\nThere were no correlations between changes associated with treatment in DLH and 6MWD or maximum BS. The results of the present study were different from those reported by O’Donnell et al21, which was probably due to differences in the methods used for evaluation of DLH between the two studies. O’Donnell et al, reported correlations between changes in DLH, exercise tolerance, and dyspnea during exercise after tiotropium monotherapy in a randomized controlled trial. In this previous study, DLH was evaluated based on the decrease in IC during exercise loading or just after exercise. On the other hand, hyperventilation and spirometer were used to evaluate DLH in the present study. It is unclear whether DLH induced by exercise loading is equivalent to DLH induced by MPIH. We are currently engaged in experiments to determine whether DLH determined by exercise loading and DLH determined by MPIH are comparable, and plan to report our findings in the near future.\n\nLimitations\nThe present study had several limitations. First, this was a pre- and post-treatment comparative study, and there was no control group. Comparison with placebo or conventional treatment was not performed. Therefore, it is possible that various confounding factors may have affected the results. Second, most of the patients had moderate disease status, and the effects on DLH may have been underestimated. As previous clinical trials examined combination therapy mainly in patients with mild to severe disease,6,9 the results of the present study may have been different if the disease status in the majority of our patients had been moderate to severe. Third, the study may have been underpowered because five patients dropped out. However, there was a significant difference in the main outcome in the 33 patients included in the analysis, and post hoc analysis demonstrated that the statistical power was ≥80%. Fourth, the washout period used in the present study was short. The recommended washout period is five times the half-life.29 As the half-lives of tiotropium, olodaterol, and ICS are 25, 7.5, and 14.4 hrs, respectively, the washout period for tiotropium was too short in the present study.\n\nConclusion\nIn conclusion, the results of this study indicated that the combination of tiotropium and olodaterol is effective for improvement of DLH following hyperventilation. In addition, this study showed a difference in the response of DLH due to exercise loading to treatment compared to previous studies. Therefore, further studies are required to examine the differences in responses between exercise loading and hyperventilation.\n\nAcknowledgments\nThe authors wish to thank Dr. Mineko Ohira (Shinsei Hospital & Higashi Nagano Hospital) and Dr. Takashi Ichiyama (Shinshu University Hospital) for their help in registration of subjects for this study. This work was supported by the Nihon Rehabilitation Shinkokai Foundation (Koganei, Tokyo, Japan).\n\nDisclosure\nThe authors received financial support from Nihon rehabilitation Shinkokai Foundation, a general incorporated foundation (Koganei, Tokyo, Japan) for this study. Keisaku Fujimoto reports grants from Murata Manufacturing Co., Ltd., Seiko Epson Corporation, Denso Corporation, Kanazawa Murata Manufacturing Co., and Koganei Corporation. He also received personal fees from Japan Association for the Advancement of Medical Equipment, Astellas Pharma Inc., AstraZeneca Co., Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetec Co., Ltd., GlaxoSmithKline Co., Ltd., Japan Respiratory Society, Kyorin Pharmaceutical Co., Ltd., MeijiSeika Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Teijin Home Healthcare Limited, and Teijin Pharma Limited. He further received grants and personal fees from MSD Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and Novartis Pharma Co., Ltd., outside the submitted work. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. O’Donnell \nDE , Revill \nSM , Webb \nKA . Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2001 ;164 :770 –777 . doi:10.1164/ajrccm.164.5.2012122 11549531 \n2. O’Donnell \nDE , Laveneziana \nP . The clinical importance of dynamic lung hyperinflation in COPD . COPD . 2006 ;3 :219 –232 .17361503 \n3. O’Donnell \nDE , Webb \nKA , Neder \nJA . Lung hyperinflation in COPD: applying physiology to clinical practice . COPD Res Pract . 2015 ;1 :1 –12 . doi:10.1186/s40749-015-0008-8 \n4. Puente-Maestu \nL , Stringer \nWW . Hyperinflation and its management in COPD . Int J Chron Obstruct Pulmon Dis . 2006 ;1 :381 .18044095 \n5. World Health Organization . Global Initiative for Chronic Obstructive Lung Disease, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (2019 report) , 2019 \n[cited 2 26 , 2019]\nAvailable from : https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf.\n6. Buhl \nR , Maltais \nF , Abrahams \nR , et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4) . Eur Respir J . 2015 ;45 :969 –979 . doi:10.1183/09031936.00136014 25573406 \n7. Beeh \nKM , Westerman \nJ , Kirsten \nAM , et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease . Pulm Pharmacol Ther . 2015 ;32 :53 –59 . doi:10.1016/j.pupt.2015.04.002 25956072 \n8. Calverley \nPM , Anzueto \nAR , Carter \nK , et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial . Lancet Respir Med . 2018 ;6 :337 –344 . doi:10.1016/S2213-2600(18)30102-4 29605624 \n9. O‘Donnell \nDE , Casaburi \nR , Frith \nP , et al. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD . Eur Respir J . 2017 ;49 :1601348 . doi:10.1183/13993003.01348-2016 28424359 \n10. Gelb \nAF , Gutierrez \nCA , Weisman \nIM , Newsom \nR , Taylor \nCF , Zamel \nN . Simplified detection of dynamic hyperinflation . Chest . 2004 ;126 :1855 –1860 . doi:10.1378/chest.126.6.1855 15596684 \n11. Kawachi \nS , Fujimoto \nK . Usefulness of a newly developed spirometer to measure dynamic lung hyperinflation following incremental hyperventilation in patients with chronic obstructive pulmonary disease . Intern Med . 2018 . doi:10.2169/internalmedicine.1212-18 \n12. Fujimoto \nK , Kitaguchi \nY , Kanda \nS , Urushihata \nK , Hanaoka \nM , Kubo \nK . Comparison of efficacy of long-acting bronchodilators in emphysema dominant and non-dominant COPD . Int J Chron Obstruct Pulmon Dis . 2011 ;6 :219 –227 . doi:10.2147/COPD.S18461 21660299 \n13. Fujimoto \nK , Yamazaki \nH , Ura \nM , Kitaguchi \nY . Efficacy of tiotropium and indacaterol monotherapy and their combination on dynamic lung hyperventilation in COPD: a random open-label crossover study . Int J Chron Obstruct Pulmon Dis . 2017 ;12 :3195 –3201 . doi:10.2147/COPD.S149054 29138547 \n14. Mosley \nJF \nII, Smith \nLL , Dutton \nBN . Tiotropium bromide/olodaterol (Stiolto Respimat): once-daily combination therapy for the maintenance of COPD . P T . 2016 ;41 :97 .26908999 \n15. Edsbäcker \nS , Johansson \nCJ . Airway selectivity: an update of pharmacokinetic factors affecting local and systemic disposition of inhaled steroids . Basic Clin Pharmacol Toxicol . 2006 ;98 :523 –536 . doi:10.1111/j.1742-7843.2006.pto_355.x 16700813 \n16. Sasaki \nE , Nakamura \nM , Kida \nK , et al. Reference values for spirogram and blood gas analysis in Japanese non-smoking healthy adults . J Jpn Respir Soc . 2001 ;39 :383 –399 .\n17. Nishida \nS , Kambe \nM , Sewake \nN , Takano \nM , Kawane \nH . Pulmonary function in healthy subjects and its prediction-5: pulmonary diffusing capacity in adults . Jpn J Clin Pathol . 1976 ;24 :941 –947 .\n18. Boren \nHG , Kory \nRC , Syner \nJC . The veterans administration army cooperative study of pulmonary function . Am J Med . 1966 ;41 :96 –114 . doi:10.1016/0002-9343(66)90008-8 \n19. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories . ATS statement: guidelines for the six-minute walk test . Am J Respir Crit Care Med . 2002 ;166 :111 –117 . doi:10.1164/ajrccm.166.1.at1102 12091180 \n20. Roskell \nNS , Anzueto \nA , Hamilton \nA , Disse \nB , Becker \nK . Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol . Int J Chron Obstruct Pulmon Dis . 2014 ;9 :813 . doi:10.2147/COPD.S60179 25114521 \n21. O‘Donnell \nDE , Flüge \nT , Gerken \nF , et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD . Eur Respir J . 2004 ;23 :832 –840 .15218994 \n22. Fujimoto \nK , Yoshiike \nF , Yasuo \nM , et al. Effects of bronchodilators on dynamic hyperinflation following hyperventilation in patients with COPD . Respirology . 2007 ;12 :93 –99 . doi:10.1111/j.1440-1843.2006.00963.x 17207032 \n23. Ichinose \nM , Minakata \nY , Motegi \nT , et al. Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity . Int J Chron Obstruct Pulmon Dis . 2018 ;13 :1407 . doi:10.2147/COPD.S166023 29750027 \n24. Singh \nD , Gaga \nM , Schmidt \nO , et al. Effects of tiotropium+ olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies . Respir Res . 2016 ;17 :73 . doi:10.1186/s12931-016-0387-7 27316465 \n25. Tashkin \nDP , Celli \nB , Decramer \nM , et al. Bronchodilator responsiveness in patients with COPD . Eur Respir J . 2008 ;31 :742 –750 . doi:10.1183/09031936.00129607 18256071 \n26. Holland \nAE , Nici \nL . The return of the minimum clinically important difference for 6-minute-walk distance in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2013 ;187 :335 –336 . doi:10.1164/rccm.201212-2191ED 23418323 \n27. Casaburi \nR , Maltais \nF , Porszasz \nJ , et al. Effects of tiotropium on hyperinflation and treadmill exercise tolerance in mild to moderate chronic obstructive pulmonary disease . Ann Am Thorac Soc . 2014 ;11 :1351 –1361 . doi:10.1513/AnnalsATS.201404-174OC 25289942 \n28. Ferguson \nGT , Fležar \nM , Korn \nS , et al. Efficacy of tiotropium+ olodaterol in patients with chronic obstructive pulmonary disease by initial disease severity and treatment intensity: a post hoc analysis . Adv Ther . 2015 ;32 :523 –536 . doi:10.1007/s12325-015-0218-0 26112656 \n29. Guideline for bioequivalence studies of generic products [homepage on the Internet] . Japan : Pharmaceutical and Food Safety Bureau ; 2012 \nAvailable from : http://www.nihs.go.jp/drug/be-guidee/Generic/GL-E_120229_BE.pdf. Accessed 3 3 , 2019.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9106",
"issue": "14()",
"journal": "International journal of chronic obstructive pulmonary disease",
"keywords": "bronchodilator agents; dynamic lung hyperinflation; hyperventilation; olodaterol; tiotropium",
"medline_ta": "Int J Chron Obstruct Pulmon Dis",
"mesh_terms": "D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000368:Aged; D048588:Benzoxazines; D001993:Bronchodilator Agents; D004338:Drug Combinations; D004417:Dyspnea; D017079:Exercise Tolerance; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006985:Hyperventilation; D007564:Japan; D008168:Lung; D008297:Male; D018727:Muscarinic Antagonists; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive; D020127:Recovery of Function; D013997:Time Factors; D000069447:Tiotropium Bromide; D016896:Treatment Outcome",
"nlm_unique_id": "101273481",
"other_id": null,
"pages": "1167-1176",
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"pmid": "31213796",
"pubdate": "2019",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D059040:Video-Audio Media",
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"title": "Efficacy of tiotropium and olodaterol combination therapy on dynamic lung hyperinflation evaluated by hyperventilation in COPD: an open-label, comparative before and after treatment study.",
"title_normalized": "efficacy of tiotropium and olodaterol combination therapy on dynamic lung hyperinflation evaluated by hyperventilation in copd an open label comparative before and after treatment study"
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"abstract": "OBJECTIVE\nThe purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS).\n\n\nMETHODS\nA retrospective analysis on pediatric MS patients treated with MX was performed with regards to demographic/clinical parameters and magnetic resonance imaging (MRI) findings.\n\n\nRESULTS\n19 definite pediatric MS cases with mean ± SD age of 15.4 ± 2.8 years underwent 20 mg MX for control of their severe/frequent relapses, high EDSS score or new and active brain MRI lesions. After a median [IQR] follow-up period of 30[12-60] months, 14 cases (73%) were relapse free; the EDSS score decreased by at least 0.5 in 16 cases (84.2%); and gadolinium-enhancing lesion volume fell by 84.2% in 16 cases. Adverse events included nausea and vomiting, fatigue, alopecia, palpitation, cardiomyopathy and mild leukopenia. All adverse events were mild and transient.\n\n\nCONCLUSIONS\nOur results suggest MX is a good candidate for treatment of children with worsening RRMS and SPMS. Recommendations regarding patient selection, treatment administration, and close follow-up should be considered. Continuing research is needed to establish its efficacy and safety profile in a multinational collaboration with careful follow-up of adverse events.",
"affiliations": "Department of Neurology, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran; Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran; Medical Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran.;Nuffield Department of Clinical Neurosciences (Clinical Neurology), University of Oxford, John Radcliffe Hospital, Oxford, London, UK.;Department of Biological Sciences, California State University, Stanislaus, Turlock, CA, USA.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran; Medical Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran; Persia Research Center, Sady Hospital, Isfahan, Iran. Electronic address: mf.esfahani@yahoo.com.",
"authors": "Etemadifar|Masoud|M|;Afzali|Parisa|P|;Abtahi|Seyed-Hossein|SH|;Ramagopalan|Sreeram V|SV|;Nourian|Sayed-Mohammadamin|SM|;Murray|Richard T|RT|;Fereidan-Esfahani|Mahboobeh|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D008942:Mitoxantrone",
"country": "England",
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"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Aggressive; Mitoxantrone; Multiple sclerosis; Pediatric",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008942:Mitoxantrone; D020528:Multiple Sclerosis, Chronic Progressive; D020529:Multiple Sclerosis, Relapsing-Remitting; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9715169",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis.",
"title_normalized": "safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis"
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"companynumb": "IR-MYLANLABS-2015M1013879",
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"abstract": "A 64-year-old woman developed diarrhea after taking clindamycin for a dental infection. We diagnosed her with Clostridium difficile infection (CDI) and performed fecal microbiota transplantation (FMT) as the initial therapy using colonoscopy on an outpatient basis. The frequency of her bowel movements decreased from 10 times per day to two times per day three days after the procedure. The key component of FMT is to restructure the protective microbiome of the natural intestinal flora. We consider that FMT could be used as an effective first-line therapy for CDI if the efficacy and safety of this procedure is established in the future.",
"affiliations": "Department of General Internal Medicine, Kitano Hospital, Tazuke-Kofukai, Medical Research Institute, Japan.",
"authors": "Tanaka|Takamasa|T|;Kato|Haru|H|;Fujimoto|Takushi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
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"issn_linking": "0918-2918",
"issue": "55(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D016360:Clostridioides difficile; D003015:Clostridium Infections; D003113:Colonoscopy; D000069467:Fecal Microbiota Transplantation; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D008875:Middle Aged; D010045:Outpatients; D012008:Recurrence",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "999-1000",
"pmc": null,
"pmid": "27086820",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Fecal Microbiota Transplantation as an Initial Therapy for Clostridium difficile Infection on an Outpatient Basis.",
"title_normalized": "successful fecal microbiota transplantation as an initial therapy for clostridium difficile infection on an outpatient basis"
} | [
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"companynumb": "JP-WATSON-2016-09929",
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"activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE"
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"abstract": "Coagulase-negative staphylococci (CoNS) are part of the normal skin flora. Although CoNS are generally considered as low pathogenic microorganisms, they can cause serious infections, particularly in the context of foreign body material.\nHere we present two cases of concomitant infectious endocarditis and spondylodiscitis; one caused by S. epidermidis, the other by S. haemolyticus. Additionally, we reviewed the literature for previously reported cases of concomitant endocarditis and spondylodiscitis due to CoNS.\nIn patients with back pain and a cardiac device in situ, CoNS should be considered as causative pathogens for possible endocarditis and/or spondylodiscitis, and should not be regarded as contamination.",
"affiliations": "Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.;Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.;Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, the Netherlands.;Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.;Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.",
"authors": "Houkes|Karlijn M G|KMG|;Mudde|Saskia E|SE|;Constantinescu|Alina A|AA|;Verkaik|Nelianne J|NJ|;Yusuf|Erlangga|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01100",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00056-1\n10.1016/j.idcr.2021.e01100\ne01100\nCase Report\nConcomitant endocarditis and spondylodiscitis due to coagulase-negative Staphylococci and a review of the literature\nHoukes Karlijn M.G. a1\nMudde Saskia E. s.e.mudde@erasmusmc.nl\na⁎1\nConstantinescu Alina A. b\nVerkaik Nelianne J. a\nYusuf Erlangga a\na Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands\nb Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, the Netherlands\n⁎ Corresponding author at: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, P.O. Box 2040, 3000, CA, Rotterdam, the Netherlands. s.e.mudde@erasmusmc.nl\n1 These authors contributed equally.\n\n31 3 2021\n2021\n31 3 2021\n24 e0110027 2 2021\n29 3 2021\n29 3 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nHighlights\n\n• When CoNS are found repetitively in the context of cardiac foreign body materials, endocarditis should be considered.\n\n• Given the subacute nature of CoNS-infections, one needs to alert to endocarditis, even if the symptoms are still mild.\n\n• When CoNS-related endocarditis patients complain of back pain, concominantly occuring spondylodiscitis should be considered.\n\n• Concominant endocarditis and spondylodiscitis caused by CoNS is rare with only 12 cases reported in literature so far.\n\nBackground\n\nCoagulase-negative staphylococci (CoNS) are part of the normal skin flora. Although CoNS are generally considered as low pathogenic microorganisms, they can cause serious infections, particularly in the context of foreign body material.\n\nCase report\n\nHere we present two cases of concomitant infectious endocarditis and spondylodiscitis; one caused by S. epidermidis, the other by S. haemolyticus. Additionally, we reviewed the literature for previously reported cases of concomitant endocarditis and spondylodiscitis due to CoNS.\n\nConclusion\n\nIn patients with back pain and a cardiac device in situ, CoNS should be considered as causative pathogens for possible endocarditis and/or spondylodiscitis, and should not be regarded as contamination.\n\nKeywords\n\nEndocarditis\nSpondylodiscitis\nCoagulase-negative staphylococci\n==== Body\nBackground\n\nCoagulase-negative staphylococci (CoNS) are colonizers of the human skin and are generally considered to be low pathogenic [1]. They are particularly associated with low-grade infections related to foreign-bodies, such as intravascular catheters, prosthetic joints or cardiac devices [1]. However, more severe and less prevalent infections, such as endocarditis and spondylodiscitis, have also been linked to CoNS. It is estimated that approximately 10 % of cases of infective endocarditis are caused by CoNS [2]. Similar proportions have been reported for CoNS-related spondylodiscitis [3]. Here, we present two cases with concomitant endocarditis and spondylodiscitis attributed to CoNS and provide a review of the literature.\n\nCases\n\nPatient A\n\nA 65-year-old man with diabetes mellitus type 2 presented to our hospital (Erasmus Medical Center, Rotterdam, The Netherlands) after he was found unconscious with hypoglycemia. His medical history included a non-invasive urothelial carcinoma and chronic heart failure. For the latter, he received an Implantable Cardioverter-defibrillator (ICD) 12 years ago. It was replaced three months before his current admission to our hospital, because the leads were visible through a local inflamed skin defect. Since then, he had lost 8 kg in body weight, and during the past three weeks he complained of progressive lower back pain. On presentation, his white blood cell count was 13.8 × 109/l (normal value: 3.5–10 × 109/l) and C-reactive protein 58 mg/l (normal value: <10 mg/l). A CT-scan of the abdomen showed lesions suggestive of spondylodiscitis at the level of L2 and L3 with epidural involvement. All four blood culture sets taken shortly after hospital admission remained negative after 5 days of incubation. After CT-guided lumbar biopsies were obtained, empirical treatment was started with cefuroxime 1500 mg i.v., thrice daily. Tissue cultures grew methicillin-resistant S. epidermidis, which was initially considered to be a contaminant. To evaluate possible sources of the spondylodiscitis, a PET-CT scan was performed (Fig. 1). FDG-avid lesions were seen at L2 and L3, and in the heart at the lateral wall of the left ventricle. On a subsequent transthoracic echocardiogram (TTE), a mobile structure attached to the ICD lead and the tricuspid valve was observed. Culture-negative, ICD-related endocarditis was suspected, and the ICD was extracted the following day. Instead of continuing cefuroxime, the therapy was switched to ceftriaxone 2000 mg once daily and vancomycin 1000 mg i.v. twice daily (adjusted to his weight), according to national antibiotic guidelines (SWAB) [4]. Four days later, progression of the lumbar lesions was seen on a follow-up MRI scan, despite antimicrobial therapy. The scan revealed abscess formation in the discus between L2 and L3 with multiple abscess pockets in the adjacent psoas muscle. There was no extensive epidural expansion of the abscess. The C-reactive protein had declined to a value of 24 mg/L. Since his symptoms did not deteriorate, the patient was treated conservatively. When blood cultures that were taken on consecutive days after ICD-extraction became positive for S. epidermidis with identical susceptibility patterns, this was considered to be the causative pathogen of both endocarditis and spondylodiscitis. Ceftriaxone was stopped and vancomycin was continued for 6 weeks following the last positive blood culture. The patient was discharged in good condition after three months of hospital admission. No control MRI scan was performed.Fig. 1 PET-CT scan of patient A showing increased FDG-uptake at lumbar discus L2-L3 (left panel) and in the heart (right panel).\n\nFig. 1\n\nPatient B\n\nA 66-year-old woman presented to our hospital with complaints of fever, malaise and lower back pain in the last weeks. Her medical history included auto immune hepatitis, for which she used prednisone and azathioprine; Hodgkin lymphoma; transcatheter aortic valve implantation (TAVI) due to aortic stenosis; and two episodes of suspected TAVI-related endocarditis, caused by E. faecalis and E. faecalis and S. haemolyticus, respectively, with a 7 month-interval. The first episode was treated with amoxicillin 2 g i.v., six times a day, and ceftriaxone 2 g, twice daily, for 6 weeks according to the SWAB guidelines [4]. The second episode was treated with amoxicillin 2 g, i.v., six times a day, and daptomycin 10 mg/kg/day for a total of 6 weeks with a good clinical response. Initially she received vancomycin for 5 days, but this was switched to daptomycin when the patient developed tubulointerstitial nephritis possibly due to vancomycin [4]. During both episodes, several imaging tests were performed, but none of them showed vegetations on the heart valves. The present complaints started 4.5 months after the second episode. Laboratory findings showed C-reactive protein of 112 mg/l and a white blood cell count of 13.3 × 109/L. One blood culture bottle obtained at the emergency department grew methicillin-resistant S. haemolyticus (daptomycin MIC 0.25 μg/mL, vancomycin MIC 1 μg/mL). Since this organism was also found during the second episode of suspected endocarditis, the patient was admitted. The additional blood cultures grew S. haemolyticus as well. Because a third episode of endocarditis was suspected, a TTE and PET-CT-scan were performed. The TTE showed a mobile structure on the prosthetic aortic valve. Although no signs of endocarditis were seen on the PET-CT scan, the scan did reveal spondylodiscitis of discus level L4-L5, which was confirmed on a MRI scan performed on the same day (Fig. 2). Due to extensive comorbidity, including radiotherapy for Hodgkin lymphoma, chirurgical intervention was not possible. No tissue biopsies were obtained. Intravenous daptomycin (10 mg/kg) was intended to be given for 12 weeks, but the patient deceased suddenly in the 5th week of antibiotic treatment. After initiation of antimicrobial therapy, the blood cultures remained positive for S. haemolyticus for three more days. No obduction was performed and the exact cause of death remained unknown.Fig. 2 PET-CT scan (left panel) and MRI scan (right panel) of patient B revealing increased FDG-uptake at lumbar discus L4-L5, indicative for spondylodiscitis.\n\nFig. 2\n\nDiscussion\n\nWe presented two cases of concomitant endocarditis and spondylodiscitis due to CoNS. CoNS cause approximately 10 % of cases of infective endocarditis [2] as well as about 10 % of the spondylodiscitis cases [3]. However, only 12 cases of concomitant endocarditis and spondylodiscitis have been reported in literature (Table 1). Among the reported cases of concomitant endocarditis and spondylodiscitis, S. epidermidis was identified in half of the published cases. Two cases were caused by S. lugdunensis (Table 1), but this microorganism, despite being categorized as a CoNS, is more virulent than other CoNS and closely resembles S. aureus in this aspect [5]. Interestingly, none of the previously reported cases were due to S. haemolyticus, which makes patient B the first described case of S. haemolyticus-related concomitant endocarditis and spondylodiscitis.Table 1 Clinical features of previously reported cases of concomitant endocarditis and spondylodiscitis caused by coagulase negative staphylococci.\n\nTable 1Case\tAge/sex\tPredisposing condition\tEndocarditis\tSpondylodiscitis\tCausative organism\tAntibiotic treatment\tTreatment duration\tOutcome\tReference\t\nLocation (heart valve)\tDiagnosed by\tLocation (vertebrae)\tDiagnosed by\t\n1\t74/F\t\tMV\tBlood cultures (repeatedly), autopsy\tT7\tBone scintigraphy,\nautopsy\tS. epidermidis\tPEN, GEN, LEX, ERY, CXA\t6 weeks\tDied\t[19]\t\n2\t66/M\tColon resection for villous adenoma, right total hip replacement\tAV, MV\tEchocardiogram, blood cultures (multiple)\tL2-L3\tRadiography, bone scintigraphy, tissue culture\tS. warneri\tVAN, GEN, RIF, DCX\t6 weeks\tSurvived\t[20]\t\n3\t64/M\tAV replacement for aortic regurgitation\tAV\tBlood cultures\tL2-L3\tRadiography, bone scintigraphy\tS. epidermidis\tPEN G, GEN, FA, TEC, FLX\t5 months\tSurvived\t[21]\t\n4\t65/M\tSubmucosal resection of urothelial carcinoma\tMV\tBlood cultures\tT10\tRadiography, bone scintigraphy\tS. epidermidis\tPEN, GEN, FLX\t3.5 months\tSurvived\t[22]\t\n5\t78/M\tPacemaker\tTV\tBlood cultures (multiple), cultures of pacemaker electrode\tL4-L5\tCT-scan, chronic osteomyelitis on histologic examination.\tCoNS\tFLX, NET, VAN, RIF, TEC, CLI\tAt least 17 weeks\tSurvived\t[23]\t\n6\t77/F\tChronic Lymphatic Leukemia (with central venous access device)\t\tBlood cultures (multiple), cultures of catheter tip\tT11-T12\tRadiography, MRI, positive tissue culture\tCoNS\tPEN G, CIP, RIF\t12 weeks\tSurvived\t[23]\t\n7\t68/M\tCoronary artery disease, sick sinus syndrome, pacemaker\t\tBlood cultures (multiple)\tL3-L4\tRadiography, CT-scan, chronic inflammation on histologic examination.\tS. lugdunensis\tPEN G, GEN, FLX, RIF, CIP\t\tSurvived\t[23]\t\n8\t79/M\tPsoriasis, rheumatoid arthritis (corticosteroids, methotrexate), left total knee replacement\tAV. MV\tBlood cultures (repeatedly), TEE, TTE, autopsy\t\tMRI scan, autopsy\tS. lugdunensis\tRIF, CIP, CLI, VAN\t5 months\tDied\t[24]\t\n9\t82/M\tPacemaker\t\tDuke criteria\tC2-C3\tOne of the following: radiography, bone scintigraphy, CT-scan or MRI scan\tS. schleifferi\tVAN, RIF\t\t\t[16]\t\n10\t72/M\tPacemaker\t\tDuke criteria\tL2-L3\tOne of the following: radiography, bone scintigraphy, CT-scan or MRI scan\tS. epidermidis\tOXA, RIF\t\t\t[16]\t\n11\t78/M\tPacemaker\t\tDuke criteria\tT8-T9\tOne of the following: radiography, bone scintigraphy, CT-scan or MRI scan\tS. epidermidis\tOXA, RIF\t\t\t[16]\t\n12\t64/M\tPacemaker\t\tDuke criteria\tL1-L2\tOne of the following: radiography, bone scintigraphy, CT-scan or MRI scan\tS. epidermidis\tOXA, GEN\t\t\t[16]\t\nAI = aortic insufficiency; AS = aortic stenosis; ICD = implantable cardioverter defibrillator; MV = mitral valve; AV = aortic valve; TV = tricuspid valve; CoNS = coagulase negative staphylococci; PEN = penicillin; GEN = gentamicin; LEX = cephalexin; ERY = erythromycin; CXA = cloxacillin; NAF = nafcillin; VAN = vancomycin; RIF = rifampicin; DCX = dicloxacillin; PEN G = penicillin G; FA = fusidic acid; TEC = teicoplanin; FLX = flucloxacillin; NET = netilmicin; CLI = clindamycin; CIP = ciprofloxacin; OXA = oxacillin; NET = netilmicin.\n\nIt can be challenging to determine the relevance of an isolated CoNS, especially if only a single blood- or tissue culture is positive. In both patient A and B, S. epidermidis and S. haemolyticus, respectively, were at first considered to be a contaminant. Only after additional blood cultures were positive for these microorganisms, they were considered to be the causative microorganisms. CoNS as pathogens in native valve endocarditis are rarely found [6]. However, in prosthetic valve endocarditis, CoNS are the second leading cause, accounting for 20.1 % of the cases [7]. Additionally, six out of 12 described cases of concomitant endocarditis and spondylodiscitis had a pacemaker. Together, this data indicates that the presence of foreign body material in the heart is a risk factor for developing CoNS-related endocarditis. This is supported by a finding by Chu et al., that showed that significantly more patients with native valve endocarditis caused by CoNS had a cardiac device, compared to patients with S. aureus- or viridans group streptococci-related endocarditis [6]. Interestingly, both patient A and patient B had undergone surgery in or near the heart (ICD replacement and TAVI, respectively) in the year prior to the endocarditis episode. The reported incidence of infectious endocarditis after aortic valve replacement is 0.9 % in the first year after surgery [8], in which CoNS-related endocarditis is 37 % [9]. The proportion of CoNS-related endocarditis declines to 18 % after the first year following replacement (p = 0.005) [9]. Cardiac device-related endocarditis prevalence has been reported between 0.5–7% [10]. In patients with cardiac device-related endocarditis, staphylococci (predominantly CoNS) account for 60–80 % of the cases [11]. CoNS can originate from the skin flora of the patient or from health care personnel during surgery and can enter into the human body during insertion of a medical device [12]. Subsequently, CoNS could thrive there by forming a biofilm on the foreign body surface of for example artificial valves, pacemakers or ICDs (2). Presumably, the ICD of patient A and the prosthetic aortic valve of patient B have attributed to the development of CoNS-related endocarditis.\n\nThe incidence of spondylodiscitis as a complication of endocarditis varies widely, ranging from 0.02 % [15] to up to 15 % [16]. This variability could partially be explained by the virulence of the involved pathogens. Le Moal et al. reported CoNS as the most common pathogens among their tested patient population, whereas viridans group streptococci and S. aureus were best represented in the study performed by Gonzalez-Juanatey et al. [15,16]. Given that endocarditis due to CoNS is often chronic with a subacute presentation, lacking the characteristic symptoms of a severe infection caused by for example S. aureus [17], we hypothesize that long-lasting CoNS bacteremia as a consequence of delay in the diagnosis of subacute infectious endocarditis may lead to prolonged exposure of bone tissue to CoNS. This might result in a higher risk of developing spondylodiscitis. However, this could also account for a subacute presentation of CoNS-related spondylodiscitis causing secondary endocarditis. In both cases, it remains unclear whether the endocarditis or the spondylodiscitis was the initial infection. However, we deemed it most likely that the infections started with the endocarditis, since patient A had a recently replaced ICD and patient B had a recently placed prosthetic valve.\n\nDiagnosing spondylodiscitis can be difficult, since back pain is a common complaint and, even in the case of spondylodiscitis, it is not always the main complaint. Likewise, back pain was no dominant symptom for patient B. The suspected spondylodiscitis was only found in the screening for metastatic infections secondary to the infectious endocarditis and confirmed on a subsequent MRI scan. Of the reported cases in literature with concomitant endocarditis and spondylodiscitis, at least 6 did not undergo a MRI scan or PET-CT scan, even though a MRI scan is considered to be the best way to confirm suspected spondylodiscitis [18]. In case of patient B, back pain had been reported by the patient upon admission. Therefore, we advise to actively ask patients with CoNS-related endocarditis if they have back pain and to consider imaging following an affirmative answer. In patient A, lower back pain was a major complaint and spondylodiscitis was identified quickly on the PET-CT scan. However, the PET-CT scan was not suspected of endocarditis, while clear vegetations on the ICD leads and tricuspid valve were seen on the TTE. The presence of a cardiac device is a risk factor of CoNS infections [1]. The IDSA guidelines for treatment and diagnosis of native vertebral osteomyelitis states that efforts should be made to exclude contamination when a common skin contaminant, eg CoNS, is isolated [18]. In patients with sustained CoNS bloodstream infection and an intravascular device or prosthetic valve, we propose to exclude endocarditis by performing a TEE or PET, respectively. In case of endocarditis, extraction of the cardiac device is indicated to control the infection, whenever possible. The ICD of patient A was safely extracted, but the TAVI of patient B could not be replaced as cardiac surgery was not possible.\n\nConclusion\n\nWe described two cases of concomitant endocarditis and spondylodiscitis due to CoNS, S. epidermidis and S. haemolyticus. As the numbers of patients with foreign body materials are rising, it is likely that CoNS will become increasingly significant pathogens [1]. Especially when CoNS are repetitively found in the setting of prosthetic valves or cardiac devices, endocarditis should be considered in an early stage, even if symptoms are (still) mild given the subacute nature of CoNS-infections [17]. These cases also illustrate that CoNS are capable of causing spondylodiscitis, which should be considered when patients report back pain and cultures are positive with CoNS. This way, missing such important diagnoses can be prevented and correct antibiotic treatment can be administered.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\n\nNot applicable.\n\nInformed consent\n\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\nAuthor statement\n\nWe confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.\n\nAuthor contributions\n\nKarlijn M.G. Houkes: Conceptualization, Data curation, Investigation, Writing – Original draft. Saskia E. Mudde: Conceptualization, Data curation, Investigation, Writing – Original draft, Visualization. Alina A. Constantinescu: Resources, Writing - Review & Editing. Nelianne J. Verkaik: Conceptualization, Resources, Writing – Review & Editing. Erlangga Yusuf: Conceptualization, Writing – Review & Editing, Supervision.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n==== Refs\nReferences\n\n1 Becker K. Heilmann C. Peters G. Coagulase-negative staphylococci Clin Microbiol Rev 27 2014 870 926 10.1128/CMR.00109-13 25278577\n2 Cahill T.J. Prendergast B.D. Infective endocarditis Lancet 387 2016 882 893 10.1016/S0140-6736(15)00067-7 26341945\n3 Lopez J. Tatar Z. Tournadre A. Couderc M. Pereira B. Soubrier M. Characteristics of spontaneous coagulase-negative staphylococcal spondylodiscitis: a retrospective comparative study versus Staphylococcus aureus spondylodiscitis BMC Infect Dis 17 2017 1 6 10.1186/s12879-017-2783-0 28049444\n4 van der Vaart T.W. Buiting A. Deckers J.W. Natour E.H. Verkaik N.J. Van der Meer J.T.M. SWAB guidelines for the antimicrobial treatment of infective endocarditis 2019\n5 Choi S.-H. Chung J.-W. Lee E.J. Kim T.H. Lee M.S. Kang J.M. Incidence, characteristics, and outcomes of Staphylococcus lugdunensis bacteremia J Clin Microbiol 48 2010 3346 3349 10.1128/JCM.00609-10 20592152\n6 Chu V.H. Woods C.W. Miro J.M. Hoen B. Cabell C.H. Pappas P.A. Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis Clin Infect Dis 46 2008 232 242 10.1086/524666 18171255\n7 Wang A. Athan E. Pappas P.A. Fowler V.G. Olaison L. Paré C. Contemporary clinical profile and outcome of prosthetic valve endocarditis J Am Med Assoc 297 2007 1354 1361 10.1001/jama.297.12.1354\n8 Glaser N. Jackson V. Holzmann M.J. Franco-Cereceda A. Sartipy U. Prosthetic valve endocarditis after surgical aortic valve replacement Circulation 136 2017 329 331 10.1161/CIRCULATIONAHA.117.028783 28716834\n9 López J. Revilla A. Vilacosta I. Villacorta E. González-Juanatey C. Gómez I. Definition, clinical profile, microbiological spectrum, and prognostic factors of early-onset prosthetic valve endocarditis Eur Heart J 28 2007 760 765 10.1093/eurheartj/ehl486 17255216\n10 Edelstein S. Yahalom M. Cardiac device-related endocarditis: epidemiology, pathogenesis, diagnosis and treatment — a review Int J Angiol 18 2009 167 172 10.1055/s-0031-1278347 22477546\n11 Cahill T.J. Baddour L.M. Habib G. Hoen B. Salaun E. Pettersson G.B. Challenges in infective endocarditis J Am Coll Cardiol 69 2017 325 344 10.1016/j.jacc.2016.10.066 28104075\n12 NNIS System National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2004 vol. 32 2004 10.1016/j.ajic.2004.10.001 issued October 2004\n15 Gonzalez-Juanatey C. Gonzalez-Gay M.A. Llorca J. Crespo F. GarcÍa-Porrua C. Corredoira J. Rheumatic manifestations of infective endocarditis in non-addicts: a 12-year study Medicine (Baltimore) 80 2001 9 19 10.1097/00005792-200101000-00002 11204504\n16 Le Moal G. Roblot F. Paccalin M. Sosner P. Burucoa C. Roblot P. Clinical and laboratory characteristics of infective endocarditis when associated with spondylodiscitis Eur J Clin Microbiol Infect Dis 21 2002 671 675 10.1007/s10096-002-0798-x 12373500\n17 Klug D. Lacroix D. Savoye C. Goullard L. Grandmougin D. Hennequin J.L. Systemic infection related to endocarditis on pacemaker leads Circulation 95 1997 2098 2107 9133520\n18 Berbari E.F. Kanj S.S. Kowalski T.J. Darouiche R.O. Widmer A.F. Schmitt S.K. Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults Clin Infect Dis 2015 61 2015 e26 46 10.1093/cid/civ482\n19 Eide J. Bone infarcts in bacterial endocarditis Hum Pathol 13 1982 631 634 10.1016/s0046-8177(82)80005-1 7084939\n20 Wood C.A. Sewell D.L. Strausbaugh L.J. Vertebral osteomyelitis and native valve endocarditis caused by Staphylococcus warneri Diagn Microbiol Infect Dis 12 1989 261 263 10.1016/0732-8893(89)90024-2 2791489\n21 Speechly-Dick M.E. Vaux E.C. Swanton R.H. A case of osteomyelitis secondary to endocarditis Br Hear J 72 1994 298 10.1136/hrt.72.3.298\n22 Speechly-Dick M.E. Swanton R.H. Osteomyelitis and infective endocarditis Postgrad Med J 70 1994 885 890 10.1136/pgmj.70.830.885 7870635\n23 Bucher E. Trampuz A. Donati L. Zimmerli W. Spondylodiscitis associated with bacteraemia due to coagulase-negative staphylococci Eur J Clin Microbiol Infect Dis 19 2000 118 120 10.1007/s100960050441 10746498\n24 Kragsbjerg P. Bomfim-Loogna J. Törnqvist E. Söderquist B. Development of antimicrobial resistance in Staphylococcus lugdunensis during treatment – report of a case of bacterial arthritis, vertebral osteomyelitis and infective endocarditis Clin Microbiol Infect 6 2000 496 499 10.1046/j.1469-0691.2000.00103.x 11168184\n\n",
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"title": "Concomitant endocarditis and spondylodiscitis due to coagulase-negative Staphylococci and a review of the literature.",
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"abstract": "Inguinal herniorrhaphy is a common outpatient procedure where analgesia can be augmented with local infiltration. We report a case of prolonged femoral nerve palsy secondary to liposomal bupivacaine use during wound infiltration after inguinal herniorrhaphy. Inadvertent transient femoral nerve palsy is a rare but known complication after ilioinguinal field block. This case both highlights the value of ultrasound imaging in evaluating the complications and demonstrates how the prolonged nature of liposomal bupivacaine can prolong adverse sequela.",
"affiliations": "From the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.",
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"title": "Inadvertent Prolonged Femoral Nerve Palsy After Field Block with Liposomal Bupivacaine for Inguinal Herniorrhaphy.",
"title_normalized": "inadvertent prolonged femoral nerve palsy after field block with liposomal bupivacaine for inguinal herniorrhaphy"
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"abstract": "Cerebellar ataxia associated with glutamic acid decarboxylase autoantibodies (GAD-ab) is a rare and usually slow progressive disease with moderate to severe gait and limb ataxia, dysarthria, and nystagmus. The treatment for this condition is still being discussed. We report the cases of three patients with GAD-ab cerebellar ataxia treated successively with intravenous immunoglobulin (IVIg) and rituximab. Symptoms improved in one case after rituximab therapy and were stabilized in another after a combined therapy of IVIg and rituximab. The third patient continued to worsen despite these treatments. We conclude that IVIg and rituximab therapy could improve or stabilize GAD-ab cerebellar ataxia. Early treatment, the lack of cerebellar atrophy on magnetic resonance imaging, and a subacute onset of the symptoms could be decisive prognostic factors.",
"affiliations": "Service de Neurologie, CHU Gabriel Montpied, 58 rue Montalembert, 63000, Clermont-Ferrand, France, planche.vincent@gmail.com.",
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"title": "Intravenous immunoglobulin and rituximab for cerebellar ataxia with glutamic acid decarboxylase autoantibodies.",
"title_normalized": "intravenous immunoglobulin and rituximab for cerebellar ataxia with glutamic acid decarboxylase autoantibodies"
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"abstract": "Radium-223 is used for treating castration-resistant prostate cancer with bone metastases. Here, we report the case of a 76-year-old man diagnosed with castration-resistant prostate cancer with bone metastases who was started on radium-223. Although the patient ultimately died from causes unrelated to the treatment before starting the third treatment course, we observed that radium-223 was more effective in areas closer to the bone cortex than in deeper tumor regions. Through histopathological analysis, we provide important mechanistic insights on the therapeutic effect of radium-223 in human prostate cancer bone metastases.",
"affiliations": "Department of Urology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan.;Department of Urology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan.;Department of Pathology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan.;Department of Urology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan.",
"authors": "Dobashi|Masato|M|;Kouguchi|Dai|D|;Kanetsuna|Yukiko|Y|;Ishii|Junichiro|J|",
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"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30118-2\n10.1016/j.eucr.2020.101230\n101230\nOncology\nHistopathology of castration-resistant prostate cancer confirms changes in bone metastasis during radium-223 treatment: A case report\nDobashi Masato mdobashi0103@gmail.coma∗1 Kouguchi Dai a Kanetsuna Yukiko b Ishii Junichiro a a Department of Urology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan\nb Department of Pathology, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan\n∗ Corresponding author. mdobashi0103@gmail.com1 Present address: Dobashi Urological Clinic, Shizuoka, Japan.\n\n\n03 5 2020 \n9 2020 \n03 5 2020 \n32 10123022 4 2020 27 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Radium-223 is used for treating castration-resistant prostate cancer with bone metastases. Here, we report the case of a 76-year-old man diagnosed with castration-resistant prostate cancer with bone metastases who was started on radium-223. Although the patient ultimately died from causes unrelated to the treatment before starting the third treatment course, we observed that radium-223 was more effective in areas closer to the bone cortex than in deeper tumor regions. Through histopathological analysis, we provide important mechanistic insights on the therapeutic effect of radium-223 in human prostate cancer bone metastases.\n\nKeywords\nRadium-223Castration-resistant prostate cancerBone metastasisHistopathologyAbbreviations\nALP, alkaline phosphataseCAB, combined androgen blockadeCRPC, castration-resistant prostate cancerOS, overall survivalRa-223, radium-223PSA, prostate-specific antigenRANKL, receptor activator of nuclear factor-κB ligandSRE, skeletal related event\n==== Body\nIntroduction\nRadium-223 (Ra-223) increases overall survival (OS) in castration-resistant prostate cancer (CRPC) patients with bone metastases. The therapeutic effect of Ra-223 on bone tumors has been reported in vitro.1 However, no study has assessed the histopathological changes of bone metastases during or after Ra-223 treatment in humans. We report the case of a patient who received Ra-223 and had visible changes in bone metastases, confirmed histopathologically at autopsy.\n\nCase presentation\nA 76-year-old man with a medical history of chronic heart failure and arteriosclerosis obliterans but no special notes on family history or allergies, was treated with combined androgen blockade (CAB) after being diagnosed with prostate cancer; however, he developed CRPC 2 years after the treatment. He was then treated with estramusutine, but the treatment was discontinued due to the exacerbation of heart failure. Since then, he had stopped visiting the Urology Department.\n\nTwo years after the discontinuation of treatment, he was admitted to the Cardiology Department because of obstructive arteriosclerosis of the lower limbs. His prostate-specific antigen (PSA) and alkaline phosphatase (ALP) levels were 36.2 ng/ml and 537 U/L, respectively, and he was referred to the Urology Department. Presence of a tumor was confirmed by computed tomography and bone scintigraphy; he then resumed treatment. Bone metastases were visible in the right seventh rib, third lumbar vertebrae, and right ilium, without lymph node or visceral metastases (Tx N0 M1b, according to the TNM Classification of Malignant Tumors). Because the patient refused hormonal therapy and owing to the previously observed severe side effects of estramustine, we resumed CAB with degarelix and bicalutamide. Five months later, PSA and ALP levels decreased to 0.705 ng/ml and 224 U/L, respectively. Denosumab was administered after a tooth extraction performed because of tooth decay, which occurred during Ra-223 administration. Denosumab was administered once every 3 months, for a total of 3 times until the end of treatment. During the administration, the ALP value decreased slightly, but the PSA value continued to increase (Fig. 1).Fig. 1 Treatment of prostate cancer from diagnosis to death and changes in PSA and ALP values.\n\nFig. 1\n\nMonthly Ra-223 treatment was initiated and no side effects were observed. Before the third dose, the patient was admitted to the Cardiovascular Department with heart failure symptoms. Despite planning to resume Ra-223 therapy once his general condition improved, the patient returned to hospital on the day of discharge (upon improvement of heart failure symptoms) with acute abdomen. Shortly after, he died. A pathological autopsy revealed that he had died of ischemic enteritis resulting in sepsis.\n\nHistopathological examination revealed fibrotic tissue in the prostate (Fig. 2A), which was suspected to be necrotic, but no viable tumor cells were detected. Macroscopic bone examination showed white-toned areas of osteosclerotic metastases on the left lateral side of the third lumbar vertebrae (Fig. 2B). Histopathology revealed fibrous tissue and inactive degenerative cells near the bone cortex in the metastatic region (Fig. 2C). However, closer to the trabecular area, we observed an increased proportion of viable tumor cells (Fig. 2D), which were found in close proximity to hematopoietic cells (Fig. 2E). No cytopathic effects were observed in normal bone marrow specimens (Fig. 2F).Fig. 2 Histopathological examination revealed fibrotic tissue in the prostate, which was suspected to be necrotic, but no viable tumor cells were detected. A) Macroscopic bone examination showed white-toned areas of osteosclerotic metastases on the left lateral side of the third lumbar vertebrae. B) Histological evaluation of bone tissue. C) Osteosclerotic changes are apparent near the bone cortex. Fibrous degenerative cells are indicated by an arrow pointing up, and inactive degenerative tumor cells are indicated by an arrow pointing down. D) Viable tumor cells are enriched in the deeper regions of the tumor (right side). E) Viable tumor and hematopoietic cells (indicated by arrows). F) Bone marrow tissue apparently unaffected by Ra-223.\n\nFig. 2\n\nDiscussion\nWe report the case of a CRPC patient who underwent two doses of Ra223 treatment before dying of ischemic enteritis resulting in sepsis. Inactive tumor cells were observed in the bone cortex but not in the trabecular area, suggesting that Ra-223 had a cytotoxic effect more pronounced in superficial areas of the tumor.\n\nA study in mice with prostate cancer bone metastases showed that active bone remodeling microenvironments near bone metastases were the major site of Ra-223 accumulation.1 According to the pathological study on bone metastasis of human prostate cancer subjected to CAB therapy,2 the bone metastasis showed not only an increase in the number of osteoblasts in the prostate cancer cells and the bones responding to the prostate cancer cells but also a large amount of osteoid and osteoclasts. They also showed high bone turnover. Histopathologically, osteogenic tissues in bone metastatic lesions exhibit a cord-like structure. As a result, the short-range α radiation emitted by Ra-223 deposited in osteoblasts exerts antitumor effects across a wide area by irradiating tumor cell cords.3 We observed tumor cell degeneration in osteogenic tissues adjacent to the bone cortex. However, this decreased with tumor depth, with a higher number of viable tumor cells present in deeper areas of the tumor. McKay reported prolongation of OS in the 5–6 Ra-223 dose group compared to the 1–4 dose group.4 In our case, Ra-223 was given only twice. Therefore, there is the possibility that a sufficient therapeutic effect could not be obtained due to the small number of doses.\n\nThe therapeutic effect of Ra-223 has been suggested even in cases where bisphosphonate treatment is resistant to bone metastatic lesions. On the other hand, denosumab not only acts to prevent skeletal-related events (SRE) in patients with bone metastasis by suppressing the receptor activator of nuclear factor κB ligand (RANKL) signaling, but also, a direct and indirect antitumor effect has been suggested.5 In this case, denosumab was also used in combination with Ra-223. No report was found on the frequency of denosumab administration and the pathological changes to bone metastases; thus, a pathological study on denosumab treatment in this case was not possible. However, since the number of doses of denosumab itself is small in this case, it is unclear whether a direct pathological treatment effect on the bone metastases appears.\n\nSince he died soon after starting the treatment; hence, long-term evaluation including imaging was not achieved. The change in bone lesions in the pathological results in this case was due to tumor degeneration and necrotic degeneration, which are considered to be therapeutic effects, on the bone surface part where the bone turnover is accelerated. This may be the expected therapeutic effect of Ra-223.\n\nConclusion\nHistopathological analysis in this case showed that Ra-223 treatment had a therapeutic effect on areas with increased bone turnover close to the bone cortex, despite other concomitant therapeutic factors. Results similar to those shown in the preclinical studies with mice were also observed in human pathological specimens.\n\nFunding\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\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1 Abou D.S. Ulmert D. Doucet M. Hobbs R.F. Riddle R.C. Thorek D.L.J. Whole-body and microenvironmental localization of radium-223 in naïve and mouse models of prostate cancer metastasis J Natl Cancer Inst 108 2015 \n2 C1 Morrissey Roudier M.P. Dowell A. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series J Bone Miner Res 28 2 2013 333 340 22936276 \n3 Bruland Ø.S. Nilsson S. Fisher D.R. Larsen R.H. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Canc Res 12 2006 6250s 6257s \n4 McKay R.R. Jacobus S. Fiorillo M. Radium-223 use in clinical practice and variables associated with completion of therapy Clin Genitourin Canc 15 2016 e289 e298 \n5 de Groot A.F. Appelman-Dijkstra N.M. Van der Burg S.H. The anti-tumor effect of RANKL inhibition in malignant solid tumors – a systematic review Canc Treat Rev 62 2018 18 28\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "32()",
"journal": "Urology case reports",
"keywords": "ALP, alkaline phosphatase; Bone metastasis; CAB, combined androgen blockade; CRPC, castration-resistant prostate cancer; Castration-resistant prostate cancer; Histopathology; OS, overall survival; PSA, prostate-specific antigen; RANKL, receptor activator of nuclear factor-κB ligand; Ra-223, radium-223; Radium-223; SRE, skeletal related event",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101230",
"pmc": null,
"pmid": "32420038",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "17062709;27651103;29154022;22936276;26683407",
"title": "Histopathology of castration-resistant prostate cancer confirms changes in bone metastasis during radium-223 treatment: A case report.",
"title_normalized": "histopathology of castration resistant prostate cancer confirms changes in bone metastasis during radium 223 treatment a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-256233",
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"activesubstancename": "DEGARELIX"
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"abstract": "In children, skin rashes are a frequent manifestation of infectious diseases, or they could also be the result of a drug hypersensitivity reaction, especially after antibiotic intake. We report the case of a 5-year-old girl investigated for a suspected post streptococcal vasculitis where differential diagnosis was improved by an allergy work-up and confirmed by lymphocyte transformation test.",
"affiliations": "From the Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital Department of Clinical and Experimental Medicine, University of Florence Rheumatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.",
"authors": "Liccioli|Giulia|G|;Parronchi|Paola|P|;Marrani|Edoardo|E|;Maniscalco|Valerio|V|;Giovannini|Mattia|M|;Barni|Simona|S|;Sarti|Lucrezia|L|;Capone|Manuela|M|;Simonini|Gabriele|G|;Mori|Francesca|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000003420",
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"issn_linking": "0891-3668",
"issue": null,
"journal": "The Pediatric infectious disease journal",
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"medline_ta": "Pediatr Infect Dis J",
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"nlm_unique_id": "8701858",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34862342",
"pubdate": "2021-11-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amoxicillin Adverse Cutaneous Reaction Versus Post Streptococcal Vasculitis: Lymphocyte Transformation Test Solved the Question.",
"title_normalized": "amoxicillin adverse cutaneous reaction versus post streptococcal vasculitis lymphocyte transformation test solved the question"
} | [
{
"companynumb": "IT-ARISTO PHARMA-AMOX+CLAV202112141",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
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"abstract": "Human T-cell lymphotropic virus (HTLV) is a human oncoretrovirus known to cause adult T-cell leukaemia/lymphoma (ATLL). Coinfection of human T-lymphotropic virus type 1 with Epstein-Barr virus (EBV) results in enhanced expression of the HTLV virus and leads to aggressive organ involvement from T-cell malignancy. It has also been observed that the prevalence of hepatitis B infection has been higher in patients with HTLV ATLL as compared with the general population in certain countries. We describe a case of a 34-year-old man who initially presented with leucocytosis, fatigue and conjunctival erythema. His radiological images revealed significant generalised adenopathy, and his flow cytometry analysis came back positive for CD4-positive T-cell lymphoma. He was subsequently diagnosed with HTLV-positive ATLL. Ultimately the patient was also diagnosed with acute hepatitis B and EBV. We describe a unique case of ATLL with coinfection with two other viruses, the association of which can be of potential prognostic value in guiding the treatment strategies for ATLL.",
"affiliations": "Internal Medicine, Albany Medical Center Hospital, Albany, New York, USA ayeshamnr6@gmail.com.;Hematology/Oncology, New York Oncology Hematology PC, Albany, New York, USA.;Department of Pathology and Laboratory Medicine, Albany Medical Center Hospital, Albany, New York, USA.;Department of Pathology and Laboratory Medicine, Albany Medical Center Hospital, Albany, New York, USA.",
"authors": "Munir|Ayesha|A|;Raval|Mihir|M|;Zuo|Chunlai|C|;Subik|M Kristina|MK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "Haematology (incl blood transfusion); Malignant and Benign haematology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D060085:Coinfection; D020031:Epstein-Barr Virus Infections; D015490:HTLV-I Infections; D006509:Hepatitis B; D006515:Hepatitis B virus; D004854:Herpesvirus 4, Human; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31645398",
"pubdate": "2019-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18702873;1942589;28315754;28088963;8833624;28202897;25753008;23162541;20887496",
"title": "HTLV-positive adult T-cell leukaemia/lymphoma with Epstein-Barr virus and hepatitis B coinfection.",
"title_normalized": "htlv positive adult t cell leukaemia lymphoma with epstein barr virus and hepatitis b coinfection"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-06049",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"... |
{
"abstract": "BACKGROUND\nAcetaminophen-cysteine adducts (APAP-CYS) are a serum biomarker of acetaminophen exposure, formed when the oxidative metabolite of acetaminophen binds to cysteine residues of hepatic proteins. APAP-CYS adducts become elevated in cases of acute liver failure following acetaminophen overdose and have been proposed as a diagnostic tool to identify acetaminophen-induced acute liver failure when standard testing is inconclusive.\n\n\nMETHODS\nA 26-year-old female with history of unexplained, severe hepatitis presented with a second episode of severe hepatitis including coagulopathy and transaminase levels >10,000 U/L. The patient reported ingesting \"only a couple\" of acetaminophen tablets several days prior to her presentation. An acetaminophen concentration of 14 mcg/mL at presentation aroused suspicion that acetaminophen might have caused the patient's liver failure, despite her adamant denial of overdose. APAP-CYS adduct levels measured from serum obtained 4 days after her presentation and in two consecutive serum samples are reported alongside previously reported APAP-CYS levels.\n\n\nCONCLUSIONS\nThe patient's APAP-CYS adduct levels were consistent with those seen in acute liver injury due to acetaminophen toxicity, even up to 1 week following presentation, and allowed for confirmation of acetaminophen toxicity as the cause of the her hepatitis. Overall, this case demonstrates the real-time application of APAP-CYS adducts as a biomarker to diagnose acetaminophen toxicity in patients with indeterminate acute liver failure.",
"affiliations": "Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.",
"authors": "Frey|Sean M|SM|;Wiegand|Timothy J|TJ|;Green|Jody L|JL|;Heard|Kennon J|KJ|;Wilkins|Diana G|DG|;Gorodetsky|Rachel M|RM|;Dart|Richard C|RC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D000082:Acetaminophen; C069744:acetaminophen cysteine; D003545:Cysteine",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-015-0476-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "11(2)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D002498:Centrifugation; D003545:Cysteine; D003956:Dialysis; D062787:Drug Overdose; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008111:Liver Function Tests",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "218-22",
"pmc": null,
"pmid": "25896948",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16530510;18923390;18608255;19439490;21274877;21319200;21401949;22697593;23052410;25681644",
"title": "Confirming the Causative Role of Acetaminophen in Indeterminate Acute Liver Failure Using Acetaminophen-Cysteine Adducts.",
"title_normalized": "confirming the causative role of acetaminophen in indeterminate acute liver failure using acetaminophen cysteine adducts"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-96573",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"dr... |
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"abstract": "Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content.",
"affiliations": "Sir Charles Gairdner Hospital, Perth, WA, Australia. jennifer.ng@health.wa.gov.au",
"authors": "Ng|Jennifer L|JL|;Morgan|David J R|DJ|;Loh|Nelson K M|NK|;Gan|Seng K|SK|;Coleman|Patrick L|PL|;Ong|Gregory S Y|GS|;Prentice|David|D|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.2011.tb02982.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "194(6)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D000141:Acidosis, Renal Tubular; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007008:Hypokalemia; D007052:Ibuprofen; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness; D018570:Risk Assessment; D012494:Sampling Studies",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "313-6",
"pmc": null,
"pmid": "21426288",
"pubdate": "2011-03-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis.",
"title_normalized": "life threatening hypokalaemia associated with ibuprofen induced renal tubular acidosis"
} | [
{
"companynumb": "AU-AMNEAL PHARMACEUTICALS-2020-AMRX-03881",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
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"drugadditional... |
{
"abstract": "OBJECTIVE\nSmall for gestational age (SGA) patients have an increased risk of developing a cardiovascular pathology, as well as a metabolic syndrome. Our objective is to evaluate the cardiac morphology and function of SGA children treated with growth hormone (GH), identifying changes that could potentially have long-term consequences.\n\n\nMETHODS\nWe selected 23 SGA school-age patients and 23 healthy children. We measured their weight, height, blood pressure and heart rate. Using transthoracic echocardiography, we evaluated cardiac chamber size, ascending and abdominal aortic diameter as well as the systolic and diastolic function of both ventricles.\n\n\nRESULTS\nSGA children have a higher systolic and diastolic blood pressure (P<.05) without significant changes in their heart rate. They also have a thicker interventricular septum (SGA Z-score 1.57 vs. 0.89; P=.026) and a worse right ventricular systolic function, with a lower TAPSE (SGA Z-score -0.98 vs. 0.95; P=.000), as well as a lower blood flow rate in the pulmonary artery (SGA 0.85m/s vs. 0.97m/s; P=.045). No significant difference was observed in the patients' left ventricular function. SGA patients' ascending aortic diameter was greater (SGA Z-score -1.09 vs. -1.93; P=.026), whereas the systolic abdominal aortic diameter was smaller (SGA Z-score-0.89 vs. -0.19; P=.015).\n\n\nCONCLUSIONS\nWe found functional and morphological cardiac changes in SGA school-age patients treated with GH. It is important to follow-up this patient group in order to determine if these changes contribute to an increased cardiac morbidity in adulthood.",
"affiliations": "Departamento de Pediatría, Hospital de Barbastro, Barbastro, Huesca, España. Electronic address: estheraurensanz@gmail.com.;Departamento de Pediatría, Hospital Universitario Miguel Servet, Zaragoza, España.;Departamento de Pediatría, Hospital Clínico Universitario de Zaragoza, Zaragoza, España.;Servicio de Medicina Intensiva, Hospital Universitario Miguel Servet, Zaragoza, España.;Departamento de Pediatría, Hospital Clínico Universitario de Zaragoza, Zaragoza, España.",
"authors": "Aurensanz Clemente|Esther|E|;Ayerza Casas|Ariadna|A|;Samper Villagrasa|Pilar|P|;Ruiz Frontera|Pablo|P|;Bueno Lozano|Gloria|G|",
"chemical_list": "D013006:Growth Hormone",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.medcli.2016.09.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7753",
"issue": "148(3)",
"journal": "Medicina clinica",
"keywords": "Echocardiography; Ecocardiografía; Estructura; Hormonas; Hormones; Pediatrics; Pediatría; Right ventricle; Structure; Ventrículo derecho",
"medline_ta": "Med Clin (Barc)",
"mesh_terms": "D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D004452:Echocardiography; D005260:Female; D006130:Growth Disorders; D013006:Growth Hormone; D006321:Heart; D006331:Heart Diseases; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D009206:Myocardium",
"nlm_unique_id": "0376377",
"other_id": null,
"pages": "101-106",
"pmc": null,
"pmid": "27871765",
"pubdate": "2017-02-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Evaluation of cardiac function in a group of small for gestational age school-age children treated with growth hormone.",
"title_normalized": "evaluation of cardiac function in a group of small for gestational age school age children treated with growth hormone"
} | [
{
"companynumb": "ES-ROCHE-2762019",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nMultiple visceral aneurysms are uncommon and usually result from connective tissue diseases, systemic arteritis, or mycotic lesions. An association between multiple visceral aneurysms and excessive oral amphetamine use has not been reported.\n\n\nMETHODS\nThe clinical features of 2 patients at the University of Michigan Medical Center for treatment of multiple visceral aneurysms and amphetamine use were reviewed.\n\n\nRESULTS\nThe patients had histories of excessive oral amphetamine use that ranged from 50 mg daily for 22 years to 200 mg daily for 2 years. No evidence was seen of systemic arteritis, connective tissue disorder, or an infectious process that may have caused the aneurysms. The arteriograms documented multiple splanchnic and renal artery aneurysms that involved both the large and the small arteries. The aneurysms of 1 patient were managed conservatively, and the patient has not had any clinical sequelae of the aneurysms during 14 years of follow-up. The second patient had hematobilia from a ruptured hepatic artery aneurysm that was treated with transcatheter embolic occlusion of the bleeding vessel. The patient had no recurrent gastrointestinal problems and continued to use amphetamines until his death from a cerebrovascular accident 6 years later.\n\n\nCONCLUSIONS\nA possible association between excessive oral amphetamine use and multiple visceral aneurysms is reported for 2 patients in whom other risk factors were absent. The potential for chronic oral amphetamine use to cause multiple visceral aneurysms is an ill-defined but not unexpected complication of this substance that is known to contribute to arterial hypertension and to produce a form of necrotizing arteritis.",
"affiliations": "Department of Surgery, University of Michigan, Ann Arbor, USA.",
"authors": "Welling|T H|TH|;Williams|D M|DM|;Stanley|J C|JC|",
"chemical_list": "D003913:Dextroamphetamine",
"country": "United States",
"delete": false,
"doi": "10.1016/s0741-5214(98)70103-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-5214",
"issue": "28(4)",
"journal": "Journal of vascular surgery",
"keywords": null,
"medline_ta": "J Vasc Surg",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000783:Aneurysm; D003913:Dextroamphetamine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy; D009767:Obesity, Morbid; D011859:Radiography; D012077:Renal Artery; D014781:Viscera",
"nlm_unique_id": "8407742",
"other_id": null,
"pages": "727-31",
"pmc": null,
"pmid": "9786273",
"pubdate": "1998-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Excessive oral amphetamine use as a possible cause of renal and splanchnic arterial aneurysms: a report of two cases.",
"title_normalized": "excessive oral amphetamine use as a possible cause of renal and splanchnic arterial aneurysms a report of two cases"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-00442",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE"
},
... |
{
"abstract": "Buprenorphine is a partial mu receptor agonist and kappa/delta antagonist commonly used for the treatment of opioid dependence or as an analgesic. It has a long plasma half-life and a high binding affinity for opioid receptors. This affinity is so high, that the effects are not easily antagonized by competitive antagonists, such as naloxone. The high affinity also prevents binding of other opioids, at commonly used clinical doses, to receptor sites - preventing their analgesic and likely minimum alveolar concentration (MAC) reducing benefits. This case report contrasts the anesthetic requirements of a patient undergoing emergency cervical spine surgery while taking buprenorphine with anesthetic requirements of the same patient undergoing a similar procedure after weaning of buprenorphine. Use of intraoperative neurophysiological monitoring prevented use of paralytics and inhalational anesthetics during both cases, therefore total intravenous anesthesia (TIVA) was maintained with propofol and remifentanil infusions. During the initial surgery, intraoperative patient movement could not be controlled with very high doses of propofol and remifentanil. The patient stopped moving in response to surgical stimulation only after the addition of a ketamine. Buprenorphine-naloxone was discontinued postoperatively. Five days later the patient underwent a similar cervical spine surgery. She had drastically reduced anesthetic requirements during this case, suggesting buprenorphine's profound effect on anesthetic dosing. This case report elegantly illustrates that discontinuation of buprenorphine is likely warranted for patients who present for major spine surgery, which necessitates the avoidance of volatile anesthetic and paralytic agents. The addition of ketamine may be necessary in patients maintained on buprenorphine in order to ensure a motionless surgical field.",
"affiliations": null,
"authors": "Khelemsky|Yury|Y|;Schauer|Jacob|J|;Loo|Nathaniel|N|",
"chemical_list": "D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D002047:Buprenorphine; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "18(2)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D002047:Buprenorphine; D002574:Cervical Vertebrae; D005260:Female; D006801:Humans; D009293:Opioid-Related Disorders; D015742:Propofol; D016103:Spinal Fractures; D016896:Treatment Outcome",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "E261-4",
"pmc": null,
"pmid": "25794231",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effect of buprenorphine on total intravenous anesthetic requirements during spine surgery.",
"title_normalized": "effect of buprenorphine on total intravenous anesthetic requirements during spine surgery"
} | [
{
"companynumb": "US-RB PHARMACEUTICALS LIMITED-RB-078632-2015",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHL... |
{
"abstract": "We report here a case of fatal respiratory failure developed during chemotherapy for diffuse large B cell lymphoma that occurred late after lung transplantation. 25-year- old man underwent lung transplantation from brain death donor for respiratory failure due to interstitial pneumonia at the age of 16 years old. Two years after transplantation, his respiratory function decreased gradually. Chronic lung allograft dysfunction including bronchiolitis obliterans( BOS) and restrictive allograft syndrome was suspected and immunosuppression was enhanced. Nine years after transplantation, he had abdominal pain and physical examination suggested intestinal obstruction. Small intestine endoscopy revealed an ulcer at jejunum and diffuse large B cell lymphoma( DLBCL) was finally diagnosed by biopsy. Chemotherapy was planned for lymphoma, but respiratory failure progressed just before chemotherapy. Chest computed tomography showed infiltrative shadow in right lung, so we suspected presence of lymphoma and chemotherapy was carried out. After chemotherapy, abnormal shadow in the right lung disappeared. Although chemotherapy was effective, respiratory failure progressed and he died. Pathological examination from autopsy showed mixture of BOS, diffuse alveolar damage, invasion of aspergillus and acute fibrinoid organizing pneumonia but no residual DLBCL was found in the lung.",
"affiliations": "Division of Thoracic and Cardiovascular Surgery, Niigata University, Niigata, Japan.",
"authors": "Kitahara|Akihiko|A|;Sato|Seijiro|S|;Koike|Terumoto|T|;Tsuchida|Masanori|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5252",
"issue": "69(11)",
"journal": "Kyobu geka. The Japanese journal of thoracic surgery",
"keywords": null,
"medline_ta": "Kyobu Geka",
"mesh_terms": "D000328:Adult; D001344:Autopsy; D017809:Fatal Outcome; D006801:Humans; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D012131:Respiratory Insufficiency; D013997:Time Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0413533",
"other_id": null,
"pages": "941-945",
"pmc": null,
"pmid": "27713201",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Respiratory Failure Developed during Chemotherapy for Diffuse Large B Cell Lymphoma that Occurred Late after Lung Transplantation.",
"title_normalized": "fatal respiratory failure developed during chemotherapy for diffuse large b cell lymphoma that occurred late after lung transplantation"
} | [
{
"companynumb": "JP-ROCHE-1843810",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE"
},
... |
{
"abstract": "To demonstrate the safety and efficacy of intraarterial chemotherapy (IAC) in small infants (<10 kg) with retinoblastoma.\n\n\n\nRetrospective, consecutive, observational case series of patients treated with IAC. Femoral arterial access was obtained using a micropuncture kit and ultrasound guidance, which enabled direct visualization. Melphalan (1.5-5.0 mg), topotecan (0.3-2.0 mg), and/or carboplatin (30-40 mg) were used. Patients underwent adjuvant therapies including laser, cryotherapy, and intravitreal melphalan if persistent disease or recurrence was observed.\n\n\n\nFifty-nine injections were administered to 11 eyes of 6 patients. All eyes but one were classified as International Classification Groups C or D. Median patient weight at first IAC cycle was 9.2 kg (mean, 8.9 kg). Median diameter of the femoral artery at the catheterization site was 3.74 mm, measured by two independent observers. Median follow-up was 21.4 months (range 13.1-34.5 months). All eyes were salvaged.\n\n\n\nThis study confirmed the safety and efficacy of IAC in infants under 10 kg. Ultrasound guidance enabled successful catheterization of femoral arteries as small as 2.7 mm in diameter. Patients in this study appeared to require fewer injections and lower total doses of chemotherapy compared with previously reported series of comparably advanced disease in larger infants.",
"affiliations": "Retina Consultants of Houston, Houston, Texas.;Department of Neurological Surgery, McGovern Medical School, The University of Texas Health Science Center, Mischer Neuroscience Institute, Memorial Hermann Hospital, Houston, Texas.;Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center, Memorial Hermann Hospital, Houston, Texas.;Retina Consultants of Houston, Houston, Texas.;Department of Pediatrics, Division of Hematology-Oncology, McGovern Medical School, The University of Texas Health Science Center, Children's Memorial Hermann Hospital, Houston, Texas.;Retina Consultants of Houston, Houston, Texas.",
"authors": "Kim|Ryan S|RS|;Dannenbaum|Mark J|MJ|;Lin|Michael W|MW|;Bretana|Maria E|ME|;Brown|Deborah L|DL|;Schefler|Amy C|AC|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000001713",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "38(7)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000970:Antineoplastic Agents; D001835:Body Weight; D002406:Catheterization, Peripheral; D004360:Drug Therapy, Computer-Assisted; D005260:Female; D005263:Femoral Artery; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D012372:ROC Curve; D012160:Retina; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "1420-1426",
"pmc": null,
"pmid": "28541962",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "USE OF FEMORAL ARTERY ULTRASOUND DURING INTRAARTERIAL CHEMOTHERAPY FOR CHILDREN UNDER 10 KG WITH RETINOBLASTOMA.",
"title_normalized": "use of femoral artery ultrasound during intraarterial chemotherapy for children under 10 kg with retinoblastoma"
} | [
{
"companynumb": "US-APOPHARMA USA, INC.-2017AP012676",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYMETAZOLINE"
},
"drugadditional":... |
{
"abstract": "Retroperitoneal haemorrhage (RH) is not uncommon in patients with provoking events like trauma. However, spontaneous RH (SRH) is a rare and life-threatening complication described as the development of bleeding into the retroperitoneal cavity, appearing spontaneously and without a preceding history of trauma or other predisposing illness. We are reporting a case of an elderly patient with recurrent deep vein thrombosis who had developed SRH secondary to concurrent use of multiple anticoagulation agents, resulting from poor healthcare follow-up and lack of sufficient medication reconciliation. This article highlights the significance of recognising risk factors for SRH, as well as management strategies through literature review.",
"affiliations": "Internal Medicine, Wayne State University, Warren, Michigan, USA mohammed.uddin2@wayne.edu.;Internal Medicine, Detroit Medical Center, Detroit, Michigan, USA.;Internal Medicine, Detroit Medical Center, Detroit, Michigan, USA.;Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA.;Internal Medicine, John Dingell VA Medical Center, Detroit, MI, USA.",
"authors": "Uddin|Mohammed M|MM|;Mir|Tanveer|T|http://orcid.org/0000-0001-6822-9600;Khalil|Amir|A|;Bhat|Zeenat|Z|;Noronha|Anita Maria|AM|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; disease and health outcomes; drug interactions; pharmacokinetics; safety",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D006470:Hemorrhage; D006801:Humans; D019338:Polypharmacy; D012187:Retroperitoneal Space",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34404650",
"pubdate": "2021-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous retroperitoneal haemorrhage secondary to anticoagulation polypharmacy.",
"title_normalized": "spontaneous retroperitoneal haemorrhage secondary to anticoagulation polypharmacy"
} | [
{
"companynumb": "US-MYLANLABS-2021M1083270",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
... |
{
"abstract": "SARS-CoV-2 nasopharyngeal shedding contributes to the spread of the COVID-19 epidemic. Among 3271 COVID-19 patients treated at the Hospital University Institute Méditerranée Infection, Marseille, France from 3 March to 27 April 2020, tested at least twice by qRT-PCR, the median SARS-CoV-2 nasopharyngeal shedding duration was 6 days (range 2-54 days). Compared with short shedders (qRT-PCR positivity < 10 days), 34 (1.04%) persistent shedders (qRT-PCR positivity ≥ 17 days; mean ± SD: 23.3 ± 3.8 days) were significantly older, with associated comorbidities, exhibiting lymphopenia, eosinopenia, increased D-dimer and increased troponin (p < 0.05), and were hospitalized in intensive care unit in 17.7% vs. 1.1% of cases (p < 0.0001). Viral culture was positive in six persistent shedders after day 10, including in one patient after day 17, and no viral co-pathogen was detected in 33 tested patients. Persistent shedders received azithromycin plus hydroxychloroquine ≥ 3 days in 26/34 (76.5%) patients, a figure significantly lower than in short shedders (86.6%) (p = 0.042). Accordingly, mortality was 14.7% vs. 0.5% (p < 0.0001). Persistent shedding was significantly associated with persistent dyspnea and anosmia/ageusia (p < 0.05). In the context of COVID-19 treatment, including treatment with azithromycin plus hydroxychloroquine, the persistence of SARS-CoV-2 nasopharyngeal shedding was a rare event, most frequently encountered in elderly patients with comorbidities and lacking azithromycin plus hydroxychloroquine treatment.",
"affiliations": "Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;IHU Méditerranée Infection, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;IHU Méditerranée Infection, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;IHU Méditerranée Infection, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.;Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France.",
"authors": "Drancourt|Michel|M|;Cortaredona|Sébastien|S|0000-0003-3523-7158;Melenotte|Cléa|C|;Amrane|Sophie|S|;Eldin|Carole|C|;La Scola|Bernard|B|0000-0001-8006-7704;Parola|Philippe|P|;Million|Matthieu|M|;Lagier|Jean-Christophe|JC|;Raoult|Didier|D|;Colson|Philippe|P|0000-0001-6285-0308",
"chemical_list": "D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/v13050890",
"fulltext": "\n==== Front\nViruses\nViruses\nviruses\nViruses\n1999-4915\nMDPI\n\n34065871\n10.3390/v13050890\nviruses-13-00890\nArticle\nSARS-CoV-2 Persistent Viral Shedding in the Context of Hydroxychloroquine-Azithromycin Treatment\nDrancourt Michel 12*\nhttps://orcid.org/0000-0003-3523-7158\nCortaredona Sébastien 23\nMelenotte Cléa 1\nAmrane Sophie 12\nEldin Carole 2\nhttps://orcid.org/0000-0001-8006-7704\nLa Scola Bernard 12\nParola Philippe 23\nMillion Matthieu 12\nLagier Jean-Christophe 12\nRaoult Didier 12\nhttps://orcid.org/0000-0001-6285-0308\nColson Philippe 12\nSchildgen Oliver Academic Editor\n1 Aix Marseille University, IRD, AP-HM, MEPHI, 13005 Marseille, France; clea-leila.melenotte@ap-hm.fr (C.M.); sophie.amrane@ap-hm.fr (S.A.); bernard.la-scola@univ-amu.fr (B.L.S.); matthieu.million@univ-amu.fr (M.M.); jean-christophe.lagier@univ-amu.fr (J.-C.L.); didier.raoult@gmail.com (D.R.); philippe.colson@univ-amu.fr (P.C.)\n2 IHU Méditerranée Infection, 13005 Marseille, France; sebastien.cortaredona@univ-amu.fr (S.C.); carole.eldin@ap-hm.fr (C.E.); philippe.parola@univ-amu.fr (P.P.)\n3 Aix Marseille University, IRD, SSA, VITROME, 13005 Marseille, France\n* Correspondence: michel.drancourt@univ-amu.fr; Tel.: +33-413-732-401\n12 5 2021\n5 2021\n13 5 89011 3 2021\n08 5 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSARS-CoV-2 nasopharyngeal shedding contributes to the spread of the COVID-19 epidemic. Among 3271 COVID-19 patients treated at the Hospital University Institute Méditerranée Infection, Marseille, France from 3 March to 27 April 2020, tested at least twice by qRT-PCR, the median SARS-CoV-2 nasopharyngeal shedding duration was 6 days (range 2–54 days). Compared with short shedders (qRT-PCR positivity < 10 days), 34 (1.04%) persistent shedders (qRT-PCR positivity ≥ 17 days; mean ± SD: 23.3 ± 3.8 days) were significantly older, with associated comorbidities, exhibiting lymphopenia, eosinopenia, increased D-dimer and increased troponin (p < 0.05), and were hospitalized in intensive care unit in 17.7% vs. 1.1% of cases (p < 0.0001). Viral culture was positive in six persistent shedders after day 10, including in one patient after day 17, and no viral co-pathogen was detected in 33 tested patients. Persistent shedders received azithromycin plus hydroxychloroquine ≥ 3 days in 26/34 (76.5%) patients, a figure significantly lower than in short shedders (86.6%) (p = 0.042). Accordingly, mortality was 14.7% vs. 0.5% (p < 0.0001). Persistent shedding was significantly associated with persistent dyspnea and anosmia/ageusia (p < 0.05). In the context of COVID-19 treatment, including treatment with azithromycin plus hydroxychloroquine, the persistence of SARS-CoV-2 nasopharyngeal shedding was a rare event, most frequently encountered in elderly patients with comorbidities and lacking azithromycin plus hydroxychloroquine treatment.\n\nSARS-CoV-2\nCOVID-19\nviral persistence\nculture\nqRT-PCR\nhydroxychloroquine\nazithromycin\n==== Body\n1. Introduction\n\nSARS-CoV-2, responsible for COVID-19, is detected in the nasopharynx, which could constitute a major portal of entry for this emerging pathogen [1]. Indeed, not only is SARS-CoV-2 RNA routinely detected in nasopharyngeal swabs of COVID-19 patients [2], but this clinical material yields living viruses after it is appropriately cultivated in cell culture systems [3,4]. These data suggest that SARS-CoV-2 nasopharyngeal shedding is of interest for the natural history of COVID-19 in patients and in populations, as it may relate to the prognosis of the infection and its contagiousness. Two meta-analyses, including 79 and 28 studies, converged to indicate a viral shedding duration of 17 days (mean) and 18.4 days (median), respectively [5,6].\n\nMonitoring more than 3200 COVID-19 patients firmly documented by real-time RT-PCR (qRT-PCR) at the Hospital University Institute Méditerranée Infection, Marseille, France in March–April 2020 provided the opportunity to clarify the clinical and virological characteristics of patients with persistent nasopharyngeal shedding of SARS-CoV-2 [2].\n\n2. Materials and Methods\n\n2.1. Patients\n\nThis retrospective study aimed to describe the duration of SARS-CoV-2 viral shedding among 3737 qRT-PCR-confirmed COVID-19 patients, followed from 3 March to 27 April 2020 in the Méditerranée Infection Institute, as previously reported [2]. Clinical, radiological and laboratory data were collected, as previously reported [2,7], and the severity of patient illness was evaluated using the National Early Warning Score version 2 (NEWS-2) and the Charlson score [8]. All patients without contraindications were offered oral hydroxychloroquine (HCQ) (200 mg, three times a day for ten days) and azithromycin (AZ) (500 mg at day 1, followed by 250 mg per day for 4 days), and ceftriaxone or ertapenem was added for seven days in case of a NEWS-2 ≥ 5 [9,10]. Initiation of medical care (i.e., medical consultation and initiation of treatment) was defined as day 0, outpatient reevaluation was offered at days 2, 6 and 10 (more if needed), while hospitalized patients were evaluated twice daily. For hospitalized patients, qRT-PCR testing was performed on respiratory samples collected every day after diagnosis. For ambulatory followed-up patients, respiratory samples were collected at days 2, 6, 10 after diagnosis, then every four days when still qRT-PCR-positive at day 10. Biological results used for the analysis were those of tests performed on the day of admission to hospital (day-care hospital or complete hospitalization). The main criteria for discharge from complete hospitalization were the mean (or a significant decrease in flow) of oxygen supplementation\n\n2.2. Virology\n\nAll patients were SARS-CoV-2-diagnosed based on at least one positive qRT-PCR test performed by nasopharyngeal swab. The time of follow-up was defined relative to the qRT-PCR diagnosis. SARS-CoV-2 genome sequencing was performed directly from nasopharyngeal swab RNA extract using the Illumina MiSeq sequencer and Nextera XT paired-end technology (Illumina, Evry, France) and genome sequences were compared with the reference SARS-CoV-2 isolate Wuhan Hu-1, genome sequence (NC 045512.2) [11]. In case of qRT-PCR cycle threshold (Ct) value >18, partial spike gene PCR amplification (nucleotides 21,296–23,424 in reference to NC 045512.2) was performed, as previously described (DOI: https://doi.org/10.35088/4y1e-ec62, accessed on 11 May 2021). Viral cultures were performed as previously described [3,4]. Briefly, 500 µL of nasopharyngeal swab fluid (Virocult, Elitech, France) or sputum sample were passed through a 0.22-µm pore sized centrifugal filter (Merck millipore, Darmstadt, Germany), then inoculated in 4 wells of 96-well culture microplates containing Vero E6 cells (ATCC CRL-1586) into Minimum Essential Medium culture medium with 4% fetal calf serum and 1% glutamine. All samples were kept for less than 24 h at +4 °C before processing. After centrifugation at 4000× g, microplates were incubated at 37 °C. They were observed daily for evidence of cytopathogenic effect. Two subcultures were performed weekly. Presumptive detection of virus in supernatant showing cytopathic effect was done using the SU5000 scanning electron microscope (Hitachi High-Tech Corporation, Tokyo, Japan), before confirmation by a qRT-PCR targeting the SARS-CoV-2 gene E [2]. Culturing was performed systematically for hospitalized patients, and prospectively or retrospectively for non-hospitalized persistent viral shedders. Patients for whom the qRT-PCRs became negative within 10 days were designated as short viral shedders, patients with positive qRT-PCRs between day 10 and 17 as long viral shedders and patients with positive qRT-PCRs after day 17 as persistent viral shedders.\n\n2.3. Co-Pathogen Detection\n\nCo-pathogens in the nasopharyngeal swabs were screened by using a multiplex test incorporating 21 targeted pathogens, following the instructions of the supplier (FTD Respiratory pathogens 21; Siemens Fast Track Diagnosis, Luxembourg).\n\n2.4. Statistical Analysis\n\nWe used the Student t-test, Mann–Whitney U test, Chi2 test or Fisher’s exact test to compare differences between short viral shedding and persistent viral shedding groups. To explore risk factors associated with the duration of viral shedding, we performed multivariable analyses using linear regression models. All variables significant at p < 0.10 in univariate analyses were introduced in the initial multivariable model. A backward approach was then used to assess the iteration of variables and to control potential confounders (the significance level value for stay was set at 0.05). A primary model was performed over the full sample and a secondary model was performed among patients aged 65 years and older [12]. A secondary analysis using a multivariable logistic regression model was also performed to identify the risk factors associated with prolonged COVID-19 symptoms. The same backward approach was applied to this secondary outcome. A two-sided α of less than 0.05 was considered statistically significant. All analyses were carried out using SAS 9.4 statistical software (SAS Institute, Cary, NC, USA).\n\n2.5. Ethics Statement\n\nData were collected retrospectively from the routine care setting. This non-interventional retrospective study was approved on 13 May 2020 by our institutional review board committee (Méditerranée Infection No.: 2020–2021). In compliance with European General Data Protection Regulation No. 2016/679, patients were informed of the potential use of their medical data and that they could refuse the use of their data. The analysis of collected data followed the reference methodology MR-004 registered on No. MR 5010010520 in the AP-HM register, in compliance with European General Data Protection.\n\n3. Results\n\n3.1. Population Description\n\nAmong 3737 COVID-19 patients followed at the Hospital University Institute Méditerranée Infection between March 3 and April 27 [2], 3271 patients had at least two positive SARS-CoV-2 qRT-PCRs performed within less than 10 days. These patients had a median duration of shedding of 6 days (range, 2–54 days): in detail, 2800 (85.6%) patients were short shedders, with a 4.8 ± 3.1 day (mean ± SD) shedding duration; 437 (13.3%) patients were long shedders, with a 15.2 ± 3.8 day shedding duration; and 34 (1.04%) patients were persistent shedders, with a 23.3 ± 3.8 day shedding duration (Table 1).\n\nCompared to short shedders, persistent shedders were significantly (p < 0.01) older (≥65 years old), although the age range was 21–93 years, and 13/34 patients were <45 years old, with age-related comorbidities including chronic heart disease, hypertension, a NEWS-2 ≥5 and a Charlson score ≥5, indicative of an 85% probability of death in 13/34 (38.2%) patients and subsequent hospitalization (Table 1). Furthermore, the initial laboratory check-up of persistent shedders indicated a higher neutrophil/lymphocyte ratio, eosinopenia and higher D-dimer, troponin and C-reactive protein levels compared to short shedders (Table 2).\n\nMultivariable linear regression indicated that the duration of viral shedding was positively associated with NEWS-2, chronic heart disease and eosinopenia <0.04 G/L (Table 3).\n\n3.2. Care and Treatment\n\nA higher percentage of persistent shedders was hospitalized in the intensive care unit compared to short shedders, 17.7% vs. 1.1% (p < 0.0001). In this cohort, 26/34 (76.5%) persistent shedders had HCQ-AZ therapy ≥ 3 days, versus 2426/2800 (86.6%) short shedders (p = 0.042, Mantel–Haenszel Chi-2 test). Indeed, 8/34 persistent shedders had HCQ-AZ therapy < 3 days: more precisely, one patient refused HCQ and AZ treatment, and seven other patients received AZ only because HCQ was contraindicated due to cardiac contraindications (n = 6) and drug interaction (n = 1) (Table 1). In contrast, 374/2800 short shedders had HCQ-AZ therapy < 3 days (Table 3). Persistent viral shedding was also associated with persistent dyspnea 30 days after the onset of the follow-up. Mortality was 14.7% among persistent shedders vs. 0.5% among short shedders (p < 0.0001). At the ~9–10-month follow-up in January 2021, 5/34 persistent shedders had died and seven had been seen in consultation: three patients had persistent post-COVID-19 dyspnea, including one patient who had persistent ageusia. Kinetics analysis showed that eosinophil and lymphocyte counts were significantly lower in patients with persistent viral shedding than in those with short viral shedding, whereas neutrophils were higher in persistent viral shedders. D-dimers and troponin were significantly and persistently higher in persistent viral shedders (Supplementary Table S1).\n\n3.3. Viral Genotype Analysis\n\nA total of 21 complete (n = 11) or partial (approximately the first half of the spike-encoding gene, n = 10) genome sequences were obtained for the 34 persistent shedders, comprising 14 classified in Nextstrain clade 20A, 3 in clade 20B and 4 in clade 20C [13]. This distribution into viral clades did not differ from that observed in non-persistent viral shedders during the same period (310 in clade 20A, 55 in clade 20B and 94 in clade 20C, for a total of 466 genome sequences). All spike sequences harbored the D614G substitution that was present in almost all SARS-CoV-2 genomes in Europe since the epidemic onset. No additional mutations were present within the spike.\n\n3.4. Viral Culture\n\nA total of 177 nasopharyngeal swabs were cultured in the 34 patients, of which 69 swabs collected in 20 patients were positive in culture. More precisely, eight swabs collected in six patients had a positive culture when collected >10 days after the beginning of follow-up, at days 11, 13, 14, 15, 17 and 33 (Figure 1).\n\n4. Discussion\n\nIn a large series of qRT-PCR-documented COVID-19 cases followed at the Méditerranée Infection Institute in March and April 2020, the median SARS-CoV-2 nasopharyngeal shedding was six days, shorter than that reported in the literature [14]. Moreover, less than 1% of cases (34/3737) exhibited shedding ≥17 days, and persistent positivity of qRT-PCR in nasopharyngeal swabs correlated with culture positivity. Testing procedures and discharge criteria remained the same during the study period. We observed positive cultures more than 10 days after the onset of the follow-up in eight of 34 patients, a situation rarely reported, as nasopharyngeal shedding is usually reported on the sole basis of qRT-PCR positivity [6]: one case of 4-month viral shedding was reported in the absence of culture and contagiousness [15], whereas anecdotal persistent viral shedding, with positive culture for up to 60 days, has been reported in cancer patients receiving chemotherapy [16].\n\nPrevious case reports and a small series of patients experienced prolonged shedding with SARS-CoV-2 (Table 4) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35], mostly involving immunocompromised individuals, including patients diagnosed with hematological malignancies in most cases.\n\nThis was not our situation, where only one patient had lymphoma and another had immunosuppression following kidney transplantation. In addition, several cases of viral shedding beyond 90 days occurred in patients who received treatments with convalescent plasma and/or remdesivir [17,18]. These situations were not encountered in this series, as no patient received remdesivir or convalescent plasma and the figures reported here were observed in the context of standardized care, including the prescription of hydroxychloroquine and azithromycin treatment. It is noteworthy that almost one quarter of the 34 persistent shedders reported here did not receive the combination of hydroxychloroquine and azithromycin, a prevalence significantly higher than that in short shedders. This standardized care notably differed in other series reporting a higher proportion of persistent shedders, yet populations may not have been similar, bringing into question the impact of combination of hydroxychloroquine plus azithromycin at the dosage prescribed in reducing the time of SARS-CoV-2 nasopharyngeal shedding.\n\nThis reported series mirrors the first COVID-19 epidemic in our region, which was caused by SARS-CoV-2 of clades 20A, 20B and 20C. Accordingly, based on next-generation population sequencing we did not observe any genotype pattern in any of the 21 patients whose viral genome could be explored. Further ultradeep sequencing of paired early and late nasopharyngeal swabs in the 34 patients reported here may nevertheless reveal quasi-species and minority genotypes that may have escaped the standard genotyping methods used in this report.\n\nWhether the data here reported on the genetic context of SARS-CoV-2 circulating in our region one year ago would apply to that of SARS-CoV-2 variants responsible for current epidemics [36] remains to be explored.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/v13050890/s1, Table S1: Comparison of epidemiological, clinical and biological data for 2800 short shedders (nasopharyngeal SARS-CoV-2 qRT-PCR positivity < 10 days) and 34 persistent shedders (nasopharyngeal SARS-CoV-2 qRT-PCR positivity ≥ 17 days).\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, M.D. and D.R.; methodology, M.D., S.C., B.L.S., M.M., D.R. and P.C.; formal analysis, M.D., S.C., C.M., B.L.S., P.P., J.-C.L., D.R. and P.C.; investigation, M.D., C.M., S.A., C.E., B.L.S., P.P., M.M., J.-C.L. and P.C.; writing—original draft preparation, M.D. and P.C.; writing—review and editing, M.D., D.R. and P.C.; supervision, M.D., B.L.S., J.-C.L., D.R., and P.C. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was funded by the French Government under the “Investments for the Future” program managed by the National Agency for Research (ANR), Méditerranée infection 10-IAHU-03, and was also supported by the Région Provence-Alpes-Côte d’Azur and European funding FEDER PRIMMI (Fonds Européen de Développement Régional-Plateformes de Recherche et d’Innovation Mutualisées Méditerranée Infection), FEDER PA 0000320 PRIMMI. This work received financial support from the Mediterranean Infection Foundation.\n\nInstitutional Review Board Statement\n\nData were collected retrospectively from the routine care setting. This non-interventional retrospective study was approved on 13 May 2020 by our institutional review board committee (Méditerranée Infection No.: 2020–2021).\n\nInformed Consent Statement\n\nIn compliance with European General Data Protection Regulation No. 2016/679, patients were informed of the potential use of their medical data and that they could refuse the use of their data. The analysis of collected data followed the reference methodology MR-004 registered on No. MR 5010010520 in the AP-HM register, in compliance with European General Data Protection.\n\nData Availability Statement\n\nData are available from the corresponding author upon reasonable request.\n\nConflicts of Interest\n\nThe funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Culture results on 34 patients with persistent viral shedding (>17 days). (A) Number of positive cultures for SARS-CoV-2 among the number of cultures performed. (B) SARS-CoV-2 cycle threshold values of samples with positive culture. Ct, cycle threshold value; 11 among the 69 samples had positive SARS-CoV-2 culture without Ct value.\n\nviruses-13-00890-t001_Table 1 Table 1 Summary of 34 COVID-19 patients with prolonged SARS-CoV-2 viral shedding ≥ 17 days, Marseille, France, March–April 2020.\n\nAge (years), Gender\tDuration of Viral Shedding (days)\tCause of IMMUNODEPRESSION\tSerology\tNEWS-2 Score\tCharlson (Probability of Death in the Following Year)\tTreatment\tDeath (days), COVID-19-Imputable\tViral Genotype\t\n60, M\t24\t-\t+\t5\t2 (26%)\tHCQ-AZ\t-\tN.a.\t\n41, M\t23\t-\t+\t6\t2 (26%)\tHCQ-AZ\t-\t20A\t\n21, M\t20\t-\tN.a.\t2\t0 (12%)\tHCQ-AZ\t-\t20C\t\n41, M\t20\t-\t+\t0\t1 (26%)\tHCQ-AZ\t-\t20A\t\n30, F\t18\t-\t-\t3\t0 (12%)\tHCQ-AZ\t-\tN.a.\t\n43, M\t19\t-\tN.a.\t4\t1 (26%)\tHCQ\t-\tN.a.\t\n37, M\t21\t-\t+\t0\t0 (12%)\tHCQ-AZ\t-\t20B\t\n37, F\t17\t-\t+\t2\t0 (12%)\tHCQ-AZ\t-\t20A/25563T/2416T/8371T\t\n74, M\t25\t-\tN.a.\t9\t8 (85%)\tAZ\t-\t20A\t\n63, M\t18\t-\t-\t4\t4 (52%)\tHCQ-AZ\t-\t20A\t\n61, F\t40\t-\t+\t4\t3 (52%)\tHCQ-AZ\t-\t20A\t\n81, M\t25\t-\t-\t6\t7 (85%)\tAZ\t-\tN.a.\t\n47, F\t21\t-\t+\t2\t1 (26%)\tHCQ-AZ\t-\t20B\t\n93, F\t17\t-\tN.a.\t4\t7 (85%)\tAZ\t-\tN.a.\t\n89, F\t20\t-\t+\t8\t5 (85%)\tHCQ-AZ\t22, Yes\t20A\t\n28, F\t26\t-\t+\t2\t0 (12%)\tHCQ-AZ\t-\t20A\t\n56, F\t54\t-\t+\t2\t2 (26%)\tHCQ-AZ\t-\tN.a.\t\n69, M\t31\t-\tN.a.\t5\t3 (52%)\tHCQ-AZ\t-\t20C\t\n71, M\t18\t-\t+\t7\t5 (85%)\tNo HCQ, No AZ\t-\tN.a.\t\n30, F\t21\t-\tN.a.\t5\t0 (12%)\tHCQ-AZ\t-\t20A/25563T/2416T/8371T\t\n52, F\t20\t-\t+\t4\t2 (26%)\tHCQ-AZ\t-\t20A\t\n88, F\t17\t-\t+\t7\t7 (85%)\tAZ\t-\t20A\t\n70, F\t17\t-\t+\t8\t6 (85%)\tHCQ\t289, No\t20B\t\n82, M\t18\t-\tN.a.\t4\t7 (85%)\tHCQ-AZ\t-\tN.a.\t\n43, F\t17\t-\t+\t0\t1 (26%)\tHCQ\t-\t20C\t\n69, M\t19\t-\tN.a.\t6\t3 (52%)\tHCQ-AZ\t-\t20A\t\n90, F\t25\t-\tN.a.\t6\t6 (85%)\tHCQ-AZ\t51, Yes\t20A\t\n76, M\t23\t-\t+\t11\t5 (85%)\tHCQ-AZ\t-\tN.a.\t\n89, M\t21\t-\tN.a.\t12\t7 (85%)\tHCQ-AZ\t-\t20C\t\n43, M\t19\tLymphoma\t+\t4\t3 (52%)\tHCQ-AZ\t-\tN.a.\t\n73, M\t19\t-\t+\t8\t7 (85%)\tHCQ-AZ\t20, Yes\tN.a.\t\n64, F\t22\t-\t+\t2\t3 (52%)\tHCQ-AZ\t-\tN.a.\t\n34, F\t23\t-\t-\t2\t0 (12%)\tHCQ-AZ\t-\tN.a.\t\n69, F\t25\tKidney transplantation\t-\t3\t7 (85%)\tHCQ-AZ\t-\t20A\t\nN.a., not available; HCQ-AZ stands for treatment combining hydroxychloroquine plus azithromycin ≥3 days (refer to text for posology).\n\nviruses-13-00890-t002_Table 2 Table 2 Comparison of biological data for 2800 short shedders (nasopharyngeal SARS-CoV-2 qRT-PCR positivity < 10 days) and 34 persistent shedders (nasopharyngeal SARS-CoV-2 qRT-PCR positivity ≥ 17 days).\n\n\tShort Viral Shedders\tPersistent Viral Shedders\t\nn = 2800\tn = 34\t\nBiological Data\tN\tMean (std)\tN\tMean (std)\t\nAge (years)\t2800\t44.2 (15.9)\t34\t58.4 (20.9)\t\nLymphocytes (G/L)\t2358\t1.44 (0.64)\t31\t1.05 (0.47) *\t\nNeutrophils (G/L)\t2285\t3.37 (1.8)\t27\t4.42 (2.6)\t\nNeutrophils/lymphocytes\t2285\t2.84 (3.19)\t27\t4.71 (3.44) *\t\nEosinophils (G/L)\t2347\t0.08 (0.09)\t31\t0.04 (0.06) *\t\nD dimers (µg/mL)\t457\t0.99 (2.19)\t19\t1.25 (1.01) *\t\nTroponin (ng/L)\t246\t9.99 (12.18)\t16\t18.71 (18.79) *\t\nCRP (mg/L)\t2130\t16.31 (34.6)\t31\t31 (48.09) *\t\nCRP, C-reactive protein; * denotes statistical significance using the Chi-square, Fisher’s exact or Wilcoxon–Mann–Whitney test where appropriate and a 0.05 p value. See Supplementary Table S1 for the complete list of data.\n\nviruses-13-00890-t003_Table 3 Table 3 Risk factors associated with duration of viral shedding as assessed by multivariable linear regression.\n\nAll (n = 2378 *)\tBeta 95% Confidence Interval\tp-Value\t\nTime between symptom onset and treatment onset (days)\t−0.16 (−0.20; −0.13)\t<0.0001\t\nNEWS-2 ≥ 5\t0.78 (0.16;1.41)\t0.0139\t\nSymptoms of COVID-19 at day 0 (reference = none)\t1.37 (0.83;1.91)\t<0.001\t\nChronic heart disease (reference = none)\t1.01 (0.28;1.74)\t0.0065\t\nEosinophils < 0.04 G/L (reference >0.04 G/L)\t0.83 (0.51;1.16)\t<0.001\t\nPatients aged 65 and older (n = 294)\tBeta 95% confidence interval\tp-value\t\nTime between symptom onset and treatment onset (days)\t−0.29 (−0.45; −0.14)\t0.0002\t\nOther treatment (reference= HCQ + AZ ≥ 3 days)\t2.39 (0.90; 3.87)\t0.0016\t\n* 456 patients with missing eosinophils data were excluded from the model. Risk factors were selected using backward selection with alpha = 0.05.\n\nviruses-13-00890-t004_Table 4 Table 4 Epidemiological, virological and clinical features of cases of prolonged SARS-CoV-2 infections in immunocompromised patients.\n\nReference\tGender, Age (Years)\tImmunodepression Cause\tDuration of Viral Shedding a\tRemdesivir\tConvalescent Plasma or anti-Spike Antibodies\tOther Therapies(s)\tNumber of Amino Acid Substitutions/Deletions in the Genome and/or in the Spike Protein\tOutcome\t\n[17]\tMale, 45 y.-o.\tSevere antiphospholipid syndrome\t151 days\tDays 0–4, 72–81, 105–109, 151–155\tASA: day 143\tGlucocorticoids, cyclophosphamide, intermittent eculizumab and rituximab, ruxolitinib\t24 substitutions, 3 deletions (spike: 12 substitutions, 1 deletion) among which substitution N501Y present in variants 20I/501Y.V1, 20H/501Y.V2 and 20J/501Y.V3 b, and E484K present in variants 20H/501Y.V2 and 20J/501Y.V3 b\tDeath on day 154\t\n[18]\tNot reported\tMarginal B cell lymphoma (received B cell depletion therapy; hypogamma-globulinemia)\t101 days\tDays 41-, 54-, 93-\tCP: days 63, 65, 95\t-\tSpike: 5 substitutions among which N501Y and deletion H69/V70 both present in 20I/501Y.V1 b\tNot reported\t\n[19]\tMale, 60 y.-o.\tMantle cell lymphoma\t156 days\tDays 30-, 122-\tCP: days 33, 122\tCD20 bispecific antibody, second B-cell directed antibody, cyclophosphamide, doxorubicine, prednisone\t6 substitutions\tPursued home hospice care\t\n[20]\tMale, 75 y.-o.\tMultiple myeloma\t71 days\tDays 5-9\tCP: days 2, 58\tDexamathasone (days 63–74)\tSpike: 9 substitutions between days 4 and 67, including D215G present in 20H/501Y.V2 b, Y144 deletion present in 20I/501Y.V1 c, and N501T at a position mutated in variants 20I/501Y.V1, 20H/501Y.V2 and 20J/501Y.V3 b\tDeath on day 74\t\n[21]\tMale, 60-70 y.-o.\tNon-Hodgkin lymphoma\t268 days\tDays 47-51, 77–86, 178–182, 205–209\tCP: day 88\tDarunavir/ritonavir, hydroxychlorquine, IV methylprednisolone, tocilizumbab, ceftaroline\t26 substitutions; spike: 7 including H69Y/P and V70G at positions mutated in variant 20I/501Y.V1 b\tDeath on day 271\t\n[22]\tFemale, 53 y.-o.\tFollicular lymphoma\t85 days\tDays 63–72, 80–84\tCP: day 85 c\t-\tNo genome sequencing reported\t\t\n[23]\tFemale, 17 y.-o.\tPre-B-cell acute lymphoblastic leukemia\t100 days\tDays 13–22, days 60–69\tCP: day 61\tHydroxychloroquine for two days; methylprednisolone\tNo genome sequencing reported\tqRT-PCR-positive on day 100; no supplemental oxygen\t\n[24]\tMale, 50-60 y.-o.\tChronic lymphocytic leukemia\t63 days\tDays 23–33, days 45–55\tCP: day 58\t-\tNo genome sequencing reported\t\t\n[25]\tFemale, 41 y.-o.\tSevere hypogammaglobulinemia\t75 days\tNo\tCP: days 71, 72\tPrednisone\tNo genome sequencing reported\tDischarge\t\n[25]\tMale, 65 y.-o.\tCommon variable immunodeficiency\t40 days\tNo\tNo\tLopinavir/ritonavir, broad-spectrum antibiotics\tNo genome sequencing reported\tDeath on day 40\t\n[26]\tFemale, 70-79 y.-o.\tFollicular lymphoma\t>134 days\tNo\tCP: ≈days 45, 65, 95, 110, and 115\tSteroids\t24 substitutions, 2 deletions; spike: 3 substitutions including E484K present in variants 20H/501Y.V2 and 20J/501Y.V3 b; one deletion Y144 present in variant 20I/501Y.V1 c\tDeath on day 156\t\n[26]\tNot reported\tB-cell depleted lymphoma\t91 days\tNo\tNo\tN.a.\tAt day 19 post-diagnosis: 2 substitutions\tRecovery\t\n[27]\tFemale, 71 y.-o.\tChronic lymphocytic leukemia, hypogammaglobulinemia\t105 days\tNo\tCP: days 70, 80\t-\t6 substitutions and 1 deletion on day 49; spike: 2 substitutions; 3 additional substitutions (2 at day 70, 1 at day 85) and one additional deletion on day 70 in the spike\tN.a.\t\n[28]\tFemale, 47 y.-o.\tFollicular lymphoma\t59 days\tNo\tNo\tObinutuzumab bimonthly, acyclovir, atovaquone, favipiravir, ciclesonide, lopinavir/ritonavir\tNo genome sequencing reported\tDischarge on day 69\t\n[29]\tNot reported, median (range), 58 y.-o. (35–77)\tHematological malignancies (n = 15); multiple sclerosis (1); common variable immune deficiency (1)\t17 patients (median duration = 56 days; max.= 83 days)\tN = 3\tNo\tAnti-CD20 monoclonal antibodies (n = 15); steroids (8); hydroxychloroquine (n = 5); tocilizumab (n = 4); lopinavir/ritonavir (n = 2)\tNo genome sequencing reported\tOne death\t\n[30]\tMale, 66 y.-o.\tHIV infection (CD4 cell count= 0/mm3)\t123 days\tNo\tNo\tMulti-antiretroviral therapy\t1 substitution, in the spike\tNeurological degradation\t\n[30]\tMale, 71 y.-o.\tHeart transplantation, diabetes mellitus\t121 days\tNo\tNo\tPrednisone, mycophenolic acid, belatacept\tNo occurrence of substitutions\tN.a.\t\n[30]\tMale, 35 y.-o.\tRheumatoid arthritis\t84 days\tNo\tNo\tRituximab\tOccurrence of 6 substitutions, 1 the spike\tImprovement\t\n[31]\tFemale, 5 y.-o.\tDermatomyositis\t35 days\tNo\tNo\tPrednisolone\tNo genome sequencing reported\tResolution\t\n[32]\tFemale, 60 y.-o.\tRheumatoid arthritis\t>35 days\tDay ≈30\tCP: Week 5\tRituximab\tNo genome sequencing reported\tDischarge\t\n[33]\tFemale, 17 y.-o.\tPreviously healthy\t97 days\tNo\tNo\tHydroxychloroquine for 5 days\tCoinfection with two SARS-CoV-2 lineages (20A, 20B)\tN.a.\t\n[34]\tMale, 61 y.-o.\tLiver transplant\tNegative on days 35 and 39, then positive again on days 41 and 48\tNo\tNo\tTacrolimus, lopinavir/ritonavir, amoxicillin, piperacillin sulbactam, Lianhua Qingwen\tNo genome sequencing reported\tDischarge on day 55\t\n[35]\tMale, 31 y.-o.\tX-linked agamma- globulinaemia\t62 days (in sputum; 36 days in nasopharyngeal samples)\tDays 34–43, 61–70\tCP: days 69, 70\tHydroxychloroquine/ azithromycine, meropenem, ceftriaxone, clarithromycin\t5 substitutions; spike: 1 substitution\tDischarge on day 73\t\na As assessed by qRT-PCR; b 20I/501Y.V1 = “UK” variant, 20H/501Y.V2 = “South African” variant and 20J/501Y.V3 = “Brazilian” variant; c at the end of second cure of remdesivir. ASA: anti-spike antibodies; CP: convalescent plasma; PML: progressive multifocal leukoencephalopathy.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. Zhao X. Huang B. Shi W. Lu R. A Novel Coronavirus from Patients with Pneumonia in China, 2019 N. Engl. J. Med. 2020 382 727 733 10.1056/NEJMoa2001017 31978945\n2. Lagier J.-C. Million M. Gautret P. Colson P. Cortaredona S. Giraud-Gatineau A. Honoré S. Gaubert J.-Y. Fournier P.-E. Tissot-Dupont H. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis Travel Med. Infect. Dis. 2020 36 101791 10.1016/j.tmaid.2020.101791 32593867\n3. La Scola B. Le Bideau M. Andreani J. Hoang V.T. Grimaldier C. Colson P. Gautret P. Raoult D. 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Doudier B. Courjon J. Giordanengo V. Vieira V.E. Dupont H.T. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial Int. J. Antimicrob. Agents 2020 56 105949 10.1016/j.ijantimicag.2020.105949 32205204\n10. Million M. Lagier J.-C. Gautret P. Colson P. Fournier P.-E. Amrane S. Hocquart M. Mailhe M. Esteves-Vieira V. Doudier B. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France Travel Med. Infect. Dis. 2020 35 101738 10.1016/j.tmaid.2020.101738 32387409\n11. Levasseur A. Delerce J. Caputo A. Brechard L. Colson P. Lagier J.-C. Fournier P.-E. Raoult D. Genomic diversity and evolution of coronavirus (SARS-CoV-2) in France from 309 COVID-19-infected patients bioRxiv 2020 39 1059 1061\n12. Zheng Z. Peng F. Xu B. Zhao J. Liu H. Peng J. Li Q. Jiang C. Zhou Y. Liu S. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis J. Infect. 2020 81 e16 e25 10.1016/j.jinf.2020.04.021 32335169\n13. Colson P. Levasseur A. Gautret P. Fenollar F. Hoang V.T. Delerce J. Bitam I. Saile R. Maaloum M. Padane A. Introduction into the Marseille geographical area of a mild SARS-CoV-2 variant originating from sub-Saharan Africa: An investigational study Travel Med. Infect. Dis. 2021 40 101980 10.1016/j.tmaid.2021.101980 33535105\n14. Widders A. Broom A. Broom J. SARS-CoV-2: The viral shedding vs infectivity dilemma Infect. Dis. Health 2020 25 210 215 10.1016/j.idh.2020.05.002 32473952\n15. Chen X. Zhu B. Hong W. Zeng J. He X. Chen J. Zheng H. Qiu S. Deng Y. Chan J.C. Associations of clinical characteristics and treatment regimens with the duration of viral RNA shedding in patients with COVID-19 Int. J. Infect. Dis. 2020 98 252 260 10.1016/j.ijid.2020.06.091 32619760\n16. Aydillo T. Gonzalez-Reiche A.S. Aslam S. van de Guchte A. Khan Z. Obla A. Dutta J. van Bakel H. Aberg J. García-Sastre A. Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer N. Engl. J. Med. 2020 383 2586 2588 10.1056/NEJMc2031670 33259154\n17. Choi B. Choudhary M.C. Regan J. Sparks J.A. Padera R.F. Qiu X. Solomon I.H. Kuo H.H. Boucau J. Bowman K. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host N. Engl. J. Med. 2020 383 2291 2293 10.1056/NEJMc2031364 33176080\n18. Kemp S.A. Collier D.A. Datir R. Ferreira I.A. Gayed S. Jahun A. Hosmillo M. Rees-Spear C. Mlcochova P. Lumb I.U. Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation medRxiv 2020 10.1101/2020.12.05.20241927v3.full\n19. Baang J.H. Smith C. Mirabelli C. Valesano A.L. Manthei D.M. Bachman M.A. Wobus C.E. Adams M. Washer L. Martin E.T. Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient J. Infect. Dis. 2021 223 23 27 10.1093/infdis/jiaa666 33089317\n20. Hensley M.K. Bain W.G. Jacobs J. Nambulli S. Parikh U. Cillo A. Staines B. Heaps A. Sobolewski M.D. Rennick L.J. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study Clin. Infect. Dis. 2021 10.1093/cid/ciab072 33507235\n21. Sepulcri C. Dentone C. Mikulska M. Bruzzone B. Lai A. Fenoglio D. Bozzano F. Bergna A. Parodi A. Altosole T. The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient—A case study MedRxiv 2021 10.1101/2021.01.23.21249554\n22. Malsy J. Veletzky L. Heide J. Hennigs A. Gil-Ibanez I. Stein A. Lütgehetmann M. Rosien U. Jasper D. Peine S. Sustained Response After Remdesivir and Convalescent Plasma Therapy in a B-Cell–Depleted Patient With Protracted Coronavirus Disease 2019 (COVID-19) Clin. Infect. Dis. 2020 10.1093/cid/ciaa1637 33103195\n23. Devine M.N. Maxwell S. Haynes A.S. MacBrayne C.E. Boguniewicz J. Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19 J. Pediatr. Hematol. 2020 10.1097/MPH.0000000000002014\n24. Helleberg M. Niemann C.U. Moestrup K.S. Kirk O. Lebech A.-M. Lane C. Lundgren J. Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of Remdesivir Therapy J. Infect. Dis. 2020 222 1103 1107 10.1093/infdis/jiaa446 32702095\n25. London J. Boutboul D. Lacombe K. Pirenne F. Heym B. Zeller V. Baudet A. Ouedrani A. Bérezné A. Severe COVID-19 in Patients with B Cell Alymphocytosis and Response to Convalescent Plasma Therapy J. Clin. Immunol. 2021 41 356 361 10.1007/s10875-020-00904-5 33219491\n26. Khatamzas E. Rehn A. Muenchhoff M. Hellmuth J. Gaitzsch E. Weiglein T. Georgi E. Scherer C. Stecher S. Weigert O. Emergence of multiple SARS-CoV-2 mutations in an immunocompromised host medRxiv 2021 10.1101/2021.01.10.20248871\n27. Avanzato V.A. Matson M.J. Seifert S.N. Pryce R. Williamson B.N. Anzick S.L. Barbian K. Judson S.D. Fischer E.R. Martens C. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer Cell 2020 183 1901 1912 10.1016/j.cell.2020.10.049 33248470\n28. Nakajima Y. Ogai A. Furukawa K. Arai R. Anan R. Nakano Y. Kurihara Y. Shimizu H. Misaki T. Okabe N. Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient J. Infect. Chemother. 2021 27 387 389 10.1016/j.jiac.2020.12.001 33328135\n29. Hueso T. Pouderoux C. Péré H. Beaumont A.L. Raillon L.A. Ader F. Chatenoud L. Eshagh D. Szwebel T.A. Martinot M. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19 Blood 2020 136 2290 2295 10.1182/blood.2020008423 32959052\n30. Tarhini H. Recoing A. Bridier-Nahmias A. Rahi M. Lambert C. Martres P. Lucet J.-C. Rioux C. Bouzid D. Lebourgeois S. Long-Term Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectiousness Among Three Immunocompromised Patients: From Prolonged Viral Shedding to SARS-CoV-2 Superinfection J. Infect. Dis. 2021 10.1093/infdis/jiab075\n31. Canarutto D. Del Barba P. Di Frenna M. Del Tedesco F. Pajno R. Guarneri M.P. Barera G. Prolonged asymptomatic SARS-CoV-2 infection in a child receiving immunosuppressive therapy Pediatr. Pulmonol. 2020 55 2504 2505 10.1002/ppul.24983 32735761\n32. Tzarnas S. Kramer M. Alberti N. Chan V. Alam Khan M.A. Madara J. 181: Convalescent Plasma Therapy in a Refractory Case of COVID-19 in an Immunocompromised Patient Crit. Care Med. 2021 49 76 10.1097/01.ccm.0000726612.71471.eb\n33. Pedro N. Silva C. Magalhães A. Cavadas B. Rocha A. Moreira A. Gomes M. Silva D. Sobrinho-Simões J. Ramos A. Dynamics of a Dual SARS-CoV-2 Lineage Co-Infection on a Prolonged Viral Shedding COVID-19 Case: Insights into Clinical Severity and Disease Duration Microorganisms 2021 9 300 10.3390/microorganisms9020300 33540596\n34. Wei L. Liu B. Zhao Y. Chen Z. Prolonged shedding of SARS-CoV-2 in an elderly liver transplant patient infected by COVID-19: A case report Ann. Palliat. Med. 2020 9 8 10.21037/apm-20-996 32005058\n35. Buckland M.S. Galloway J.B. Nic Fhogartaigh C. Meredith L. Provine N.M. Bloor S. Ogbe A. Zelek W.M. Smielewska A. Yakovleva A. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: A case report Nat. Commun. 2020 11 1 11 10.1038/s41467-020-19761-2 31911652\n36. Fournier P.E. Colson P. Levasseur A. Gautret P. Luciani L. Bedotto M. Delerce J. Brechard L. Lagier J.C. Chaudet H. Genome sequence analysis enabled deciphering the atypical evolution of COVID-19 in Marseille, France MedRxiv 2021 10.35088/kmct-tj43\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1999-4915",
"issue": "13(5)",
"journal": "Viruses",
"keywords": "COVID-19; SARS-CoV-2; azithromycin; culture; hydroxychloroquine; qRT-PCR; viral persistence",
"medline_ta": "Viruses",
"mesh_terms": "D000328:Adult; D000368:Aged; D017963:Azithromycin; D000086382:COVID-19; D015897:Comorbidity; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D006760:Hospitalization; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D009305:Nasopharynx; D000086402:SARS-CoV-2; D017201:Virus Shedding",
"nlm_unique_id": "101509722",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34065871",
"pubdate": "2021-05-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32205269;33103195;32735761;33556961;33235142;32959052;33219491;32387409;33540596;32619760;33318491;32986798;33535105;32342252;33089317;32473952;33176080;32205204;33259154;32702095;33507235;31978945;33077007;32335169;33183020;32593867;33248470;33328135;32660623;33521734",
"title": "SARS-CoV-2 Persistent Viral Shedding in the Context of Hydroxychloroquine-Azithromycin Treatment.",
"title_normalized": "sars cov 2 persistent viral shedding in the context of hydroxychloroquine azithromycin treatment"
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"abstract": "Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis characterized by cutaneous manifestations in the form of palpable purpura, and rarely bullae, vesicles, and ulcerations. Although rare, cephalosporins such as cefazolin, should be recognized to have a potential to trigger LCV.",
"affiliations": "Department of Internal Medicine Abington Memorial Hospital/Abington Jefferson Health 1200 Old York Road Abington 19001 PA.;Department of Internal Medicine Abington Memorial Hospital/Abington Jefferson Health 1200 Old York Road Abington 19001 PA.;Department of Pathology Abington Memorial Hospital/Abington Jefferson Health 1200 Old York Road Abington 19001 PA.",
"authors": "Ali|Naveed|N|0000-0002-5545-390X;Karia|Nidhi|N|;Goldhahn|Richard|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.992",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.992CCR3992Clinical ImageClinical ImagesCefazolin as a cause of leukocytoclastic vasculitis N. Ali et al.Ali Naveed http://orcid.org/0000-0002-5545-390Xnaveed86_medicine@hotmail.comnaveed.ali@jefferson.edu \n1\nKaria Nidhi \n1\nGoldhahn Richard \n2\n1 Department of Internal MedicineAbington Memorial Hospital/Abington Jefferson Health1200 Old York RoadAbington19001PA2 Department of PathologyAbington Memorial Hospital/Abington Jefferson Health1200 Old York RoadAbington19001PA* Correspondence\n\nNaveed Ali, Department of Internal Medicine, Abington Memorial Hospital/ Abington Jefferson Health, 1200 Old York Road, Abington, 19001 PA. Tel.: 215‐481‐ 4105, Fax: 215‐481‐4361 E‐mails: naveed86_medicine@hotmail.com and naveed.ali@jefferson.edu\n12 5 2017 6 2017 5 6 10.1002/ccr3.2017.5.issue-61051 1053 05 6 2016 29 8 2016 27 9 2016 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nLeukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis characterized by cutaneous manifestations in the form of palpable purpura, and rarely bullae, vesicles, and ulcerations. Although rare, cephalosporins such as cefazolin, should be recognized to have a potential to trigger LCV.\n\nCefazolincolchicinecorticosteroidsleukocytoclastic vasculitis source-schema-version-number2.0component-idccr3992cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:05.06.2017\n==== Body\nCase Presentation\nQuestion 1: What is the diagnosis when a patient develops a rash as shown in Figure 1A and B?\n\nFigure 1 (A) shows palpable purpurae (thin arrows) and an unruptured bullous (thick arrow) on the anterior aspect of the right leg; (B) shows a ruptured bullous (thick arrow) and vesicles (thin arrow) on the anterior aspect of the left leg; (C) shows extravasated red blood cells (star) that give rise to palpable purpura; (D) shows vesicular and spongiotic epidermis (thick arrow), extravasated red blood cells (star) and melanin pigment deposition related to patient's race (thin arrow); (E) shows polymorphonuclear infiltration (thick arrow) around the vessel (star) and areas of nuclear fragmentation or leukocytoclasia (thin arrow); (F) shows polymorphonuclear infiltration (thick arrow) around the vessel (stars) along with eosinophils (thin arrows).\n\nAnswer 1: A 67‐year‐old male with a history of hypertension, diabetes mellitus, atrial fibrillation, and right total knee arthroplasty presented with a progressive rash in the lower extremities. Two weeks earlier, he had right knee debridement for septic arthritis caused by methicillin‐sensitive Staphylococcus aureus for which cefazolin was initiated for 6 weeks. Upon presentation, his vital signs were within normal limits. Examination demonstrated clusters of palpable, purplish purpurae with associated intact and ruptured blisters scattered over anterior, medial, and lateral aspects of the legs bilaterally below the knees. Laboratory investigations revealed urea of 17 mg/dL, creatinine of 0.89 mg/dL, ESR of 117 mm/h, CRP of 88.14 mg/L, WBC count of 10.6 k/μL without peripheral eosinophilia, hemoglobin of 8.1 g/dL, and platelet count of 312 k/μL. Urinalysis was significant for 2+ proteinuria and microhematuria. Investigations for hepatitis B, hepatitis C, ANA, ANCA, and cryoglobulins were negative. Biopsy of the rash showed perivascular papillary dermal infiltration of polymorphonuclear leukocytes and eosinophils with prominent foci of leukocytoclasis and extravasated RBCs along with a spongiotic intraepidermal and subepidermal bullous change. Based on the clinical presentation, characteristic rash and biopsy results, he was diagnosed with leukocytoclastic vasculitis (LCV) secondary to cefazolin with cutaneous and renal involvement.\n\nCorticosteroids were deferred in light of an ongoing infection and normal renal functions in this patient. Cefazolin was switched to vancomycin and colchicine was commenced with resultant improvement in the rash. When encountered with drug‐induced leukocytoclastic vasculitis, a thorough review of medications should be made to identify the implicated drug and should be discontinued promptly. In the absence of overt organ damage, discontinuation of the offending drug is usually sufficient and immunosuppressive therapy may not be necessary as demonstrated by this case.\n\nMost cases of leukocytoclastic vasculitis are idiopathic; however, drugs, bacterial, or viral infections, sepsis, connective tissue diseases, and underlying malignancies are associated in the rest 1. Histopathologically, the hallmark of diagnosis is perivascular polymorphonuclear infiltration, leukocytoclasia (degranulation and nuclear fragmentation, also known as karyorrhexis) of the neutrophils, and fibrinoid necrosis 2.\n\nConsent\nWritten informed consent was obtained from the patient\n\nConflict of Interest\nNone declared.\n\nAuthorship\nNA: prepared the entire manuscript. NK, RG: contributed to manuscript preparation.\n==== Refs\nReferences\n1 \n\nMartinez‐Taboada , V. M. \n, \nR. \nBlanco \n, \nM. \nGarcia‐Fuentes \n, and \nV. \nRodriguez‐Valverde \n. 1997 \nClinical features and outcome of 95 patients with hypersensitivity vasculitis . Am. J. Med. \n102 :186 –191 .9217569 \n2 \n\nJennette , J. C. \n, and \nR. J. \nFalk \n. 1997 \nSmall‐vessel vasculitis . N. Engl. J. Med. \n337 :1512 –1523 .9366584\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(6)",
"journal": "Clinical case reports",
"keywords": "Cefazolin; colchicine; corticosteroids; leukocytoclastic vasculitis",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1051-1053",
"pmc": null,
"pmid": "28588872",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "9217569;9366584",
"title": "Cefazolin as a cause of leukocytoclastic vasculitis.",
"title_normalized": "cefazolin as a cause of leukocytoclastic vasculitis"
} | [
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"companynumb": "PHHY2017US112362",
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"occurcountry": "US",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "An 80-year-old female with a history of hypertension and atrial fibrillation had been receiving warfarin anticoagulant therapy and had stably maintained an international normalized ratio (INR) within the 2.0-3.0 range. Due to dental extractions, she was prescribed aspirin (100 mg/day) as an alternative therapy to warfarin. Three days later, the patient complained of hemoptysis without obvious inducement and the INR was 3.51. The aspirin was immediately discontinued and intravenous vitamin K was administered. Hemoptysis did not reappear and the INR returned to the normal limits. According to the Drug Interaction Probability Scale, a causal relationship between aspirin and warfarin and an increased INR value is possible.",
"affiliations": "Respiratory Department, the First Affiliated Hospital with Nanjing Medical University, China.",
"authors": "Song|Wei|W|;Cao|Jia|J|;Xu|Yazhou|Y|;Han|Zhonglin|Z|;Wen|Hao|H|;Cui|Xuefan|X|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4695",
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"issn_linking": "0918-2918",
"issue": "54(20)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D001241:Aspirin; D001281:Atrial Fibrillation; D004347:Drug Interactions; D005260:Female; D006469:Hemoptysis; D006801:Humans; D019934:International Normalized Ratio; D014081:Tooth Extraction; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "9204241",
"other_id": null,
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"pmid": "26466698",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hemoptysis due to aspirin treatment alternative to warfarin therapy in a patient with atrial fibrillation.",
"title_normalized": "hemoptysis due to aspirin treatment alternative to warfarin therapy in a patient with atrial fibrillation"
} | [
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"companynumb": "CN-IPCA LABORATORIES LIMITED-IPC201511-000793",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"activesubstance": {
"activesubstancename": "WARFARIN"
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"abstract": "Clozapine is a potent antipsychotic commonly used for refractory schizophrenia. Adverse effects are well recognised including constipation, intestinal obstruction, agranulocytosis and cardiomyopathy. We present a case of paradoxical refractory hypotension following epinephrine administration in a patient taking clozapine. A psychiatric inpatient who had been taking clozapine for many years developed paralytic ileus and obstruction requiring surgical intervention. Following initiation of epinephrine administration intraoperatively he developed refractory hypotension which improved only when epinephrine was weaned off. This effect is likely due to uninterrupted β2-agonist activity in the presence of clozapine-induced α-blockade. Clinicians need to have greater awareness of this serious interaction and avoid the use of epinephrine in patients taking clozapine.",
"affiliations": "Department of Intensive Care and Anaesthesia, Western General Hospital, NHS Lothian, Edinburgh, UK.;Department of Intensive Care and Anaesthesia, Western General Hospital, NHS Lothian, Edinburgh, UK.;Department of Adult Psychiatry, Royal Edinburgh Hospital, NHS Lothian, Edinburgh, UK.;Department of Acute Medicine, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK euan.sandilands@nhslothian.scot.nhs.uk.",
"authors": "Alagappan|Anand|A|http://orcid.org/0000-0002-0676-0006;Baruah|Rosaleen|R|;Cockburn|Alastair|A|;Sandilands|Euan A|EA|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine; D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243363",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(11)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; anaesthesia; pharmacology and therapeutics; schizophrenia",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D014150:Antipsychotic Agents; D003024:Clozapine; D004837:Epinephrine; D006801:Humans; D007022:Hypotension; D008297:Male; D012559:Schizophrenia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34725057",
"pubdate": "2021-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxical refractory hypotension following adrenaline administration in a patient taking clozapine.",
"title_normalized": "paradoxical refractory hypotension following adrenaline administration in a patient taking clozapine"
} | [
{
"companynumb": "GB-TASMAN PHARMA, INC.-2022TSM00019",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
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{
"abstract": "We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/refractory myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01166113.",
"affiliations": "Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy;",
"authors": "Larocca|Alessandra|A|;Montefusco|Vittorio|V|;Bringhen|Sara|S|;Rossi|Davide|D|;Crippa|Claudia|C|;Mina|Roberto|R|;Galli|Monica|M|;Marcatti|Magda|M|;La Verde|Giacinto|G|;Giuliani|Nicola|N|;Magarotto|Valeria|V|;Guglielmelli|Tommasina|T|;Rota-Scalabrini|Delia|D|;Omedé|Paola|P|;Santagostino|Alberto|A|;Baldi|Ileana|I|;Carella|Angelo Michele|AM|;Boccadoro|Mario|M|;Corradini|Paolo|P|;Palumbo|Antonio|A|",
"chemical_list": "D013792:Thalidomide; D003520:Cyclophosphamide; C467566:pomalidomide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2013-03-488676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "122(16)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma; D011241:Prednisone; D012008:Recurrence; D013792:Thalidomide; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2799-806",
"pmc": null,
"pmid": "23954889",
"pubdate": "2013-10-17",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study.",
"title_normalized": "pomalidomide cyclophosphamide and prednisone for relapsed refractory multiple myeloma a multicenter phase 1 2 open label study"
} | [
{
"companynumb": "IT-CELGENE-083-C4047-13083235",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
... |
{
"abstract": "L. pneumophila is an unusual cause of pneumonia with a prevalence of 2.7%, and it is even more uncommon in pregnancy. To date, only 11 cases of Legionnaire's Disease in pregnancy have been reported, though this small number could possibly be attributed to underdiagnoses and under documentation. Case Presentation: In this paper, we present a 31-year-old Hispanic female, gravida 4, para 1 from the southwest United States who presented with a 3-week history of fever, worsening cough, dyspnea on exertion, and hypoxemia. Chest x-ray showed bibasilar infiltrates, with positive serology for Legionella IgM and IgG (1:250 and 1:640 respectively), as well as positive urinary antigen. Despite appropriate treatment with azithromycin 500 mg, she continued to have dyspnea and mild respiratory distress. Conclusion: Upon follow up, mother and fetus initially remained stable without any signs of sequelae from Legionnaire's disease, but the patient miscarried 5 weeks after the second admission to the hospital. The chest x-ray eventually cleared up after almost 21 days of azithromycin.",
"affiliations": "Burrell College of Osteopathic Medicine, Department of Medicine, Section of Infectious Diseases, Las Cruces, NM, United States.;Burrell College of Osteopathic Medicine, Department of Medicine, Section of Infectious Diseases, Las Cruces, NM, United States.",
"authors": "Kleinberg|Katherine A|KA|;Antony|Suresh J|SJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017963:Azithromycin",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1871526519666190119110657",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1871-5265",
"issue": "20(2)",
"journal": "Infectious disorders drug targets",
"keywords": "Legionella pneumophila; Legionnaire's Disease; antigen; azithromycin; pneumonia; pregnancy.",
"medline_ta": "Infect Disord Drug Targets",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D017963:Azithromycin; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016952:Legionella pneumophila; D007877:Legionnaires' Disease; D018410:Pneumonia, Bacterial; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D015995:Prevalence; D011859:Radiography",
"nlm_unique_id": "101269158",
"other_id": null,
"pages": "247-252",
"pmc": null,
"pmid": "30659551",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Legionella pneumophila Pneumonia in Pregnancy: A Case Report and Review of the Literature.",
"title_normalized": "legionella pneumophila pneumonia in pregnancy a case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2020324761",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dr... |
{
"abstract": "BACKGROUND\nThough a single nonmedical switch from the originator infliximab (IFX) to a biosimilar is considered effective and safe for most patients with inflammatory bowel disease (IBD), very limited data are available on multiple successive switches.\n\n\nMETHODS\nWe performed a prospective multicenter cohort study of adult IBD patients who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3). Patients were assessed at 4 and 12 months since the most recent switch for remission using clinical (physician's assessment) and biochemical (C-reactive protein [CRP], and fecal calprotectin [FC]) measures. Patients discontinuing treatment for ineffectiveness or adverse events before month 12 were imputed as nonremitters.\n\n\nRESULTS\nOne hundred seventy-six patients (Crohn's disease 71%, ulcerative colitis 27.8%, IBD unclassified 1.2%; group 1, 69; group 2, 80; group 3, 27) were included. At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively. There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups. Infusion reactions occurred in 1.7% of patients (3/176), all in patients with antidrug antibodies from group 2.\n\n\nCONCLUSIONS\nMultiple successive switching and switching between biosimilars of IFX seemed to be effective and safe.",
"affiliations": "Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Martini Ziekenhuis, Groningen, the Netherlands.;Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands.",
"authors": "Hanzel|Jurij|J|0000-0003-3158-8014;Jansen|Jeroen M|JM|;Ter Steege|Rinze W F|RWF|;Gecse|Krisztina B|KB|;D'Haens|Geert R|GR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ibd/izab099",
"fulltext": "\n==== Front\nInflamm Bowel Dis\nInflamm Bowel Dis\nibd\nInflammatory Bowel Diseases\n1078-0998\n1536-4844\nOxford University Press US\n\n34013959\n10.1093/ibd/izab099\nizab099\nLeading Off\nAcademicSubjects/MED00260\nMultiple Switches From the Originator Infliximab to Biosimilars Is Effective and Safe in Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study\nhttps://orcid.org/0000-0003-3158-8014\nHanzel Jurij MD 12\nJansen Jeroen M MD 3\nter Steege Rinze W F MD, PhD 4\nGecse Krisztina B MD, PhD 1\nD’Haens Geert R MD, PhD 1\n1 Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands\n2 Medical Faculty, University of Ljubljana, Department of Gastroenterology, UMC Ljubljana, Ljubljana, Slovenia\n3 Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands\n4 Department of Gastroenterology and Hepatology, Martini Ziekenhuis, Groningen, the Netherlands\nAddress correspondence to: Jurij Hanžel, Medical Faculty, University of Ljubljana, University Medical Centre Ljubljana, Ljubljana, Slovenia. E-mail: jurij.hanzel@gmail.com.\n4 2022\n20 5 2021\n20 5 2021\n28 4 495501\n21 1 2021\n01 4 2021\n© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nThough a single nonmedical switch from the originator infliximab (IFX) to a biosimilar is considered effective and safe for most patients with inflammatory bowel disease (IBD), very limited data are available on multiple successive switches.\n\nMethods\n\nWe performed a prospective multicenter cohort study of adult IBD patients who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3). Patients were assessed at 4 and 12 months since the most recent switch for remission using clinical (physician’s assessment) and biochemical (C-reactive protein [CRP], and fecal calprotectin [FC]) measures. Patients discontinuing treatment for ineffectiveness or adverse events before month 12 were imputed as nonremitters.\n\nResults\n\nOne hundred seventy-six patients (Crohn’s disease 71%, ulcerative colitis 27.8%, IBD unclassified 1.2%; group 1, 69; group 2, 80; group 3, 27) were included. At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively. There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups. Infusion reactions occurred in 1.7% of patients (3/176), all in patients with antidrug antibodies from group 2.\n\nConclusions\n\nMultiple successive switching and switching between biosimilars of IFX seemed to be effective and safe.\n\nSB2\nCT-P13\nmultiple switches\n==== Body\npmcIntroduction\n\nIn recent years, biosimilar tumor necrosis factor (TNF) antagonists have become available, and their use in treating inflammatory bowel diseases (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) is increasingly common.1 The first infliximab (IFX) biosimilar to receive approval was CT-P13 based on data from rheumatoid arthritis2 and ankylosing spondylitis,3 followed by extrapolation to other indications of originator IFX. The second IFX biosimilar, SB2, received authorization based on a pharmacokinetic study in healthy volunteers4 and a study in rheumatoid arthritis.5\n\nThe introduction of biosimilars in clinical practice has raised a number of concerns, namely the extrapolation from other indications to IBD and the potential for subtle differences in attributes and tertiary and quaternary structure to result in increased immunogenicity.6 Randomized trials7, 8 and prospective cohort studies9–11 have not found convincing evidence for any of these reservations with single switches from originator to biosimilar. This is reflected in the position statement of the European Crohn’s and Colitis Organization, which describes switching from an originator to a biosimilar as acceptable.12 Biosimilars are cost-effective and may expand patient access to biologics.1 The increasing number of available IFX biosimilars and changes in reimbursement policies inevitably lead to switching between biosimilars or multiple successive switches from originator to different biosimilars. Outcomes for these 2 groups of patients were only reported for small cohorts of no more than 43 patients.13, 14 It is unlikely that an adequately powered randomized controlled trial on multiple switches will ever be performed due to high cost and marginal commercial benefit.\n\nThe aim of our study was to evaluate the effectiveness and safety of multiple successive switching from originator to a second IFX biosimilar compared with a single switch from originator to CT-P13 and a single switch between CT-P13 and SB2 in IBD patients.\n\nMaterials and Methods\n\nPatients\n\nThis was a multicenter prospective cohort study. In the 2 participating nonacademic hospitals (Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands and Martini Ziekenhuis, Groningen, the Netherlands), adult IBD patients underwent a switch from originator IFX to CT-P13 from August 2015 onward as part of routine care. This was followed by a routine switch for economic reasons from CT-P13 to SB2 from July 2018 onward. The dose and interval remained unchanged after the switch unless clinical need dictated otherwise—trough concentrations <3 mg/L in the absence of antidrug antibodies prompted dosing adjustment. The switching procedures yielded 3 groups: patients who successively switched from originator IFX to CT-P13 and finally to SB2, patients who switched from originator IFX to CT-P13, and patients who switched from CT-P13 to SB2. Patients starting treatment with a different form of IFX more than 4 months after the last exposure to the previous form (eg, upon disease flare after treatment discontinuation for stable remission) were excluded from the study.\n\nStudy Design and Outcomes\n\nThe most recent switch was regarded as the index switch for this study (ie, the switch from CT-P13 to SB2 in patients undergoing multiple successive switching). Patient demographics, disease phenotype, and concomitant IBD medication were recorded at index switch. Patients were followed according to protocolized switch pathways with C-reactive protein (CRP) and fecal calprotectin (FC) measurements before the index switch and at 4 and 12 months after the index switch. Measurements of IFX serum concentrations and antibodies to IFX were performed at the discretion of the treating physician, using a drug-sensitive assay (Sanquin, Amsterdam, the Netherlands).15 Clinical disease activity was assessed at baseline, at 4 months, and at 12 months per the physician’s global assessment. Infusion-related adverse events were prospectively recorded in infusion unit protocols. Information about IBD-related hospitalizations and other adverse events was also recorded prospectively.\n\nThe primary efficacy outcome was clinical remission per physician’s assessment without concomitant steroid therapy 12 months since the index switch. Secondary efficacy end points included CRP remission defined as CRP < 5 mg/L, FC remission defined as FC < 250 mg/kg, and time to treatment discontinuation for reasons other than long-term sustained remission. The primary safety end point was the occurrence of infusion reactions, with IBD-related hospitalization and other adverse events as secondary end points. Treatment discontinuation and switchbacks were recorded together with the reason for discontinuation. Patients with missing biochemical measurements at a given time point, and patients discontinuing treatment for long-term sustained remission were censored. Patients discontinuing treatment due to adverse events, nonresponse, or the presence of antidrug antibodies before completing 12 months of follow-up were imputed as nonremitters at subsequent time points.\n\nStatistical Analysis\n\nContinuous variables were presented as medians with interquartile ranges (IQRs) and categorical values as frequency and percentages. The Kruskal-Wallis test was used to compare medians in the 3 treatment groups, and the χ 2 test or Fisher exact test were used for categorical variables. Binary logistic regression was used to identify associations between baseline characteristics and clinical remission at 12 months after the index switch patients who discontinued treatment before that time point for adverse events or inefficacy were imputed as nonremitters. Kaplan-Meier estimates were used to plot treatment persistence for the 3 groups, which was compared using log-rank tests. Cox proportional hazard models were used to evaluate the association between baseline characteristics and time to treatment discontinuation for inefficacy or adverse events. Patients discontinuing treatment for sustained remission were censored in survival analyses, as this was indicative of treatment efficacy. Variables with P < 0.1 in univariable analysis were subjected to multivariable regression. Median serum concentrations of IFX between time baseline and 12 months were compared using the Wilcoxon signed-rank test. Statistical analyses were performed using SPSS, version 26.0 (Armonk, NY, USA), and a 2-tailed P value < 0.05 was considered statistically significant.\n\nEthical Considerations\n\nAll patients provided consent for the switches and the collection of routine clinical and biochemical data; the study was approved by the local ethical committees at both hospitals.\n\nResults\n\nPatients\n\nA total of 193 patients underwent switching, 16 were excluded because they had started a biosimilar after a drug holiday, and 1 was younger than 18 years, which yielded a final cohort of 176 patients (Table 1). Patients undergoing multiple successive switching had a longer disease duration and longer duration of exposure to IFX before the index switch. For the majority of patients (156 of 176; 88.6%), IFX was the first biological drug. At the time of the index switch, patients switching from CT-P13 to SB2 had a lower rate of clinical remission than patients from the other 2 groups.\n\nTable 1. Patient Characteristics at Index Switch (Most Recent Switch for Patients Undergoing Multiple Successive Switches)\n\nVariable\tOriginator to CT-P13 to SB2 (n = 69)\tCT-P13 to SB2 (n = 80)\tOriginator to CT-P13 (n = 27)\tP\t\nFemale, n (%)\t37 (53.6)\t43 (53.8)\t13 (48.1)\t0.87\t\nAge (years), median (IQR)\t44 (32–56)\t39.5 (30–55)\t34 (29–56)\t0.22\t\nDisease type, n (%)\t\t\t\t0.60\t\n CD\t49 (71)\t54 (67.5)\t22 (81.5)\t\t\n UC\t19 (28)\t25 (31.3)\t5 (18.5)\t\t\n IBD-U\t1 (1.4)\t1 (1.3)\t\t\t\nDisease duration (years), median (IQR)\t13 (8–23)\t5 (2–9)\t8 (6–17)\t<0.001\t\nDisease extent, n (%)\t\t\t\t\t\n CD\t\t\t\t<0.001\t\n Ileal\t12 (24)\t26 (48)\t5 (23)\t\t\n Colonic\t18 (37)\t10 (19)\t6 (27)\t\t\n Ileocolonic\t19 (39)\t18 (33)\t11 (50)\t\t\n Upper GI\t3 (6)\t1 (2)\t1 (5)\t\t\n Perianal\t19 (39)\t18 (33)\t7 (32)\t0.827\t\n UC\t\t\t\t0.224\t\n Proctitis\t0\t\t1 (20)\t\t\n Left-sided\t9 (47)\t10 (40)\t1 (20)\t\t\n Extensive\t10 (53)\t15 (60)\t3 (60)\t\t\nCD behavior, n (%)\t\t\t\t0.51\t\n Inflammatory\t34 (68)\t36 (67)\t16 (72)\t\t\n Stricturing\t12 (24)\t10 (19)\t5 (23)\t\t\n Penetrating\t3 (6)\t8 (14)\t1 (5)\t\t\nHistory of extraintestinal manifestations, n (%)\t10 (14)\t8 (10)\t7 (26)\t0.12\t\nPrevious IBD-related surgery, n (%)\t18 (26)\t14 (18)\t6 (22)\t0.436\t\nCombination therapy with immunosuppressant at most recent switch, n (%)\t25 (36)\t45 (56)\t6 (22)\t0.003\t\nSystemic steroids at most recent switch, n (%)\t0\t1 (1.3)\t0\tNA\t\nPrevious exposure to biologics other than IFX, n (%)\t7 (10)\t10 (13)\t3 (11)\t0.99\t\nDuration of IFX exposure before index switch (years), median (IQR)\t6.8 (4.1–10.2)\t1.9 (0.9–2.6)\t3.2 (1.3–6.1)\t<0.001\t\nSerum infliximab concentration at index switch (mg/L), median (IQR)\t4.2 (1.9–6.5)\t5.0 (1.7–7.1)\t3.4 (1.8–6.5)\t0.911\t\nClinical remission at index switch, n (%)\t58 (84)\t55 (69)\t25 (93)\t0.026\t\nCRP at index switch (mg/L), median (IQR)\t1.7 (0.6–5.4)\t2.6 (0.7–6.1)\t0.9 (0.6–3.2)\t0.038\t\nFC at index switch (mg/kg), median (IQR)\t35 (15–150)\t108 (41–381)\t41 (10–198)\t0.008\t\n\nThe total follow-up time for patients successively switching from the originator to CT-P13 to SB2 was 54.6 patient-years (PYs), 66.7 PYs for patients switching from CT-P13 to SB2, and 21.8 PYs for patients switching from the originator to CT-P13.\n\nEffectiveness\n\nAt 12 months after the index switch, 76.9% (40 of 52) of patients successively switching from the originator to CT-P13 and then to SB2, 65.7% (46 of 70) of patients switching from CT-P13 to SB2, and 76.9% (20 of 26) of patients switching from the originator to CT-P13 were in clinical remission. There were no significant differences in the rate of clinical, CRP, or FC remission at 12 months, although rates were numerically lower in patients switching from CT-P13 to SB2 (Fig. 1). There were no significant differences in need for dosing escalation between the 3 groups (2.9% [2 of 69] vs 3.8% [3 of 80] vs 3.7% [1 of 27]; P = 0.956). On univariable logistic regression, only clinical remission at the index switch was associated with clinical remission at 12 months (Table 2). In a sensitivity analysis with a patient group forced into a multivariable model together with clinical remission at index switch, the switching group was not significantly associated with clinical remission at 12 months (originator to CT-P13 as reference; odds ratio [OR] for CT-P13 to SB2, 0.861; 95% confidence interval [CI], 0.298–2.764; OR for originator to CT-P13 to SB2, 0.880; 95% CI, 0.288–2.690). In a further sensitivity analysis including only patients in clinical remission at the most recent switch, the switching group was not associated with clinical remission at 12 months (originator to CT-P13 as reference; OR for CT-P13 to SB2, 1.281; 95% CI, 0.371–4.422; OR for originator to CT-P13 to SB2, 0.788; 95% CI, 0.247–2.519).\n\nTable 2. Variables Associated with Clinical Remission at 12 Months After Index Switch\n\nVariable\tUnivariable logistic regression\t\t\t\n\tOdds’ ratio\t95% CI\tP\t\nDisease duration\t1.005\t0.938–1.078\t0.881\t\nDuration of IFX exposure before index switch\t1.044\t0.957–1.140\t0.330\t\nClinical remission at index switch\t7.846\t3.47–17.8\t<0.001\t\nImmunomodulator at index switch\t1.376\t0.705–2.681\t0.350\t\nUC versus CD\t1.481\t0.692–3.170\t0.312\t\nPatient group\t\t\t\t\n Originator to CT-P13\t1\t\t\t\n Originator to CT-P13 to SB2\t0.730\t0.253–2.104\t0.560\t\n CT-P13 to SB2\t0.516\t0.185–1.441\t0.207\t\n\nFigure 1. Rates of clinical remission (A), C-reactive protein (CRP) < 5 mg/L (B), and fecal calprotectin <250 mg/kg (C) across the treatment groups at switch, 4, and 12 months following the most recent switch. Patients discontinuing treatment for inefficacy, appearance of antidrug antibodies, or adverse events were imputed as nonremitters at subsequent time points. Patients with missing biochemical measurements were censored.\n\nSafety\n\nInfusion reactions occurred in 3.8% (3 of 80) of patients switching from CT-P13 to SB2, and 6.3% (5 of 80) of patients from this group had an IBD-related hospitalization; all hospitalizations were associated with disease flares. All 3 patients with infusion reactions had antidrug antibodies; IFX was discontinued in these patients. No infusion reactions or IBD-related hospitalizations were recorded in the other 2 groups. Other adverse events included worsening of eczema in 1 patient with previous exposure to the originator upon switching from CT-P13 to SB2, worsening headache in 3 patients switching from originator to CT-P13, and musculoskeletal pain in 1 patient from the same group. All these patients were switched back to the previously effective formulation of IFX, which led to the resolution of side effects with maintained efficacy. In 1 patient exposed to the originator and successively switching to CTP13 and SB2, malignant melanoma was diagnosed during treatment, which was subsequently interrupted.\n\nTreatment Persistence\n\nAt 12 months, the estimated treatment persistence was 85.0% for patients successively switching from originator to CT-P13 to SB2, 87.0% for patients switching from CT-P13 to SB2, and 70.1% for patients switching from the originator to CT-P13 (log rank P = 0.153; Fig. 2). On univariable Cox regression, clinical remission at the most recent switch and patient group (originator to CT-P13 to SB2 and CT-P13 to SB2) were associated with a reduced hazard of treatment discontinuation for inefficacy or adverse events (Table 3). The same variables were significant on multivariable Cox regression. In the group of patients successively switching from the originator to CT-P13 to SB2, 8.7% (6 of 69) discontinued treatment for active disease, 8.7% (6 of 69) for long-term sustained remission, and 2.9% (2 of 69) for adverse events. In the group of patients switching from CT-P13 to SB2, 8.8% (7 of 80) discontinued treatment for active disease, 3.8% (3 of 80) for adverse events, and 1.3% (1 of 80) for long-term sustained remission. Among patients switching from the originator to CT-P13, 14.8% (4 of 27) discontinued treatment for active disease, 22.2% (6 of 27) for long-term sustained remission, and 14.8% (4 of 27) for adverse events.\n\nFigure 2. Kaplan-Meier curves for treatment persistence in the 3 treatment groups. Patients discontinuing treatment for long-term sustained remission were censored at discontinuation.\n\nTable 3. Variables Associated With Treatment Discontinuation for Inefficacy or Adverse Event\n\nVariable\tUnivariable Cox Regression\t\t\tMultivariable Cox Regression\t\t\t\n\tHazard Ratio\t95% CI\tP\tHazard Ratio\t95% CI\tP\t\nDisease duration\t1.01\t0.97–1.05\t0.638\t\t\t\t\nDuration of prior IFX exposure\t0.99\t0.90–1.09\t0.884\t\t\t\t\nClinical remission at index switch\t0.33\t0.15–0.75\t0.008\t0.51\t0.33–0.78\t0.002\t\nImmunomodulator at index switch\t0.61\t0.26–1.42\t0.250\t\t\t\t\nUC versus CD\t1.27\t0.78–2.09\t0.339\t\t\t\t\nPatient group\t\t\t\t\t\t\t\n Originator to CT-P13\t1\t\t\t1\t\t\t\n Originator to CT-P13 to SB2\t0.39\t0.14–1.11\t0.077\t0.33\t0.11–0.94\t0.038\t\n CT-P13 to SB2\t0.42\t0.16–1.12\t0.083\t0.27\t0.10–0.78\t0.015\t\n\nImmunogenicity and Pharmacokinetics\n\nAt the moment of the index switch, antidrug antibodies were detected in 5.8% (4 of 69) of patients successively switching from the originator to CT-P13 and SB2, in 8.8% (7 of 80) of patients switching from CT-P13 to SB2, and in no patients switching from originator IFX to CT-P13. De novo antidrug antibodies were not detected in any of the patients successively switching from originator IFX to CT-P13 and SB2, in 3.8% (3 of 80) of patients switching from CT-P13 and SB2, and in 3.7% (1 of 27) of patients switching from originator IFX to CT-P13. Infliximab was discontinued in these 4 patients.\n\nIn the group of patients successively switching from the originator to CT-P13 to SB2, median IFX serum concentrations increased nonsignificantly from 4.2 mg/L (IQR, 1.9–6.5) to 5.0 mg/L (IQR, 2.1–6.3) at 4 months and 5.3 mg/L (IQR, 3.6–7.6) at 12 months (P = 0.429). In patients switching from CT-P13 to SB2, median IFX serum concentrations decreased nonsignificantly from 5.0 mg/L (IQR, 1.7–7.1) to 3.8 mg/L (IQR, 2.2–6.5) at 4 months and 3.3 mg/L (IQR, 1.9–5.8) at 12 months (P = 0.084). In patients switching from the originator to CT-P13, median IFX serum concentrations first increased nonsignificantly from 3.4 mg/L (IQR, 1.8–6.5) to 4.0 mg/L (IQR, 0.7–7.3) at 4 months and then decreased to 2 mg/L (IQR, 1.6–4.7) at 12 months (P = 0.593).\n\nDiscussion\n\nThis is the largest study evaluating the efficacy and safety of multiple successive switches between IFX originator and biosimilars in a real-world cohort of patients with IBD to date. We observed similar rates of clinical and biochemical remission at 12 months in patients undergoing multiple successive switches, a single switch between biosimilars, or a single switch from the originator to CT-P13. No unexpected adverse events or de novo immunogenicity were observed in patients after multiple successive switches.\n\nVirtually all studies on biosimilars in IBD have focused on a single switch between originator IFX and CT-P13. Available randomized controlled trials were not ideally designed to address this question from a daily clinical practice viewpoint for IBD patients. The NOR-SWITCH study demonstrated noninferiority of switching to CT-P13 compared with ongoing maintenance treatment with originator IFX as measured by the end point of disease worsening but was not powered to show this for each individual indication.7 The difference in disease worsening for CD was only just within the prespecified noninferiority margin of 15%. A subsequent randomized controlled trial in CD showed noninferiority of CT-P13 to originator IFX for induction and maintenance until week 30 but was not powered to assess noninferiority beyond week 30 when a quarter of patients switched from the originator to CT-P13—although clinical outcomes were numerically similar.8 Randomized controlled trials with multiple switching have only been conducted in psoriasis.16 These observations underscore the difficulty and limited interest in performing randomized controlled trials on this subject, which nonetheless remains highly relevant to clinical practice.\n\nIn the absence of data from randomized controlled trials, clinicians have relied on real-world cohort studies to support single switches from the originator to CT-P13. Recognizing the limitations of uncontrolled studies mostly reporting clinical well-being, a single nonmedical switch from originator IFX to CT-P13 seems to be safe and effective in most patients.17 Shifting reimbursement policies and the availability of several IFX biosimilars have resulted in a situation where practice precedes the accumulation of evidence: multiple successive switches from the originator to different biosimilars and switches between biosimilars. The efficacy of multiple successive switches was evaluated in a prospective study of 24 patients with 16.2 PYs of follow-up, where the treatment persistence was 82.4% at 48 weeks.14 In an additional study published in abstract form, the treatment persistence in 58 patients at week 48 was 86%, and 92% of patients were in clinical remission.18 These observations are broadly in line with our findings; the lower rate of clinical remission in our cohort may be a result of nonresponder imputation, which was not explicitly mentioned in the study cited previously. Our findings are further corroborated by objective biochemical markers of disease activity, which also support the efficacy of multiple successive switches.\n\nSwitching from CT-P13 to SB2 was assessed in a study with 43 patients with 28 PYs of follow-up,14 and an additional study of 133 patients followed for 16 weeks.19 Treatment persistence at 48 weeks was 75.3%14 and 86.5% at 16 weeks, which is somewhat lower than the treatment persistence of 87.0% at 52 weeks in our study. Our study was not powered or designed to compare differences in the rates of remission between different types of single switches and multiple successive switches, nor were any adjustments made for baseline differences between the 3 study groups. Nonetheless, neither remission rates nor treatment persistence at 12 months differed significantly between the 3 switching groups in our study. Although direct comparisons in treatment persistence with other real-world studies examining the efficacy of switching from the originator to CT-P13 are confounded by differences in baseline characteristics, treatment persistence at 12 months for multiple successive switches and switches between biosimilars is within the range observed for a single switch from the originator (57%–85%).9,11,20–22 Importantly, our study re-emphasizes the strong association between remission at the time of switching and subsequent maintenance of remission. Despite differences between groups in the duration of exposure to IFX at the time of the most recent switch, this factor was not associated with subsequent outcomes, suggesting that switching may also be considered in patients in remission who started IFX more recently.\n\nThe incidence of infusion reactions in our study was 4.5 per 100 PYs (3.8% of patients) in the group of patients switching from CT-P13 to SB2, as none were recorded in the other 2 groups. The pooled rate for the entire study was 2.1 per 100 PYs (1.7% of patients). The observed rate of infusion reactions is within the range reported in real-world studies on switching from the originator to CT-P13.10, 11, 20, 22–24 The adverse events profile was consistent with previous reports, no serious infections were recorded. Switchbacks to the previous formulation of IFX resulted both in maintaining effectiveness and the disappearance of side effects. The emergence of side effects after switching and their resolution after reverting to the formulation of IFX used previously may have been a result of the nocebo effect,25 although at least a subset of emerging adverse effects, such as hemolytic anemia,26 may also reflect incompletely understood immune-mediated mechanisms.\n\nThe potential of increased immunogenicity is one of the key concerns about multiple successive switches. Results of studies evaluating the development of antidrug antibodies should be interpreted with attention for and knowledge of the characteristics of the assay used for their detection. Studies on patients undergoing multiple successive switches, including ours, used drug-sensitive assays, which may have resulted in the underestimation of antibody development. In a French study of patients with immune-mediated inflammatory diseases including IBD, the rate of antidrug antibody formation with multiple successive switches regardless of diagnosis was 3 per 100 PYs compared with a single switch, and multiple switches were not found to be a risk factor for immunogenicity.13 No antidrug antibodies developed de novo in patients with multiple successive switches in our study; the rate was 2.5 per 100 PYs in patients switching from CT-P13 to SB2. These estimates should only be regarded as the lower limit of immunogenicity because antidrug antibodies were not sought consistently and systematically in all our patients. An in vitro study using sera of patients who had developed antibodies to IFX after treatment with originator IFX, CT-P13, or both demonstrated full cross-reactivity with SB2.27 This observation, however, cannot be taken as evidence of interchangeability or equal rates of immunogenicity between biosimilars; it merely confirms that the negative consequences of antidrug antibodies cannot be overcome by switching to a different biosimilar. No statistically significant differences in serum IFX concentrations were observed in any of the switching groups in our study. This is in line with previous work that showed the noninferiority of switching from the originator to CT-P13 for the stability of serum concentrations.28\n\nOur study is the first and largest to primarily focus on IBD patients undergoing multiple successive switches from the originator to biosimilars with clinical and biochemical end points at 12 months, together with the first report on pharmacokinetics in this particular patient group to date. Nonetheless, our findings should be interpreted within the context of the limitations of our study. It was an observational study based on routine clinical care, which may have resulted in the underreporting of adverse events that were perceived as less serious by the patient or the treating physician. Inevitably, the characteristics of patients within each group were affected by the timing of switches, with patients undergoing multiple successive switches having a longer disease duration than patients who switched from CT-P13 to SB2. Patients undergoing a single switch from the originator to CT-P13 either discontinued treatment or were lost to follow-up beyond 12 months, as they would otherwise have undergone multiple successive switches due to mandatory switching after July 2018.\n\nConflicts of Interest: JH has received speaker’s fees from Biogen, Janssen, Pfizer, and Takeda. JMJ has served on advisory boards, or as speaker or consultant for Abbvie, Amgen, Ferring, Fresenius, Janssen, MSD, Pfizer, and Takeda. RWFS has nothing to declare. KBG has received consultancy fees and/or speaker’s honoraria fromfrom AbbVie, Boehringer Ingelheim, Celltrion, Ferring, Gilead, Immunic Therapeutics, Janssen, Pfizer, Sandoz, Samsung Bioepis, Takeda, and Tillotts. GRD has served as advisor for Abbvie, Ablynx, Alimentiv, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dohme, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor.\n\nConclusion\n\nOur findings suggest that multiple successive switches from originator IFX to biosimilars are effective and safe, particularly if patients are in remission at the time of the switch. The treatment persistence, remission rates, and adverse event profile were consistent with reports from studies of a single switch from the originator to CT-P13.\n\nAbbreviations\n\nCD Crohn’s disease\n\nCI confidence interval\n\nCRP C-reactive protein\n\nFC fecal calprotectin\n\nIBD inflammatory bowel disease\n\nIFX infliximab\n\nIQR interquartile range\n\nPY patient-year\n\nUC ulcerative colitis\n==== Refs\nReferences\n\n1. Kim H , AltenR, AvedanoL, et al. The future of biosimilars: maximizing benefits across immune-mediated inflammatory diseases. Drugs. 2020;80 :99–113.32002851\n2. Yoo DH , HrycajP, MirandaP, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72 :1613–1620.23687260\n3. Park W , HrycajP, JekaS, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72 :1605–1612.23687259\n4. Shin D , KimY, KimYS, et al. A Randomized, Phase I pharmacokinetic study comparing SB2 and infliximab reference product (Remicade(®)) in healthy subjects. Biodrugs. 2015;29 :381–388.26577771\n5. Choe JY , ProdanovicN, NiebrzydowskiJ, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2017;76 :58–64.26318384\n6. Reinisch W , GecseK, HalfvarsonJ, et al. Clinical practice of adalimumab and infliximab biosimilar treatment in adult patients with Crohn’s disease. Inflamm Bowel Dis. 2021;27 :106–122.32634212\n7. Jørgensen KK , OlsenIC, GollGL, et al. ; NOR-SWITCH study group. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389 :2304–2316.28502609\n8. Ye BD , PesegovaM, AlexeevaO, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: an international, randomised, double-blind, phase 3 noninferiority study. Lancet. 2019;393 :1699–1707.30929895\n9. Bergqvist V , KadivarM, MolinD, et al. Switching from originator infliximab to the biosimilar CT-P13 in 313 patients with inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11 :1756284818801244.\n10. Bronswijk M , MoensA, LenfantM, et al. Evaluating efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar CT-P13: experience from a large tertiary referral center. Inflamm Bowel Dis. 2020;26 :628–634.31400283\n11. Chaparro M , GarreA, Guerra VelozMF, et al. Effectiveness and safety of the switch from Remicade(R) to CT-P13 in patients with inflammatory Bowel disease. J Crohn’s Colitis. 2019;13 :1380–1386.30976785\n12. Danese S , FiorinoG, RaineT, et al. ECCO position statement on the use of biosimilars for inflammatory Bowel disease-an update. J Crohns Colitis. 2017;11 :26–34.27927718\n13. Lauret A , MoltóA, AbitbolV, et al. Effects of successive switches to different biosimilars infliximab on immunogenicity in chronic inflammatory diseases in daily clinical practice. Semin Arthritis Rheum. 2020;50 :1449–1456.32268935\n14. Macaluso FS , FriesW, ViolaA, et al. The SPOSIB SB2 sicilian cohort: safety and effectiveness of infliximab biosimilar SB2 in inflammatory bowel diseases, including multiple switches. Inflamm Bowel Dis. 2021;27 :182–189.32083291\n15. Wolbink GJ , VisM, LemsW, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54 :711–715.16508927\n16. Griffiths CEM , ThaçiD, GerdesS, et al. ; EGALITY study group. The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol. 2017;176 :928–938.27787890\n17. Bernard EJ , FedorakRN, JairathV. Systematic review: nonmedical switching of infliximab to CT-P13 in inflammatory Bowel disease. Dig Dis Sci. 2020;65 :2354–2372.31970610\n18. Mazza S , FasciA, CasiniV, et al. Safety and clinical efficacy of double switch from originator infliximab to biosimilars CT-P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): a multicentre study. J Crohn’s Colitis. 2020;14 :S342tre.\n19. Harris C , HarrisR, YoungD, et al. IBD biosimilar to biosimilar infliximab switching study: preliminary results. United European Gastroenterol J. 2019;7 :P0419.\n20. Schmitz EMH , BoekemaPJ, StraathofJWA, et al. Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: a 12-month multicentre observational prospective cohort study. Aliment Pharmacol Ther. 2018;47 :356–363.29205444\n21. Razanskaite V , BetteyM, DowneyL, et al. Biosimilar infliximab in inflammatory Bowel disease: outcomes of a managed switching programme. J Crohns Colitis. 2017;11 :690–696.28130330\n22. Plevris N , JonesGR, JenkinsonPW, et al. Implementation of CT-P13 via a managed switch programme in Crohn’s disease: 12-month real-world outcomes. Dig Dis Sci. 2019;64 :1660–1667.30535885\n23. Smits LJ , DerikxLA, de JongDJ, et al. Clinical outcomes following a switch from Remicade(R) to the Biosimilar CT-P13 in inflammatory Bowel disease patients: a prospective observational cohort study. J Crohn’s Colitis. 2016;10 :1287–1293.27095751\n24. Fiorino G , ManettiN, ArmuzziA, et al. ; PROSIT-BIO Cohort. The PROSIT-BIO cohort: a prospective observational study of patients with inflammatory Bowel disease treated with infliximab biosimilar. Inflamm Bowel Dis. 2017;23 :233–243.28092307\n25. Pouillon L , DaneseS, HartA, et al. Consensus report: clinical recommendations for the prevention and management of the nocebo effect in biosimilar-treated IBD patients. Aliment Pharmacol Ther. 2019;49 :1181–1187.30932219\n26. Strik AS , D’HaensGR, LöwenbergM. Hemolytic anemia after switching from infliximab originator to biosimilar CT-P13 in a patient with inflammatory bowel disease: A case report. Clin Case Rep. 2019;7 :2049–2053.31788249\n27. Fiorino G , Ruiz-ArgüelloMB, MagureguiA, et al. Full interchangeability in regard to immunogenicity between the infliximab reference biologic and biosimilars CT-P13 and SB2 in inflammatory Bowel disease. Inflamm Bowel Dis. 2018;24 :601–606.29462398\n28. Strik AS , van de VrieW, Bloemsaat-MinekusJPJ, et al. ; SECURE study group. Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): an open-label, multicentre, phase 4 noninferiority trial. Lancet Gastroenterol Hepatol. 2018;3 :404–412.29606564\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1078-0998",
"issue": null,
"journal": "Inflammatory bowel diseases",
"keywords": "CT-P13; SB2; multiple switches",
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": null,
"nlm_unique_id": "9508162",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34013959",
"pubdate": "2021-05-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Multiple Switches From the Originator Infliximab to Biosimilars Is Effective and Safe in Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study.",
"title_normalized": "multiple switches from the originator infliximab to biosimilars is effective and safe in inflammatory bowel disease a prospective multicenter cohort study"
} | [
{
"companynumb": "NL-CELLTRION INC.-2021NL019317",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe association of concomitant immunosuppressant use with infliximab (IFX) and therapeutic outcomes in correlation with pharmacokinetic properties in ulcerative colitis (UC) remains unclear.\n\n\nOBJECTIVE\nTo assess the effect of concomitant immunosuppressant use on the duration of IFX therapy, and the pharmacokinetic properties of IFX in patients with UC.\n\n\nMETHODS\nA retrospective analysis of UC patients treated with IFX. Duration of efficacious IFX therapy, and serum IFX and antibody-to-IFX (ATI) levels were compared between those receiving IFX as monotherapy and in combination with an immunosuppressant.\n\n\nRESULTS\nAmong the 85 UC patients who received IFX, 46 (54.1%) received concomitant immunosuppressants, and 38 (45.9%) received IFX monotherapy. Concomitant immunosuppressant use was associated with increased duration of IFX therapy as 90% of patients receiving immunosuppressants remained on therapy at 1 year versus 61% of patients on monotherapy (Log-rank, P = 0.016). Concomitant immunosuppressant use, as compared with monotherapy, was associated with greater IFX levels (20.4 mg/L vs 10.5 mg/L, P = 0.025) and less frequent ATI formation (4.5% vs 33.3%, P = 0.031). Patients receiving greater than 2.0 mg/kg of azathioprine had greater IFX lev l than those receiving less than 2.0 mg/kg (26.0 vs 10.6 mcg/mL, P = 0.03) and those receiving IFX monotherapy (26.0 vs 11.2 mcg/mL, P = 0.03). The duration of IFX therapy among patients receiving less than 2.0 mg/kg azathioprine was indistinguishable from patients on IFX monotherapy (Log-rank, P = 0.95).\n\n\nCONCLUSIONS\nConcomitant immunosuppressant therapy with IFX improves outcomes in UC as shown by increased duration of therapy, decreased immunogenicity against IFX, and increased blood levels of IFX. Our data suggest that this benefit may be dependent on the dose of concomitant immunosuppression.",
"affiliations": null,
"authors": "Hayes|Michael J|MJ|;Stein|Adam C|AC|;Sakuraba|Atsushi|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.12517",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "29(6)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": null,
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003093:Colitis, Ulcerative; D004359:Drug Therapy, Combination; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1177-85",
"pmc": null,
"pmid": "24955449",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparison of efficacy, pharmacokinetics, and immunogenicity between infliximab mono- versus combination therapy in ulcerative colitis.",
"title_normalized": "comparison of efficacy pharmacokinetics and immunogenicity between infliximab mono versus combination therapy in ulcerative colitis"
} | [
{
"companynumb": "US-JNJFOC-20140604735",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "With the growing class of CFTR modulator therapy available to more patients and with increasing pregnancies in individuals with CF, there is a growing need to understand the effects of these agents during pregnancy. There are few reports of their continued use in the literature, although it is likely that this is not an uncommon occurrence. We report the uncomplicated and successful pregnancy of a woman treated with lumacaftor/ivacaftor, as well as the clinical course of the infant during the first 9 months of life. We also report drug levels in plasma from the mother, cord blood, breast milk, and infant to estimate fetal and infant drug exposure.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, The University of North Carolina at Chapel Hill, 4 th Floor Bioinformatics, CB 7020, Chapel Hill, NC, 27516, United States. Electronic address: atrimble@med.unc.edu.;Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, 301 Pharmacy Lane, CB 7355, Chapel Hill, NC 27599, United States.;Division of Pediatric Pulmonology, The University of North Carolina at Chapel Hill, 450 MacNider CB 7217, Chapel Hill, NC 27599, United States.;Department of Obstetrics & Gynecology, The University of North Carolina at Chapel Hill, 3009 Old Clinic Building, CB 7570, Chapel Hill, NC 27599, United States.;Division of Pediatric Pulmonology, The University of North Carolina at Chapel Hill, 450 MacNider CB 7217, Chapel Hill, NC 27599, United States.",
"authors": "Trimble|Aaron|A|;McKinzie|Cameron|C|;Terrell|Mary|M|;Stringer|Elizabeth|E|;Esther|Charles R|CR|",
"chemical_list": "D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D065101:Chloride Channel Agonists; D004338:Drug Combinations; D015363:Quinolones; C000599212:lumacaftor, ivacaftor drug combination; D019005:Cystic Fibrosis Transmembrane Conductance Regulator",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcf.2018.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-1993",
"issue": "17(6)",
"journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society",
"keywords": "CFTR modulators; Ivacaftor; Lumacaftor; Pregnancy",
"medline_ta": "J Cyst Fibros",
"mesh_terms": "D000328:Adult; D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D001942:Breast Feeding; D065101:Chloride Channel Agonists; D003550:Cystic Fibrosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004338:Drug Combinations; D016903:Drug Monitoring; D005260:Female; D005312:Fetal Blood; D006801:Humans; D007231:Infant, Newborn; D008111:Liver Function Tests; D008895:Milk, Human; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D015363:Quinolones; D016896:Treatment Outcome",
"nlm_unique_id": "101128966",
"other_id": null,
"pages": "779-782",
"pmc": null,
"pmid": "29866531",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25981758;25311995;29099344;29233472;22047557;26698017;27875677;25101886;28190780;10696089;28930490",
"title": "Measured fetal and neonatal exposure to Lumacaftor and Ivacaftor during pregnancy and while breastfeeding.",
"title_normalized": "measured fetal and neonatal exposure to lumacaftor and ivacaftor during pregnancy and while breastfeeding"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0105890",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,... |
{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a rare clinical-radiological entity characterised by seizures, severe headache, mental status instability and visual disturbances. Hypertension is typically present. We report a case of a 13-year old boy with Burkitt lymphoma/leukaemia, who presented with posterior leukoencephalopathy 24 hours after intrathecal methotrexate (MTX) infusion. The child presented with headache, seizures, elevated blood pressure and gradual deterioration of his neurological status. Midazolam, dexamethazone and furosemide were initiated leading to reduction of cerebral oedema and clinical improvement. A thorough literature review is discussed in this report. Pathophysiology of leukoencephalopathy remains unclear. It develops within 5-14 days after intrathecal MTX and resolves within a week usually without permanent neurological sequelae. Broad use of MRI has led to an increasing number of identified cases of PRES. Treatment approach is mainly to manage the underlying cause of PRES. Prognosis is generally benign; however delayed diagnosis and improper management may result in permanent brain insult.",
"affiliations": "The second Paediatric Department, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece.;The second Paediatric Department, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece.;Radiology Department, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.;The second Paediatric Department, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece.;The second Paediatric Department, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece.;Paediatric Neurology Department, Chelsea and Westminster Hospital NHS, London, UK.;The second Paediatric Department, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece.",
"authors": "Pavlidou|Efterpi|E|;Pavlou|Evangelos|E|;Anastasiou|Athanasia|A|;Pana|Zoi|Z|;Tsotoulidou|Vasiliki|V|;Kinali|Maria|M|;Hatzipantelis|Emmanuel|E|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/qims.2016.10.07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2223-4306",
"issue": "6(5)",
"journal": "Quantitative imaging in medicine and surgery",
"keywords": "Posterior reversible encephalopathy; children; leukaemia; lymphoma; methotrexate (MTX)",
"medline_ta": "Quant Imaging Med Surg",
"mesh_terms": null,
"nlm_unique_id": "101577942",
"other_id": null,
"pages": "605-611",
"pmc": null,
"pmid": "27942481",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "10954269;19956935;24292045;14586746;7776773;17170721;19386731;21572160;24167801;22954513;10715035;19880556;15705136;20572911;22307182;23965484;24190154;19517377;24780237;11516610;17441477;25006290;18079186;24949044;18268188;24126039;8559202;18504683;25013187;18055853;25120830;17947226;24065581;16317748;23127265;18661498;22971098;23175479;17698535",
"title": "Posterior reversible encephalopathy syndrome after intrathecal methotrexate infusion: a case report and literature update.",
"title_normalized": "posterior reversible encephalopathy syndrome after intrathecal methotrexate infusion a case report and literature update"
} | [
{
"companynumb": "GR-ACCORD-046397",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"... |
{
"abstract": "We present a case series of four previously healthy, employed adults without significant prior medical history in each of whom symptoms developed while on fluoroquinolones (FQs), with progression that continued following discontinuation evolving to a severe, disabling multisymptom profile variably involving tendinopathy, muscle weakness, peripheral neuropathy, autonomic dysfunction, sleep disorder, cognitive dysfunction and psychiatric disturbance. Physicians and patients should be alert to the potential for FQ-induced severe disabling multisymptom pathology that may persist and progress following FQ use. Known induction by FQs of delayed mitochondrial toxicity provides a compatible mechanism, with symptom profiles (and documented mechanisms of FQ toxicity) compatible with the hypothesis of an exposure-induced mitochondrial neurogastrointestinal encephalomyopathy.",
"affiliations": "Department of Medicine, University of California, San Diego, La Jolla, California, USA.;Department of Medicine, University of California, San Diego, La Jolla, California, USA.;Department of Anthropology, University of Kansas, Lawrence, Kansas, USA.",
"authors": "Golomb|Beatrice Alexandra|BA|;Koslik|Hayley Jean|HJ|;Redd|Alan J|AJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D004823:Epididymitis; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D008875:Middle Aged; D017237:Mitochondrial Encephalomyopathies; D010254:Paranasal Sinus Diseases; D010612:Pharyngitis; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26438672",
"pubdate": "2015-10-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23605987;12587511;12196055;15251620;20725547;9531191;21658328;7860672;11409663;15619227;22452935;14576967;7996468;11793615;22098607;17334015;21333952;11322015;2222106;2056957;8652078;12534327;3311275;9674866;2646053;19161929;16269178;23734036;17213006;15478945;15251629;9816984;7706350;22535840;8913349;15745724;10388331;18175142;19281725;10832955;25488035;19197127;15486915;17268904;7802511;19235604;17270116;8350109;1552063;9916602;19591530;12641485;20731847;2260307;12766835;15827068;3281368;15589446;17523709;2235669;19276313;21569745;10225576;16951028;10970974;10193688;18236349;10090432;22035890;8722551;15002793;22474205;12398567;16580096;20034766;18648734;11258173;17068466;19387967;20655887;24878949;17904461;10917380;3279499;17163235;14982977;14569066;20210367;16574493;10877041;12399240;17645801;2376981;16477578;19545207;1592498;15198194;14557312;7856152;15851230;19159124",
"title": "Fluoroquinolone-induced serious, persistent, multisymptom adverse effects.",
"title_normalized": "fluoroquinolone induced serious persistent multisymptom adverse effects"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201506563",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe tolerance and efficacy of oxaliplatin desensitization in patients who were intolerant of carboplatin desensitization were determined.\n\n\nMETHODS\nWe retrospectively reviewed the Gynecologic Oncology patients who received carboplatin or oxaliplatin from December 2007 until August 2014. The number of treatments and number of patients of carboplatin standard infusions, carboplatin desensitizations, and oxaliplatin desensitizations were determined.\n\n\nRESULTS\nCarboplatin infusions (2294) were administered to 281 patients. Twenty-eight (10%) of these patients developed carboplatin hypersensitivity and were treated with 205 carboplatin desensitizations. Nine (29%) patients were subsequently treated with 61 oxaliplatin desensitizations due to intolerance of carboplatin desensitization. Nine of the 10 patients tolerated this infusion well. Four of 9 evaluable patients had an objective response, 2 complete and 2 partial.\n\n\nCONCLUSIONS\nOxaliplatin desensitization seems well tolerated and effective in most patients who are intolerant of carboplatin desensitization.",
"affiliations": "*Division of Gynecologic Oncology, Cleveland Clinic; Departments of †Oncology Nursing, and ‡Oncology Pharmacy, Hillcrest Hospital, Cleveland Clinic of Healthcare System, Cleveland, OH.",
"authors": "Rose|Peter G|PG|;Metz|Carol|C|;Link|Nicolas|N|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000000295",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "24(9)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D016190:Carboplatin; D018284:Cystadenocarcinoma, Serous; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D016889:Endometrial Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D010051:Ovarian Neoplasms; D000077150:Oxaliplatin; D011379:Prognosis",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1603-6",
"pmc": null,
"pmid": "25304679",
"pubdate": "2014-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Desensitization with oxaliplatin in patients intolerant of carboplatin desensitization.",
"title_normalized": "desensitization with oxaliplatin in patients intolerant of carboplatin desensitization"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01906",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe management of lymphoma diagnosed during pregnancy is controversial and has been guided largely by findings from case reports and small series.\n\n\nOBJECTIVE\nTo determine maternal and fetal outcomes of women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy.\n\n\nMETHODS\nThis retrospective analysis studied a cohort of 39 pregnant women diagnosed with HL and NHL (31 HL and 8 NHL) at a single specialized cancer institution between January 1991 and December 2014.\n\n\nMETHODS\nWe examined data on disease and treatment characteristics, as well as maternal and fetal complications and outcomes. The Kaplan-Meier method was used to compare progression free survival (PFS) and overall survival (OS) according to receipt of antenatal therapy and other clinical factors. Univariate and multivariate analyses were performed by using Cox proportional hazard regression models to identify potential associations between clinical and treatment factors and survival.\n\n\nRESULTS\nThe median (range) age of the 39 women in the patient cohort was 28 (19-38) years; 32 women (82%) had stage I or II disease at diagnosis, and 13 had bulky disease. Three women electively terminated the pregnancy to allow immediate systemic therapy; of the remaining 36 women, 24 received antenatal therapy (doxorubicin based combination chemotherapy in 20 of 24 patients), and 12 deferred therapy until after delivery. Four women experienced miscarriage, all of whom had received antenatal systemic therapy and 2 during the first trimester. Delivery occurred at a median (range) of 37 (32-42) weeks and was no different based on receipt of antenatal (median [range], 37 [33-42] weeks) vs postnatal (median [range], 37 [32-42] weeks) therapy (P = .21). No gross fetal malformations or anomalies were detected. At a median (range) follow-up time of 67.9 (8.8-277.5) months since the diagnosis of lymphoma, 5-year rates of PFS and OS were 74.7% and 82.4%, respectively; these rates did not differ according to timing of therapy. On univariate analysis, bulky disease (>10 cm), extranodal nonbone marrow involvement, and poor performance status (Eastern Cooperative Oncology Group score, ≥2) predicted increased risk of disease progression. On multivariate analysis, extranodal nonbone marrow disease and performance status remained significant for both PFS and OS.\n\n\nCONCLUSIONS\nSystemic therapy given for lymphoma after the first trimester of pregnancy is likely safe and results in acceptable maternal and fetal outcomes.",
"affiliations": "Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston.;Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Radiation Oncology, University of Southern California, Los Angeles.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Pinnix|Chelsea C|CC|;Osborne|Eleanor M|EM|;Chihara|Dai|D|;Lai|Peter|P|;Zhou|Shouhao|S|;Ramirez|Mildred M|MM|;Oki|Yasuhiro|Y|;Hagemeister|Frederick B|FB|;Rodriguez|Alma M|AM|;Samaniego|Felipe|F|;Fowler|Nathan|N|;Romaguera|Jorge E|JE|;Turturro|Francesco|F|;Fayad|Luis|L|;Westin|Jason R|JR|;Nastoupil|Loretta|L|;Neelapu|Sattva S|SS|;Cheah|Chan Y|CY|;Dabaja|Bouthaina S|BS|;Milgrom|Sarah A|SA|;Smith|Grace L|GL|;Horace|Patricia|P|;Milbourne|Andrea|A|;Wogan|Christine F|CF|;Ballas|Leslie|L|;Fanale|Michelle A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2016.1396",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "2(8)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D000013:Congenital Abnormalities; D019468:Disease Management; D018572:Disease-Free Survival; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin; D008279:Magnetic Resonance Imaging; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D049590:Postpartum Period; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D016016:Proportional Hazards Models; D011878:Radiotherapy; D012189:Retrospective Studies; D016896:Treatment Outcome; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "1065-9",
"pmc": null,
"pmid": "27227654",
"pubdate": "2016-08-01",
"publication_types": "D016428:Journal Article",
"references": "23813932;26886537;19745695;25684034;22511239;23749243;22326925;22902483;25113753;24043736;12185292",
"title": "Maternal and Fetal Outcomes After Therapy for Hodgkin or Non-Hodgkin Lymphoma Diagnosed During Pregnancy.",
"title_normalized": "maternal and fetal outcomes after therapy for hodgkin or non hodgkin lymphoma diagnosed during pregnancy"
} | [
{
"companynumb": "US-JNJFOC-20160820623",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8+ PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy.\n\n\n\nWe conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8+ PCAETL, 4 of whom also underwent allogeneic HSCT.\n\n\n\nEight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow-up.\n\n\n\nAllogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course.",
"affiliations": "Department of Dermatology, Yale University School of Medicine, New Haven, CT. Electronic address: benoit.cyrenne@yale.edu.;Department of Dermatology, Yale University School of Medicine, New Haven, CT.;Department of Dermatology and Pathology, Yale University School of Medicine, New Haven, CT.;Department of Dermatology, Yale University School of Medicine, New Haven, CT.;Hematology and Bone Marrow Transplantation, Yale University School of Medicine, New Haven, CT.;Hematology and Bone Marrow Transplantation, Yale University School of Medicine, New Haven, CT.;Hematology and Bone Marrow Transplantation, Yale University School of Medicine, New Haven, CT.",
"authors": "Cyrenne|Benoit M|BM|;Gibson|Juliet Fraser|JF|;Subtil|Antonio|A|;Girardi|Michael|M|;Isufi|Iris|I|;Seropian|Stuart|S|;Foss|Francine|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(1)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Algorithms; CD8(+) PCAETL; CTCL; Hematopoietic stem cell transplantation; Outcome; Response",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e85-e93",
"pmc": null,
"pmid": "29223388",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma.",
"title_normalized": "transplantation in the treatment of primary cutaneous aggressive epidermotropic cytotoxic cd8 positive t cell lymphoma"
} | [
{
"companynumb": "US-009507513-1801USA007266",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of cytomegalovirus encephalitis in a hematopoietic stem cell transplant recipient. A previously uncharacterized V787E mutation in UL54 was identified in cerebrospinal fluid but not plasma specimens. For the V787E recombinant virus, the half maximal effective concentrations for ganciclovir, foscarnet, and cidofovir were 8.6-, 3.4- and 2.9-fold higher than for wild-type virus, and the replicative capacity was lower. The introduction of a bulkier and negatively charged glutamate residue at position 787 could destabilize the finger domain of UL54 DNA polymerase. Viral genotyping of cerebrospinal fluid is warranted in subjects with cytomegalovirus encephalitis, owing to the low penetration of antivirals in this compartment.",
"affiliations": "Centre de recherche en infectiologie, CHU de Québec-Université Laval.;Laboratory of Virology and Infectious Diseases Division, Geneva, Switzerland.;Institut de Biologie Intégrative et des Systèmes, Université Laval.;INSERM, CHU Limoges, RESINFIT, Université de Limoges.;Hematology Division, Geneva University Hospitals, Geneva, Switzerland.;Hematology Division, Geneva University Hospitals, Geneva, Switzerland.;Laboratory of Virology and Infectious Diseases Division, Geneva, Switzerland.;Centre de recherche en infectiologie, CHU de Québec-Université Laval.;INSERM, CHU Limoges, RESINFIT, Université de Limoges.;Institut de Biologie Intégrative et des Systèmes, Université Laval.;Centre de recherche en infectiologie, CHU de Québec-Université Laval.",
"authors": "Piret|Jocelyne|J|;Schibler|Manuel|M|;Pham|Van Dung|VD|;Hantz|Sébastien|S|;Giannotti|Federica|F|;Masouridi-Levrat|Stavroula|S|;Kaiser|Laurent|L|;Goyette|Nathalie|N|;Alain|Sophie|S|;Shi|Rong|R|;Boivin|Guy|G|",
"chemical_list": "D000998:Antiviral Agents; D017874:Immediate-Early Proteins; C558833:UL54 protein, herpes simplex virus type II; D014764:Viral Proteins; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jiz298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "220(8)",
"journal": "The Journal of infectious diseases",
"keywords": "Cytomegalovirus; cerebrospinal fluid; compartmentalization; drug resistance; encephalitis; hematopoietic stem cell transplantation; recombinant phenotyping; replicative capacity; three-dimensional modeling",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000212:Acyclovir; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents; D002555:Cerebrospinal Fluid; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024921:Drug Resistance, Multiple, Viral; D018792:Encephalitis, Viral; D005260:Female; D006084:Graft Rejection; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017874:Immediate-Early Proteins; D007165:Immunosuppression Therapy; D008875:Middle Aged; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014764:Viral Proteins",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "1302-1306",
"pmc": null,
"pmid": "31199457",
"pubdate": "2019-09-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11050017;11577375;12393485;12535263;12599051;16638752;16705640;19718023;20190836;22921815;23863570;24108608;26872863;26990717;30690043",
"title": "Compartmentalization of a Multidrug-Resistant Cytomegalovirus UL54 Mutant in a Stem Cell Transplant Recipient with Encephalitis.",
"title_normalized": "compartmentalization of a multidrug resistant cytomegalovirus ul54 mutant in a stem cell transplant recipient with encephalitis"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201913269",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR SODIUM"
},
"drugadditional": "3... |
{
"abstract": "Temporal relation of myocardial infarction with cocaine use was first reported in 1982, coronary spasm being the presumed aetiology since most patients presented with normal coronary arteries. However, severe and diffused coronary atherosclerosis is also common in cocaine users with myocardial infarction. The management of these patients presenting with chest pain includes therapy directed to antagonize sympathetic activation and mechanical reperfusion or thrombolytic therapy if ischaemia continues.",
"affiliations": "Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal. Electronic address: inesdalmeida@chbm.min-saude.pt.;Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal.;Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal.;Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal.;Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal.;Cardiology Department of Centro Hospitalar Barreiro-Montijo, Portugal.",
"authors": "Almeida|Inês|I|;Miranda|Hugo|H|;Santos|Hélder|H|;Santos|Mariana|M|;Paula|Sofia|S|;Chin|Joana|J|",
"chemical_list": "D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jelectrocard.2021.04.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-0736",
"issue": "67()",
"journal": "Journal of electrocardiology",
"keywords": "Cocaine; Myocardial infarction",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D002637:Chest Pain; D003042:Cocaine; D003329:Coronary Vasospasm; D004562:Electrocardiography; D006801:Humans; D009203:Myocardial Infarction",
"nlm_unique_id": "0153605",
"other_id": null,
"pages": "11-12",
"pmc": null,
"pmid": "33984569",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cocaine-associated myocardial infarction: Features of diagnosis and treatment.",
"title_normalized": "cocaine associated myocardial infarction features of diagnosis and treatment"
} | [
{
"companynumb": "PT-MYLANLABS-2021M1074120",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nCOVID-19 infection results in a hypercoagulable state predisposing patients to thrombotic events. We report the 3- and 6-month follow-up of 27 patients who experienced acute arterial thrombotic events in the setting of COVID-19 infection.\n\n\nMETHODS\nData were prospectively collected and maintained for all vascular surgery consultations in the Mount Sinai Health System from patients who presented between March 16 and May 5, 2020.\n\n\nRESULTS\nTwenty-seven patients experienced arterial thrombotic events. The average length of stay was 13.3 ± 15.4 days. Fourteen patients were treated with open surgical intervention, six were treated with endovascular intervention, and seven were treated with anticoagulation only. At 3-month follow-up, 11 patients (40.7%) were deceased. Nine patients who expired did so during the initial hospital stay. The 3-month cumulative primary patency rate for all interventions was 72.2%, and the 3-month primary patency rates for open surgical and endovascular interventions were 66.7 and 83.3, respectively. There were 9 (33.3%) readmissions within 3 months. Six-month follow-up was available in 25 (92.6%) patients. At 6-month follow-up, 12 (48.0%) patients were deceased, and the cumulative primary patency rate was 61.9%. The 6-month primary patency rates of open surgical and endovascular interventions were 66.7% and 55.6%, respectively. The limb-salvage rate at both 3 and 6 months was 89.2%.\n\n\nCONCLUSIONS\nPatients with COVID-19 infections who experienced thrombotic events saw high complication and mortality rates with relatively low patency rates.",
"affiliations": "Department of Surgery, Division of Vascular Surgery, New York, NY. Electronic address: Christopher.faries@icahn.mssm.edu.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Interventional Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Interventional Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.;Department of Surgery, Division of Vascular Surgery, New York, NY.",
"authors": "Faries|Christopher M|CM|;Rao|Ajit|A|;Ilonzo|Nicole|N|;Hwong|Songhon|S|;Krishnan|Prakash|P|;Farhan|Serdar|S|;Ting|Windsor|W|;Vouyouka|Ageliki G|AG|;Tadros|Rami O|RO|;Marin|Michael L|ML|;Faries|Peter L|PL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvs.2021.08.092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-5214",
"issue": null,
"journal": "Journal of vascular surgery",
"keywords": "Amputation; COVID-19; Limb ischemia; Patency; Thrombosis",
"medline_ta": "J Vasc Surg",
"mesh_terms": null,
"nlm_unique_id": "8407742",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34597784",
"pubdate": "2021-09-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Follow-up after acute thrombotic events following COVID-19 infection.",
"title_normalized": "follow up after acute thrombotic events following covid 19 infection"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2022-024637",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugaddit... |
{
"abstract": "Severe bullous eruptions in systemic lupus erythematosus (SLE) patients include bullous SLE, Rowell syndrome, toxic epidermal necrolysis (TEN), and TEN-like eruption of acute cutaneous lupus (TEN-like ACLE). TEN-like ACLE, a rare manifestation of SLE that closely mimics TEN, can be distinguished by characteristic clinical and laboratory findings. A 27-year-old man with SLE who developed TEN-like ACLE after initiating mycophenolate mofetil for active SLE is reported. The reports of 37 women and six men including our patient with TEN-like ACLE were also reviewed. The diagnosis of SLE or subacute cutaneous lupus erythematosus was either previously confirmed or established at the time of diagnosis of TEN-like ACLE in 41 patients. Fever was present in 59% of patients. The onset of TEN-like ACLE was either subacute (73%) or acute (27%). Thirteen cases did not clarify the nature of disease onset. The skin lesions often presented initially on sun-exposed sites (29 patients) and involved one or more mucous membranes (21 patients). A new medication may have caused the TEN-like ACLE in 67% of the patients. Systemic corticosteroids either alone or combined with hydroxychloroquine, intravenous immunoglobulin, or mycophenolate mofetil were the most commonly used treatment. Patients with TEN-like ACLE patients had an 89% survival.",
"affiliations": "Department of Dermatology, University of California San Diego, La Jolla, California. lromero@ucsd.edu.",
"authors": "Romero|Laura S|LS|;Bari|Omar|O|;Forbess Smith|Chelsey J|CJ|;Schneider|Jeremy A|JA|;Cohen|Philip R|PR|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "24(5)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D008297:Male; D009173:Mycophenolic Acid; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30142736",
"pubdate": "2018-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus: report of a case and review of the literature.",
"title_normalized": "toxic epidermal necrolysis like acute cutaneous lupus erythematosus report of a case and review of the literature"
} | [
{
"companynumb": "ES-AMNEAL PHARMACEUTICALS-2021-AMRX-02881",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditiona... |
{
"abstract": "Camptocormia is a rare, involuntary movement disorder, presenting as truncal flexion while standing or walking, and is mainly observed as a feature of Parkinson's disease (PD) and primary dystonia. Deep brain stimulation (DBS) of the globus pallidus internus is effective for refractory camptocormia observed with PD or dystonia. However, the effectiveness of pallidotomy for camptocormia has not been investigated. The authors report the case of a 38-year-old man with anterior truncal bending that developed when he was 36 years old. Prior to the onset of the symptom, he had been taking antipsychotic drugs for schizophrenia. There were no features of PD; the symptom severely interfered with his walking and daily life. He was given anticholinergics, clonazepam, and botulinum toxin injections, which did not result in much success. Because of the patient's unwillingness to undergo implantation of a hardware device, he underwent staged bilateral pallidotomy with complete resolution for a diagnosis of tardive dystonic camptocormia. The Burke-Fahn-Marsden dystonia rating scale subscore for the trunk before and after bilateral pallidotomy was 3 and 0, respectively. No perioperative adverse events were observed. Effects have persisted for 18 months. Bilateral pallidotomy can be a treatment option for medically refractory dystonic camptocormia without the need for device implantation.",
"affiliations": null,
"authors": "Horisawa|Shiro|S|;Oka|Mieko|M|;Kohara|Kotaro|K|;Kawamata|Takakazu|T|;Taira|Takaomi|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": "131(3)",
"journal": "Journal of neurosurgery",
"keywords": "AC-PC = anterior commissure–posterior commissure; BFMDRS = Burke-Fahn-Marsden dystonia rating scale; DBS = deep brain stimulation; ECT = electroconvulsive therapy; GPi = globus pallidus internus; PD = Parkinson’s disease; STN = subthalamic nucleus; camptocormia; functional neurosurgery; pallidotomy; tardive dystonia",
"medline_ta": "J Neurosurg",
"mesh_terms": "D000328:Adult; D004421:Dystonia; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal; D053860:Pallidotomy; D013121:Spinal Curvatures",
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "839-842",
"pmc": null,
"pmid": "30497197",
"pubdate": "2018-10-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Staged bilateral pallidotomy for dystonic camptocormia: case report.",
"title_normalized": "staged bilateral pallidotomy for dystonic camptocormia case report"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1125233",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PALIPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Introduction: HTX-019 (CINVANTI®) is a novel injectable emulsion formulation of the neurokinin 1 receptor antagonist (RA) aprepitant, approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 has demonstrated a tolerable safety profile when administered via 30-min intravenous (IV) infusion and 2-min IV injection in healthy volunteers. This prospective study evaluated the safety of HTX-019 administered via 30-min IV infusion and 2-min injection (IV push) in patients with cancer. Materials and methods: This prospective single-center, randomized, safety, 2-sequence, 2-period, crossover study evaluated HTX-019 130 mg within a guideline-recommended 3-drug regimen for CINV prophylaxis in patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC). Treatment-emergent adverse events (TEAEs) were assessed at 0-30 (primary endpoint), 30-60, and >60 mins (chemotherapy administration period) following the initiation of the HTX-019 administration, focusing on infusion-site adverse events and hypersensitivity reactions (dyspnea, anaphylaxis). Results: Among 135 patients (35 MEC, 100 HEC), the most common diagnoses were ovarian (32), lung (17), endometrial (17), and colorectal (15) cancer. Patients were randomized 1:1 to a 2-min injection and a 30-min infusion of HTX-019 (sequence AB or BA), followed by a 5-hydroxytryptamine type 3 RA IV (palonosetron 0.25 mg for 30 s or ondansetron 8-16 mg for 5-10 mins), dexamethasone IV (8-12 mg for 15 mins), and the chemotherapy regimen. Both administration methods were generally well tolerated. No TEAEs occurred within 30 mins after start of HTX-019 administration. All TEAEs occurred during chemotherapy administration; 2 patients experienced 2 TEAEs following injection, and 5 experienced 8 TEAEs following infusion. Three adverse events following infusion (2 dyspnea, 1 throat closing) were considered serious. No TEAEs were considered related to HTX-019. Conclusion: Short injection of HTX-019 has a tolerable safety profile in patients with cancer, and represents an alternative method of HTX-019 administration for CINV prevention.",
"affiliations": "Department of Medicine, University of Alabama Birmingham, Birmingham, AL, USA.;Biostatistics, EMB Statistical Solutions, LLC, Overland Park, KS, USA.",
"authors": "Navari|Rudolph M|RM|;Mosier|Michael C|MC|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S201609",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOTTottOncoTargets and therapy1178-6930Dove 20160910.2147/OTT.S201609Original ResearchCrossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy Navari and MosierNavari and MosierNavari Rudolph M 1Mosier Michael C 21 Department of Medicine, University of Alabama Birmingham, Birmingham, AL, USA2 Biostatistics, EMB Statistical Solutions, LLC, Overland Park, KS, USACorrespondence: Rudolph M NavariUniversity of Alabama Birmingham, 1802 Sixth Avenue, North Pavilion 2540K, Birmingham, AL35294, USATel +1 205 975 2833Fax +1 205 975 3910Email rnavari@uabmc.edu30 4 2019 2019 12 3277 3284 16 1 2019 10 3 2019 © 2019 Navari and Mosier.2019Navari and MosierThis work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Introduction: HTX-019 (CINVANTI®) is a novel injectable emulsion formulation of the neurokinin 1 receptor antagonist (RA) aprepitant, approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 has demonstrated a tolerable safety profile when administered via 30-min intravenous (IV) infusion and 2-min IV injection in healthy volunteers. This prospective study evaluated the safety of HTX-019 administered via 30-min IV infusion and 2-min injection (IV push) in patients with cancer.\n\nMaterials and methods: This prospective single-center, randomized, safety, 2-sequence, 2-period, crossover study evaluated HTX-019 130 mg within a guideline-recommended 3-drug regimen for CINV prophylaxis in patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC). Treatment-emergent adverse events (TEAEs) were assessed at 0–30 (primary endpoint), 30–60, and >60 mins (chemotherapy administration period) following the initiation of the HTX-019 administration, focusing on infusion-site adverse events and hypersensitivity reactions (dyspnea, anaphylaxis).\n\nResults: Among 135 patients (35 MEC, 100 HEC), the most common diagnoses were ovarian (32), lung (17), endometrial (17), and colorectal (15) cancer. Patients were randomized 1:1 to a 2-min injection and a 30-min infusion of HTX-019 (sequence AB or BA), followed by a 5-hydroxytryptamine type 3 RA IV (palonosetron 0.25 mg for 30 s or ondansetron 8–16 mg for 5–10 mins), dexamethasone IV (8–12 mg for 15 mins), and the chemotherapy regimen. Both administration methods were generally well tolerated. No TEAEs occurred within 30 mins after start of HTX-019 administration. All TEAEs occurred during chemotherapy administration; 2 patients experienced 2 TEAEs following injection, and 5 experienced 8 TEAEs following infusion. Three adverse events following infusion (2 dyspnea, 1 throat closing) were considered serious. No TEAEs were considered related to HTX-019.\n\nConclusion: Short injection of HTX-019 has a tolerable safety profile in patients with cancer, and represents an alternative method of HTX-019 administration for CINV prevention.\n\nVideo abstract\n\n\nPoint your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:\n\nhttps://youtu.be/AZY3gSe4gVw\n\nKeywords\naprepitantbag shortageCINVHTX-019real worldshort injection\n==== Body\nPlain language summary\nThis study evaluated the safety of HTX-019, a treatment for preventing a common side effect of chemotherapy known as chemotherapy-induced nausea and vomiting (CINV)\n\nHTX-019 is an IV formulation of aprepitant—a drug recommended by treatment guidelines for use in combination with other drugs to prevent CINV; HTX-019 was approved in 2017 as a 30 min infusion for CINV prevention\n\nSome study results have shown that HTX-019 is also safe and well tolerated when given as a short (2 min) IV injection in healthy volunteers; this is an advantage in reducing the need for IV bags and in decreasing administration times, compared to 30 min infusions\n\nThis real-world study in patients with cancer is of clinical value because it demonstrated that HTX-019 was safe when given as a 2 min injection and 30 min infusion in patients receiving chemotherapy\n\nShort injection of HTX-019 is a viable method of delivery for preventing CINV within a guideline-recommended drug regimen\n\n\n\n\nIntroduction\nChemotherapy-induced nausea and vomiting (CINV) is associated with a significant decrease in quality of life and may lead to delay or discontinuation of chemotherapy.1–3 Antiemetic guidelines provide comprehensive recommendations for combination antiemetic regimens to prevent CINV.1,4–8\n\nThe current National Comprehensive Cancer Network (NCCN) guidelines recommend the inclusion of a substance P/neurokinin 1 (NK-1) receptor antagonist (RA) as part of an antiemetic regimen for patients receiving highly emetogenic chemotherapy (HEC) and for appropriate patients receiving moderately emetogenic chemotherapy (MEC).1 HTX-019 (CINVANTI®; Heron Therapeutics, Inc., San Diego, CA, USA), approved by the Food and Drug Administration (FDA) in November 2017, is a novel injectable emulsion formulation of the NK-1 RA aprepitant. HTX-019 is indicated in adults for administration in combination with other antiemetic agents for the prevention of acute and delayed CINV associated with initial and repeat courses of HEC including high-dose cisplatin, and nausea and vomiting associated with initial and repeat courses of MEC.9 Safety concerns exist with intravenous (IV) formulations of other NK-1 RAs (fosaprepitant and rolapitant), such as hypersensitivity reactions (HSRs) including anaphylaxis and anaphylactic shock, and infusion-site adverse events (ISAEs), which may be attributed to their synthetic surfactants (polysorbate 80 and Koliphor HS 15, respectively).10,11 HTX-019 is an NK-1 RA formulation free of polysorbate 80 and other synthetic surfactants to improve the safety profile; unlike fosaprepitant and rolapitant, HTX-019 contains only natural excipients. The formulation delivers 130 mg of aprepitant (150 mg fosaprepitant equivalent) per 18 mL of emulsion.9 HTX-019 utilizes lipid components with a long history of use in parenteral products, such as IV nutrition.12 The NCCN guidelines list HTX-019 130 mg IV as a category 1 recommendation, in combination with other antiemetics, for the prevention of CINV in patients receiving HEC or MEC.1 This recommendation, as well as the FDA approval, was based on the findings of 2 bioequivalence studies of HTX-019 130 mg and fosaprepitant,13,14 in which single-dose HTX-019 130 mg IV (30-min infusion) was bioequivalent to single-dose fosaprepitant 150 mg IV, infused over 20 or 30 mins.13,14 Furthermore, HTX-019 was well tolerated and demonstrated a consistent safety profile in the 200 healthy subjects included across both studies. HTX-019 displayed a more tolerable safety profile than fosaprepitant, as the percentage of subjects who reported any TEAEs and the total number of TEAEs, including those within the first 30 mins after infusion, were lower following HTX-019 treatment compared with fosaprepitant.13,14\n\nThe two initial bioequivalence studies evaluated HTX-019 infused for 30 mins; however, an acute shortage of IV fluids and bags, along with the desire to reduce administration times, has prompted the administration of small-volume parenteral solutions as short injections (5 mins or less) whenever possible.15 A third bioequivalence study in 50 healthy volunteers showed that administration of HTX-019 130 mg as an IV push (2-min injection) was comparable to 30-min infusion in terms of pharmacokinetics and safety.16 HTX-019 was well tolerated when administered as either an injection or an infusion.16 The crossover design of that study allowed comparison of IV infusion and IV push in the same subjects, but a limitation was that it was conducted in healthy volunteers. The objective of the present prospective study was to evaluate the safety of HTX-019 administered as 30-min IV infusion or 2-min IV push, in a crossover manner, as part of a guideline-recommended 3-drug regimen for CINV prophylaxis in patients with cancer receiving emetogenic chemotherapy (HEC or MEC).\n\nMaterials and methods\nStudy design and objectives\nThis study was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and the Declaration of Helsinki. The study was approved by the institutional review board at the University of Alabama Birmingham. Written informed consent was obtained from each patient.\n\nThis prospective study evaluated the safety profile of HTX-019 administered as part of a guideline-recommended 3-drug antiemetic prophylactic CINV regimen in patients receiving either HEC or MEC, with chemotherapy cycles ranging from 14 to 28 days. Patients were treated in a randomized sequence in crossover fashion (AB or BA) across 2 treatment periods as follows: treatment A—2-min IV injection of HTX-019 130 mg; treatment B—30-min IV infusion of HTX-019 130 mg (in a 130-mL bag). There was a washout period between the 2 treatment periods for each patient (≥14 days corresponding to the next chemotherapy cycle). The primary objective was the assessment of adverse events for 30 mins from the start of HTX-019 administration as either a 2-min injection or a 30-min infusion while patients received the chemotherapy regimen.\n\nPatients\nEnrolled patients were adult men and women aged 20–92 with cancer who were receiving at least two cycles (14–28 days for each cycle) of the same chemotherapy regimen (HEC or MEC) and were eligible to receive a guideline-recommended 3-drug antiemetic regimen of an NK-1 RA (HTX-019), 5-hydroxytryptamine type 3 (5-HT3) RA, and dexamethasone. Patients were excluded if they were pregnant; were lactating; had evidence or history of clinically significant allergic hematologic, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic disease; or had any contraindication or known or suspected hypersensitivity/idiosyncratic reaction to aprepitant or any component of HTX-019, or any drug in the NK-1 RA class.\n\nTreatment regimens\nPatients received the antiemetic treatment regimen starting at least 60 mins prior to chemotherapy in the following order: HTX-019 130 mg (2-min injection or 30-min infusion), followed by a 5-HT3 RA (palonosetron 0.25 mg IV for 30 s, or ondansetron 8 mg IV [MEC] or 8–16 mg IV [HEC] for 5–10 mins), followed by dexamethasone 8–12 mg IV for 15–20 mins, followed by the chemotherapy regimen (at least 60 mins after start of HTX-019 administration). Patients scheduled to receive a taxane chemotherapy were given IV diphenhydramine and IV ranitidine (for 30 mins) following the dexamethasone and prior to the chemotherapy.\n\nStudy assessments\nAll adverse events, regardless of causality or seriousness, were recorded from the time the patient signed the informed consent (24–48 hrs prior to the start of treatment) through the end of the study period. Any adverse events occurring at 0–30 (primary endpoint) and 30–60 mins following the start of HTX-019 administration during the first and second cycles were recorded. Any adverse events noted after the 60-min period and during the administration of the chemotherapy were also recorded. Serious adverse events (SAEs) were defined as resulting in the following outcomes: death, life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, or persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. Other assessments included cancer diagnosis, baseline Eastern Cooperative Oncology Group performance status, baseline physical examination, review of current and past medications, standard blood tests, emetogenic potential of the chemotherapy regimen administered (HEC or MEC), cycle of chemotherapy received based on the crossover design (1 or 2), method of administration of HTX-019 (injection or infusion via a peripheral line or central line), and additional antiemetics administered during the study.\n\nStatistical methods\nSample size justification\nThis crossover study was designed to demonstrate that delivery of HTX-019 via IV push was noninferior to delivery of HTX-019 via IV infusion in terms of infusion-site reaction (ISR) rate. Assuming an expected ISR rate of 5% for both delivery methods (ie, equivalence), and that an absolute difference of 4% was clinically acceptable as not significantly worse, a sample size of 130 patients was required. This sample size for comparison of paired proportions was computed using an assumed 1% random chance of discordant pairs (ie, an ISR with one method but not with the other), and provided 80% power to demonstrate the noninferiority of IV push to IV infusion using a 95% upper 1-sided confidence limit, meaning the upper confidence limit for the difference in rates would be <4%.\n\nStatistical analysis\nThe primary endpoint was the evaluation of adverse events occurring during the 30 mins following the start of a 2-min injection or a 30-min infusion of HTX-019. Of particular interest was the occurrence of either ISAEs or HSRs, such as dyspnea or anaphylaxis. These are collectively referred to as ISRs. The difference in the ISR rate between methods was estimated using a 1-sided upper 95% confidence limit, computed using Newcombe’s method 10.17 If this upper confidence limit for the difference in proportions was ≤0.04 (the chosen noninferiority margin), it would be concluded that the 2-min IV injection (IV push method) was noninferior to the 30-min IV infusion method.\n\nResults\nPatients\n\nA total of 139 patients were enrolled and randomized, 4 of whom did not complete the study as a result of declining to participate after signing the consent (n=1), significant delay in treatment (n=1), and change in chemotherapy agents (n=2). The demographics and baseline characteristics of the remaining 135 patients are summarized in Table 1. Of 135 patients, 35 received a MEC regimen and 100 received a HEC regimen, with the most common chemotherapy regimens including carboplatin area under the concentration-time curve (AUC) >4, taxanes, anthracycline+cyclophosphamide, and cisplatin. The most common diagnoses were ovarian, lung, endometrial, and colorectal cancer (Table 1). Each patient received a 2-min injection and a 30-min infusion of HTX-019 130 mg according to the 2-treatment, 2-period, 2-sequence crossover design (Figure 1).Table 1 Demographics and baseline characteristics\n\nParameter\tHTX-019 IV 130 mg N = 135\t\nMedian age (range), years\t59 (20-92)\t\nSex, n (%)\t\t\n Male\t25 (19)\t\n Female\t110 (81)\t\nRace, n (%)\t\t\n White\t87\t\n African American\t39\t\n Asian\t9\t\nPatient disposition, n (%)\t\t\n ECOG\t\t\n 0\t35 (26)\t\n 1\t95 (70)\t\n 2\t5 (4)\t\nType of cancer\t\t\n Ovarian\t32 (24)\t\n Lung\t17 (13)\t\n Endometrial\t17 (13)\t\n Colorectal\t15 (11)\t\n Bladder\t11 (8)\t\n Cervical\t10 (7)\t\n Osteosarcoma\t8 (6)\t\n Breast\t7 (5)\t\n Head and neck\t7 (5)\t\n Pancreatic\t4 (3)\t\n Lymphoma\t4 (3)\t\n Gastrointestinal (gastric, esophagus)\t3 (2)\t\nEmetogenic risk\t\t\n HEC\t100 (74)\t\n MEC\t35 (26)\t\nIV access\t\t\n Central\t92 (68)\t\n Peripheral\t43 (32)\t\n5-HT3 RA\t\t\n Palonosetron (0.25 mg)\t92\t\n Ondansetron (8-16 mg)\t43\t\nChemotherapy regimen\t\t\n Carboplatin AUC >4\t57\t\n Taxanes\t43\t\n AC\t20\t\n Cisplatin\t19\t\n Carboplatin, AUC <4\t10\t\n Oxaliplatin\t10\t\n Irinotecan\t10\t\n Othera\t2\t\nNotes:\naAzacitidine (n=1); ifosfamide (n=1); treatment A=2-min IV injection HTX-019 130 mg; treatment B=30-min IV infusion HTX-019 130 mg.\n\nAbbreviations: 5-HT3, 5-hydroxytryptamine; AC, anthracycline+cyclophosphamide; AUC, area under the concentration-time curve; ECOG, Eastern Cooperative Oncology Group; HEC, highly emetogenic chemotherapy; HTX-019, aprepitant injectable emulsion; IV, intravenous; MEC, moderately emetogenic chemotherapy; RA, receptor antagonist.\n\n\nFigure 1 Study design. \n\nAbbreviation: IV, intravenous.\n\n\n\nSafety and tolerability of HTX-019 injection and infusion\n\nHTX-019 administered as either an injection or an infusion was generally well tolerated. The number of treatment-emergent adverse events (TEAEs) of any cause and the percentage of patients experiencing a TEAE are shown in Table 2. None of the TEAEs occurred within 30 mins or within the 30–60 mins following HTX-019 injection or infusion. All 10 TEAEs reported in 7 patients occurred at least 60 mins following HTX-019 administration in patients who received HTX-019 infusion or injection followed by IV diphenhydramine, ranitidine, dexamethasone, and palonosetron or ondansetron, then followed by chemotherapy (diphenhydramine and ranitidine were administered as premedications for patients receiving taxane chemotherapy). Given their timing, none of these TEAEs were considered by the investigator to be related to HTX-019 administration.Table 2 Summary of treatment-emergent adverse events of any cause occurring in either group\n\nCategory/preferred term\t2-min IV injection HTX-019 130 mg (N=135)\t30-min IV infusion HTX-019 130 mg (N=135)\tOverall (N=135)\t\nPatients with ≥1 TEAE, n (%)\t2 (1)\t5 (4)\t7 (5)\t\nTotal number of TEAEs\t2\t8\t10\t\nTotal number of SAEs\t0\t3\t3\t\nTreatment-related TEAEs\t0\t0\t0\t\nTEAEs within 30 mins following start of HTX-019 administration\t0\t0\t0\t\nTEAEs within 30-60 minutes following start of HTX-019 administration\t0\t0\t0\t\nTEAEs occurring ≥60 mins following start of HTX-019 administration\t\nDyspnea\t0\t2 (1)\t2 (1)\t\nErythema\t0\t2 (1)\t2 (1)\t\nDiaphoresis\t0\t1 (1)\t1 (1)\t\nDizziness\t1 (1)\t0\t1 (1)\t\nItching\t1 (1)\t0\t1 (1)\t\nPhlebitis\t0\t1 (1)\t1 (1)\t\nRash\t0\t1 (1)\t1 (1)\t\nThroat closing\t0\t1 (1)\t1 (1)\t\nNotes: The denominator for percentages was based on the number of patients in the safety population exposed to each treatment. Patients with multiple adverse events are counted only once within each MedDRA level within each preferred term. Events occurring prior to the dose in the second period are classified with the first treatment, and events on or after the dose in the second period are classified with the second treatment. Events were classified according to MedDRA, Version 18.1.\n\nAbbreviations: IV, intravenous; SAE, serious adverse event; TEAE, treatment-emergent adverse event.\n\n\n\n\nSafety and tolerability of HTX-019 2-min injection\nIn the 2-min HTX-019 IV injection group (IVP), 2 TEAEs were reported after chemotherapy administration in 2 of 135 patients (1%) (patients IVP1 and IVP2), dizziness (n=1) and itching (n=1). Both patients received HEC via central venous access. Patient IVP1 was 65 years old with ovarian cancer receiving doxorubicin and carboplatin (AUC >4) who reported mild transient dizziness occurring 50 mins after the start of chemotherapy (≥110 mins after start of HTX-019 administration in period 2, lasting 5 mins and resolving spontaneously. Patient IVP2 was 48 years old with lung cancer receiving cisplatin who reported itching of the arms and legs with no rash, occurring 30 mins after the start of chemotherapy (≥90 mins after start of HTX-019 administration) in period 2 and resolving after 15–20 mins with additional IV diphenhydramine.\n\nSafety and tolerability of HTX-019 30-min infusion\nIn the 30-min HTX-019 infusion group (IVI), 8 TEAEs were reported after the start of chemotherapy administration in 5 of 135 patients (4%) (patients IVI1-5), the most common being erythema (n=2) and dyspnea (n=2) (Table 2). Four of the 5 patients who had TEAEs were receiving HEC (peripheral venous access, n=3; central venous access, n=1); 1 of the 5 received MEC via central venous access. Patient IVI1 was 63 years old with bladder cancer receiving cisplatin and gemcitabine who developed phlebitis at the site of the peripheral line 30 mins after the start of chemotherapy (≥90 mins after start of HTX-019 administration) in period 1, which resolved in 72 hrs with no additional treatment. Patient IVI2 was 49 years old with ovarian cancer receiving paclitaxel and carboplatin (AUC >4) who developed a rash at the site of the peripheral line 30 mins after the start of chemotherapy (≥90 mins after start of HTX-019 administration) in period 1, which resolved in 72 hrs with no additional treatment. Patient IVI3 was 68 years old with ovarian cancer receiving docetaxel and carboplatin (AUC >4) who developed erythema at the site of the peripheral line 20 mins after the start of chemotherapy (≥80 mins after start of HTX-019 administration) in period 2. The erythema persisted for 10 days and slowly resolved without any additional treatment. Patient IVI4 was 48 years old with endometrial cancer treated with carboplatin (AUC >4) and docetaxel via a central line who developed dyspnea, total-body erythema, and diaphoresis 15 mins after beginning docetaxel (≥75 mins after start of HTX-019 administration) in period 2. Following additional treatment with IV diphenhydramine and IV dexamethasone, symptoms resolved within 20–30 mins; this was thought to be a taxane reaction. Patient IVI5 was 29 years old with rectal cancer treated with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) via a central line who developed dyspnea and throat closing 10 mins after starting oxaliplatin (≥70 mins after start of HTX-019 administration) in period 2. Following additional treatment with IV diphenhydramine and IV dexamethasone, symptoms resolved within 30 mins.\n\nPatients IVI4 and IVI5 had 3 SAEs (dyspnea n=2; throat closing n=1) (Table 2), none of which was fatal or led to study drug or chemotherapy discontinuation or withdrawal. Of the 5 patients in the 30-min infusion group who had at least 1 TEAE, 3 received carboplatin plus docetaxel or paclitaxel; they experienced a total of 5 TEAEs, all related to taxanes.\n\nTEAEs in first 30 mins after the start of HTX-019 administration\nAs outlined above, 6 patients (injection, n=1; infusion, n=5) experienced a total of 9 TEAEs 10–30 mins after start of chemotherapy administration, which was at least 70–90 mins after start of HTX-019 administration. None of these TEAEs occurred within the first 30 mins after start of HTX-019 administration, and none were deemed by the investigator to be related to HTX-019 treatment. All of the TEAEs were resolved by the end of the study.\n\nNoninferiority analysis of ISRs with HTX-019 injection and infusion\nNo ISRs or other TEAEs were reported in the first 30 mins following the start of HTX-019 130 mg administration with either 2-min injection or 30-min infusion. The adverse events reported with either 2-min injection or 30-min infusion of HTX-019 130 mg were not considered to be ISRs. Therefore, statistical analysis to demonstrate noninferiority with regard to ISRs was not conducted. Instead, the analysis was performed using a “conservative” approach, and included any adverse event reported at any time after the start of HTX-019 treatment. There were 2 such TEAEs reported with the 2-min injection and 5 TEAEs reported with the 30-min infusion, all which occurred more than 60 mins following the start of HTX-019 administration. None of the patients reported a TEAE on both treatments. The point estimate for the difference in TEAE rates was −0.022, and the upper 1-sided 95% confidence limit for the difference in TEAE rates was 0.0127. Since this was well below the 0.04 noninferiority margin set for ISR rates, the 2-min injection would be declared noninferior to the 30-min infusion of HTX-019 130 mg, for the occurrence of TEAEs at any time following the start of HTX-019 administration.\n\nDiscussion\nHTX-019 130 mg administered as a 2-min injection or a 30-min infusion in a crossover fashion in patients with cancer was well tolerated. No TEAEs occurred within 30 mins after start of HTX-019 administration. Overall, there were 10 TEAEs, with 2 TEAEs occurring in 2 patients (1%) receiving the 2-min injection and 8 TEAEs occurring in 5 patients (4%) receiving the 30-min infusion. All these TEAEs were seen following administration of chemotherapy and were therefore not considered related to HTX-019. The only TEAEs reported following the 2-min injection were itching and dizziness. The most common TEAEs reported with the 30-min infusion were erythema and dyspnea. Six patients experienced a total of 9 TEAEs in the first 30 mins after start of chemotherapy administration (≥70–90 mins after HTX-019 administration). There were 3 SAEs (dyspnea n=2; throat closing n=1) that occurred following the start of chemotherapy administration in 2 patients receiving the 30-min infusion of HTX-019. Given the timing of the TEAEs during chemotherapy administration, none were deemed by the investigators to be related to HTX-019 treatment. All TEAEs were observed in patients receiving taxane-based chemotherapy who had been pretreated with IV diphenhydramine, ranitidine, and palonosetron after HTX-019. The 5 TEAEs reported in 3 patients who received a 30-min infusion were considered taxane-related. All TEAEs resolved by end of the study. In addition, none of the TEAEs in the study were considered ISRs, and administration via the 2-min injection demonstrated noninferiority to the 30-min infusion for TEAEs that occurred at any time following the start of HTX-019 administration.\n\nHTX-019 was approved by the FDA as a 30-min infusion and, more recently, as a 2-min injection for use in adults, in combination with other antiemetics, for the prevention of acute and delayed nausea and vomiting with initial and repeat courses of HEC and MEC.9 The approval of HTX-019 was based on the findings of 2 bioequivalence studies (104 and 106).13,14 A pooled analysis of the 2 studies showed that headache (in 3% of subjects) and fatigue (2%) were the most commonly reported TEAEs after HTX-019 administration, whereas ISAEs (10%) and headache (7%) were the most commonly reported TEAEs after fosaprepitant administration. No serious or severe TEAEs or deaths were reported; all TEAEs were resolved by the end of the studies. Taken together, the percentage of subjects who reported any TEAEs and the number of TEAEs were much less following treatment with HTX-019 130 mg (30-min infusion) compared with fosaprepitant 150 mg (20- or 30-min infusion). Similar results were seen with the percentage of subjects reporting treatment-related TEAEs and the number of treatment-related TEAEs, which were lower in subjects treated with HTX-019.13,14 In addition, the number of TEAEs reported within the first 30 mins following the start of infusion was much lower after HTX-019 (2.6%) compared with fosaprepitant (15%) treatment.13,14\n\nThe approved dosage of HTX-019 is 100 (MEC) or 130 mg (HEC) infused for 30 mins.9 In November 2017, the FDA announced a significant acute shortage of small-volume parenteral solutions, including those used for HTX-019 dilution, referring to the American Society of Health-System Pharmacists (ASHP) recommendation that clinicians switch parenteral administration to IV push (injection of 5 mins or less) whenever possible.15 A recent Phase I study (study 108) addressed the ASHP recommendation by showing that a 2-min injection and a 30-min infusion of HTX-019 130 mg had comparable pharmacokinetic and safety profiles. The most common treatment-related TEAEs were headache (4%) and fatigue (6%) in the 2-min injection group and 30-min infusion group, respectively. Only 1 patient (2%) for each method of administration experienced a TEAE (feeling hot) within the first 30-min posttreatment.16 The results of the current prospective study in patients with cancer receiving chemotherapy are consistent with the study 108 findings16 in that HTX-019 administration was well tolerated, especially in patients receiving the 2-min injection. These results are of clinical relevance, as they provide safety information on administering HTX-019 as a short injection within a guideline-recommended 3-drug regimen for CINV prophylaxis in patients receiving emetogenic chemotherapy.\n\nConclusion\nThese findings demonstrate that a short injection of HTX-019 has a tolerable safety profile in patients with cancer, and may be used as a potential alternative method of administration in CINV prevention while decreasing the need for IV bags.\n\nAcknowledgments\nMedical writing support was provided by Phillip Giannopoulos, PhD, of SciStrategy Communications, and funded by Heron Therapeutics, Inc. The authors would like to thank the University of Alabama Birmingham pharmacy administration and staff as well as the nursing infusion center staff for their assistance with the study.\n\nAuthor contributions\nRudolph M Navari was responsible for the conception and design, and collection and assembly of data. Michael C Mosier was responsible for the data analysis and interpretation. Rudolph M Navari and Michael C Mosier were responsible for the writing and critical revisions of the manuscript, read and approved the final manuscript, and agree to be accountable for all aspects of the work.\n\nDisclosure\nRudolph M Navari and Michael C Mosier have served in a consultant/advisory role for Heron Therapeutics, Inc. Dr Michael C Mosier reports personal fees from Heron Therapeutics, Inc., during the conduct of the study. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. NCCN clinical practice guidelines in oncology: antiemesis―version 1.2019 .Available from : https://www.nccn.org/professionals/physician_gls/default.aspx#supportive. Accessed March 21, 2019.\n2. Bloechl-Daum \nB , Deuson \nRR , Mavros \nP , Hansen \nM , Herrstedt \nJ . Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment . J Clin Oncol . 2006 ;24 (27 ):4472 –4478 . doi:10.1200/JCO.2006.05.6382 16983116 \n3. Cohen \nL , de Moor \nCA , Eisenberg \nP , Ming \nEE , Hu \nH . Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings . Support Care Cancer . 2007 ;15 (5 ):497 –503 . doi:10.1007/s00520-006-0173-z 17103197 \n4. Herrstedt \nJ , Roila \nF , Warr \nD , et al. 2016 Updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high emetic risk chemotherapy . Support Care Cancer . 2017 ;25 (1 ):277 –288 . doi:10.1007/s00520-016-3313-0 27443154 \n5. Hesketh \nPJ , Kris \nMG , Basch \nE , et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update . J Clin Oncol . 2017 ;35 (28 ):3240 –3261 . doi:10.1200/JCO.2017.74.4789 28759346 \n6. Roila \nF , Warr \nD , Hesketh \nPJ , et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following moderately emetogenic chemotherapy . Support Care Cancer . 2017 ;25 (1 ):289 –294 . doi:10.1007/s00520-016-3365-1 27510316 \n7. Hilarius \nDL , Kloeg \nPH , van der Wall \nE , van den Heuvel \nJJ , Gundy \nCM , Aaronson \nNK . Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study . Support Care Cancer . 2012 ;20 (1 ):107 –117 . doi:10.1007/s00520-010-1073-9 21258948 \n8. Gilmore \nJW , Peacock \nNW , Gu \nA , et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study . J Oncol Pract . 2014 ;10 (1 ):68 –74 . doi:10.1200/JOP.2012.000816 24065402 \n9. CinvantiTM (Aprepitant) Injectable Emulsion, for Intravenous Use . San Diego, CA : Heron Therapeutics ; 2019 .\n10. Emend (Fosaprepitant) for Injection, for Intravenous Use [Prescribing Information] . Whitehouse Station, NJ : Merck & Co ; 2019 .\n11. Varubi (Rolapitant) Tablets, for Oral Use. Varubi® (Rolapitant) Injectable Emulsion, for Intravenous Use [Prescribing Information] . Waltham, MA : Tesaro Inc ; 2018 .\n12. Raman \nM , Almutairdi \nA , Mulesa \nL , Alberda \nC , Beattie \nC , Gramlich \nL . Parenteral nutrition and lipids . Nutrients . 2017 ;9 (4 ):388 . doi:10.3390/nu9040388 \n13. Ottoboni \nT , Keller \nMR , Cravets \nM , Clendeninn \nN , Quart \nB . Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a phase I, open-label, randomized, two-way crossover evaluation . Drug Des Devel Ther . 2018 ;12 :429 –435 . doi:10.2147/DDDT.S155875 \n14. Ottoboni \nT , Lauw \nM , Keller \nMR , et al. Safety of HTX-019 (intravenous aprepitant) and fosaprepitant in healthy subjects . Future Oncol . 2018 ;14 (27 ):2849 –2859 . doi:10.2217/fon-2018-0311 29873529 \n15. ASHP and the University of Utah Drug Information Service . Small-volume parenteral solutions shortages: suggestions for management and conservation . US Food and Drug Administration Web site ; 2017 \nAvailable from : https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM582461.pdf. Accessed 10 17 , 2018.\n16. Ottoboni \nT , Lauw \nM , Keller \nMR , et al. HTX-019 via 2-min injection or 30-min infusion in healthy subjects . Future Oncol . 2019;15(8):865-874. doi:10.2217/fon-2018-0809 \n17. Newcombe \nRG . Improved confidence intervals for the difference between binomial proportions based on paired data . Stat Med . 1998 ;17 (22 ):2635 –2650 .9839354\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "12()",
"journal": "OncoTargets and therapy",
"keywords": "CINV; HTX-019; aprepitant; bag shortage; real world; short injection",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "3277-3284",
"pmc": null,
"pmid": "31118678",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "16983116;17103197;21258948;24065402;27443154;27510316;28420095;28759346;29535504;29873529;30574797;9839354",
"title": "Crossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy.",
"title_normalized": "crossover safety study of aprepitant 2 min injection vs 30 min infusion in cancer patients receiving emetogenic chemotherapy"
} | [
{
"companynumb": "US-PFIZER INC-2019227596",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTenofovir disoproxil fumarate (TDF)-containing regimens in the treatment of HIV-infected children have safety concerns with respect to renal and bone toxicity.\n\n\nOBJECTIVE\nThe aim of this study was to systematically review and critically appraise the literature relating to the reported renal and bone adverse effects of TDF-based regimens in the treatment of HIV-infected children from 2 to 19 years old.\n\n\nMETHODS\nSearches were performed using the Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, OvidSP, ScienceDirect and Web of Science databases and platforms. All primary studies involving tenofovir use in HIV-infected children were sought. Studies that involved the use of TDF for pre- and post-exposure prophylaxis, and treatment of chronic hepatitis B virus infection were excluded. Data on study characteristics, participant's characteristics, therapeutic intervention and adverse effects were extracted using a piloted tool. In addition, pharmacovigilance data from the WHO Adverse Reaction database were included.\n\n\nRESULTS\nWe identified 19 studies that reported the presence of renal and bone adverse effects of TDF and these included a total of 1100 study participants. The reports were in distinctly heterogeneous participant groups. A total of 287 renal and bone adverse effects were reported (250 renal and 37 bone adverse effects). Approximately 238 (21.6 %) participants were affected by these adverse effects. Of these, 15 participants stopped their TDF-containing regimen due to these adverse effects. In addition, the pharmacovigilance data from the WHO Adverse Reaction database reported 101 renal and bone adverse effects for patients whose indication was HIV/AIDS.\n\n\nCONCLUSIONS\nThis systematic review summarises the reports of renal and bone adverse effects of a TDF-containing regimen in the treatment of HIV-infected children. Our findings suggest that the benefits of using TDF in children need to be balanced against the potential risk of toxicity.",
"affiliations": "Department of Child Health, University of Benin Teaching Hospital, P.M.B. 1111, Benin City, Edo State, Nigeria. roseezimuo@yahoo.com.;School of Pharmacy, Faculty of Health and Social Care, Robert Gordon University, Aberdeen, UK.;Internal Medicine, Faculty of Medicine and Dentistry, University of Calabar, Calabar, Cross River State, Nigeria.",
"authors": "Okonkwo|Rose I|RI|;Weidmann|Anita E|AE|;Effa|Emmanuel E|EE|",
"chemical_list": "D019380:Anti-HIV Agents; D000068698:Tenofovir",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-015-0371-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "39(3)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D019380:Anti-HIV Agents; D001847:Bone Diseases; D002648:Child; D015658:HIV Infections; D006801:Humans; D007674:Kidney Diseases; D016032:Randomized Controlled Trials as Topic; D000068698:Tenofovir; D016896:Treatment Outcome",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "209-18",
"pmc": null,
"pmid": "26692394",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "9448521;18346519;22304601;22269183;19183077;18705824;20673002;23097583;16430197;20874420;21528939;19209091;25247583;22301477;14715822;16923923;22878694;16466494;23249917;16291735;23636286;25760565;23031418;19622512;21716719;17638398;15579182;24067562;11794218;17901802;11579244;17615054;22301411;21076275;16280700;21041922;16773419;12650292;17661851",
"title": "Renal and Bone Adverse Effects of a Tenofovir-Based Regimen in the Treatment of HIV-Infected Children: A Systematic Review.",
"title_normalized": "renal and bone adverse effects of a tenofovir based regimen in the treatment of hiv infected children a systematic review"
} | [
{
"companynumb": "GB-CIPLA LTD.-2018GB16308",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR"
},
"drugadditional": "3",
... |
{
"abstract": "A previously fit and well 19 year old male presents with a progressive ataxic - sensory neuropathy worsening over 2 - 3 weeks. History and investigations revealed extensive recreational use of nitrous oxide resulting in functional B12 deficiency and consequent subacute combined degeneration of the cord. Abstinence and B12 supplementation resulted in a rapid and full neurological recovery. This case report highlights the importance of considering nitrous oxide abuse in the differential diagnosis of atypical neurological symptoms and signs, and emphasizes the possibility of good clinical outcomes with treatment.",
"affiliations": "Acute Medical Unit (AMU), University College Hospital, 235 Euston Road, London, NW1 2BU.;Acute Medical Unit (AMU), University College Hospital, 235 Euston Road, London, NW1 2BU.",
"authors": "Friedlander|G|G|;Davies|T|T|",
"chemical_list": "D009609:Nitrous Oxide; D014805:Vitamin B 12",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4884",
"issue": "17(4)",
"journal": "Acute medicine",
"keywords": null,
"medline_ta": "Acute Med",
"mesh_terms": "D001259:Ataxia; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D009609:Nitrous Oxide; D014805:Vitamin B 12; D014806:Vitamin B 12 Deficiency; D055815:Young Adult",
"nlm_unique_id": "101553725",
"other_id": null,
"pages": "232-235",
"pmc": null,
"pmid": "30882108",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Last Laugh - Reversible myeloneuropathy induced by chronic nitrous oxide use.",
"title_normalized": "the last laugh reversible myeloneuropathy induced by chronic nitrous oxide use"
} | [
{
"companynumb": "GB-LINDE-GB-LHC-2019008",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITROUS OXIDE"
},
"drugadditional": "1",
... |
{
"abstract": "We report the case of a 46-year-old diabetic man receiving treatment for rhino-orbital-cerebral mucormycosis with liposomal amphotericin B and surgical debridement. The patient's condition worsened clinically, accompanied by the loss of ocular motility and a visual acuity of absence of light perception. Radiological extension of the infection was evidenced, with invasion of the cavernous sinus. Based on ophthalmological findings, exenteration (a potentially disfiguring procedure) was indicated, but we opted for wide surgical debridement and administration of amphotericin B via intraconal catheter. Clinical improvement and resolution of inflammation occurred after 2 weeks of treatment. Thus, rhino-orbital-cerebral mucormycosis was effectively controlled through intraconal administration of amphotericin B, while avoiding exenteration. The intervention should be considered as an adjuvant treatment in selected rhino-orbital-cerebral mucormycosis cases before attempting exenteration.",
"affiliations": "Department of Ophthalmology and Otorhinolaryngology, Universidade Estadual de Campinas, Campinas, SP, Brazil.;Neuro-Ophthalmology Service, Department of Ophthalmology and Otorhinolaryngology, Universidade Estadual de Campinas, Campinas, SP, Brazil.",
"authors": "Guimarães|Juliana A de|JA|0000-0002-4574-7293;Moura|Frederico C|FC|0000-0002-7949-6832",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.5935/0004-2749.20220009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2749",
"issue": "85(1)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": null,
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "77-81",
"pmc": null,
"pmid": "34468552",
"pubdate": "2022",
"publication_types": "D016422:Letter",
"references": null,
"title": "Refractory rhino-orbito-cerebral mucormycosis treated with intraconal amphotericin B.",
"title_normalized": "refractory rhino orbito cerebral mucormycosis treated with intraconal amphotericin b"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-330669",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"... |
{
"abstract": "Background. Novel coronavirus-19 disease (COVID-19) is associated with significant cardiovascular morbidity and mortality. However, there have been very few reports on complete heart block (CHB) associated with COVID-19. This case series describes clinical characteristics, potential mechanisms, and short-term outcomes of critically ill COVID-19 patients complicated by CHB. Case Summary. We present three cases of new-onset CHB in critically ill COVID-19 patients. Patient 1 is a 41-year-old male with well-documented history of Familial Mediterranean Fever (FMF) who required mechanical ventilator support for acute hypoxic respiratory failure from severe COVID-19 pneumonia. He developed new-onset CHB without a hemodynamic derangement but subsequently had acute coronary syndrome complicated by cardiogenic shock. Patient 2 is a 77-year-old male with no past medical history who required intubation for severe COVID-19 pneumonia acute hypoxic respiratory failure. He developed CHB with sinus pause requiring temporary pacing but subsequently developed multiorgan failure. Patient 3 is 36-year-old lady 38 + 2 weeks pregnant, gravida 2 para 1 with no other medical history, who had an emergency Lower Section Caesarean Section (LSCS) as she required intubation for acute hypoxic respiratory failure. She exhibited new-onset CHB without hemodynamic compromise. The CHB resolved spontaneously after 24 hours. Discussion. COVID-19-associated CHB is a very rare clinical manifestation. The potential mechanisms for CHB in patients with COVID-19 include myocardial inflammation or direct viral infiltration as well as other causes such as metabolic derangements or use of sedatives. Patients diagnosed with COVID-19 should be monitored closely for the development of bradyarrhythmia and hemodynamic instability.",
"affiliations": "Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.;Cardiology Unit, Department of Medicine, Sultan Qaboos University, Muscat 123, Oman.;Cardiology Unit, Medical Department of Universiti Teknologi MARA (UiTM) Sungai Buloh, Malaysia.;Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK.",
"authors": "Ahmad|Farook|F|https://orcid.org/0000-0001-7216-6040;Gandre|Priti|P|;Nguekam|Julien|J|;Wall|Alanna|A|https://orcid.org/0000-0001-6129-8320;Ong|ShiYu|S|;Karuppamakkantakath|Abdul N|AN|;Tasopoulos|Konstantinos|K|;Sadiq|Muhammad Athar|MA|;Kasim|Sazzli|S|;Cuesta|Jeronimo M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/9955466",
"fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420\n2090-6439\nHindawi\n\n10.1155/2021/9955466\nCase Series\nComplete Heart Block as a Clinical Feature in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series of Three Cases\nhttps://orcid.org/0000-0001-7216-6040\nAhmad Farook farook.ahmad@nhs.net\n1 2\nGandre Priti 1\nNguekam Julien 1\nhttps://orcid.org/0000-0001-6129-8320\nWall Alanna 1\nOng ShiYu 1\nKaruppamakkantakath Abdul N. 1\nTasopoulos Konstantinos 1\nSadiq Muhammad Athar 3\nKasim Sazzli 2\nCuesta Jeronimo M. 1\n1Critical Care Unit, North Middlesex University, Hospital NHS Trust, Sterling Way, London N18 1QX, UK\n2Cardiology Unit, Medical Department of Universiti Teknologi MARA (UiTM) Sungai Buloh, Malaysia\n3Cardiology Unit, Department of Medicine, Sultan Qaboos University, Muscat 123, Oman\nAcademic Editor: Mehmet Doganay\n\n2021\n11 8 2021\n2021 995546622 3 2021\n31 5 2021\n27 7 2021\nCopyright © 2021 Farook Ahmad et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nBackground. Novel coronavirus-19 disease (COVID-19) is associated with significant cardiovascular morbidity and mortality. However, there have been very few reports on complete heart block (CHB) associated with COVID-19. This case series describes clinical characteristics, potential mechanisms, and short-term outcomes of critically ill COVID-19 patients complicated by CHB. Case Summary. We present three cases of new-onset CHB in critically ill COVID-19 patients. Patient 1 is a 41-year-old male with well-documented history of Familial Mediterranean Fever (FMF) who required mechanical ventilator support for acute hypoxic respiratory failure from severe COVID-19 pneumonia. He developed new-onset CHB without a hemodynamic derangement but subsequently had acute coronary syndrome complicated by cardiogenic shock. Patient 2 is a 77-year-old male with no past medical history who required intubation for severe COVID-19 pneumonia acute hypoxic respiratory failure. He developed CHB with sinus pause requiring temporary pacing but subsequently developed multiorgan failure. Patient 3 is 36-year-old lady 38 + 2 weeks pregnant, gravida 2 para 1 with no other medical history, who had an emergency Lower Section Caesarean Section (LSCS) as she required intubation for acute hypoxic respiratory failure. She exhibited new-onset CHB without hemodynamic compromise. The CHB resolved spontaneously after 24 hours. Discussion. COVID-19-associated CHB is a very rare clinical manifestation. The potential mechanisms for CHB in patients with COVID-19 include myocardial inflammation or direct viral infiltration as well as other causes such as metabolic derangements or use of sedatives. Patients diagnosed with COVID-19 should be monitored closely for the development of bradyarrhythmia and hemodynamic instability.\n==== Body\n1. Introduction\n\nIn January 2020, the World Health Organization declared the outbreak of novel coronavirus, SARS-CoV-2 (COVID-19) a Public Health Emergency of International Concern [1, 2]. The primary clinical manifestation of COVID-19 is the respiratory system, but involvement of other systems has been reported, especially the cardiovascular system [1–3]. Cardiovascular complications of COVID-19 include myocardial infarction, myocarditis, heart failure, cardiogenic shock, and cardiac arrhythmias [3]. However, CHB is a very rare cardiovascular complication of COVID-19 disease. We present a case series of 3 patients with no prior cardiovascular history and otherwise normal cardiac structure and function who were admitted to the Intensive Care Unit with COVID-19 and developed CHB during their clinical course. We believe that this is a rare yet fatal cardiovascular complication of COVID-19 disease. Thus, it is important for clinicians to be aware of this severe manifestation of the disease.\n\n2. Case 1\n\nPatient 1 was a 41-year-old businessman, with history of Familial Mediterranean Fever (FMF) on long-term colchicine, who presented to our institution with 1 week of fever associated with pleuritic chest pain and breathlessness. On arrival, he was noted to be hypotensive with elevated jugular venous pressure as well as severe respiratory distress requiring mechanical ventilator support. A nasopharyngeal swab test for SARS-CoV-2 by polymerase chain reaction was positive, and he was treated with Tocilizumab and Dexamethasone as per institutional practice. He was further managed in the Intensive Care Unit (ICU) for COVID-19 pneumonitis. Initial laboratory investigations showed lymphopenia (688 cells/mm3) and raised inflammatory markers (CRP 110 mg/L, fibrinogen 888 mg/dL, and D-dimer 11000 ng/mL Fibrinogen Equivalent Units (FEU)). His renal markers, electrolytes, and troponin T on admission were all within normal limits (Table 1, Supplementary Data). Electrocardiogram (ECG) on presentation showed normal sinus rhythm at a rate of 82 beats per minute (bpm), normal intervals, normal axis, and no ST-T wave changes. There was no previous ECG for comparison.\n\nHe was proned immediately after endotracheal intubation. On day 5 of ICU admission, the patient was noted to be in complete heart block on cardiac telemetry monitoring. Figure 1(a) shows that a 12-lead electrocardiogram performed confirmed the diagnosis of CHB with a ventricular rate of approximately 50 bpm. Immediate laboratory investigations including thyroid function, cardiac biomarkers, and electrolytes were unremarkable. Echocardiogram revealed a normal left ventricular ejection fraction with no regional wall motion abnormalities or valvular pathology. The ongoing medication list was checked and found to be unremarkable for precipitating atrioventricular (AV) block. The complete heart block continued with a spontaneous and stable ventricular rate of 40-45 beats per minute with stable hemodynamics for a further three days. It was managed conservatively under vigilant monitoring with invasive cardiac output monitoring. On day 8 of ICU admission, he acutely deteriorated and had cardiogenic shock requiring noradrenaline and adrenaline. ECG showed ST elevation in AVR with global ST depression (Figure 1(b)). Cardiac troponins were significantly raised, and a repeat 2-D echocardiogram showed global hypokinesia with severely reduced ejection fraction of 20%. Shortly after, the patient deteriorated further and developed ventricular tachycardia (Figure 1(c)) and passed away later that day following a failed cardiopulmonary resuscitation (CPR). A timeline event for this patient is provided in Table 2, Supplementary data.\n\n3. Case 2\n\nPatient 2 is a 77-year-old Italian man with no significant past medical history who was brought in by ambulance to the emergency department with acute onset of shortness of breath for 3-day duration. He was noted to be severely hypoxic with SpO2 < 50% upon arrival of paramedics at his residential home. He was intubated and proned immediately upon arrival from the emergency department. A nasopharyngeal swab was positive for SARS-CoV-2 by polymerase chain reaction and was treated with Tocilizumab and Dexamethasone as per institutional practice. Initial laboratory workup showed lymphopenia (628 cells/mm3) and elevated inflammatory markers (CRP 128 mg/L, fibrinogen 818 mg/dL, and D-dimer 17000 ng/mL FEU). His other laboratory workup was within normal limits, including a normal troponin T (Table 1, Supplementary Data). His initial ECG showed a normal sinus rhythm with heart rate of 94 bpm, but no other abnormalities were found. There was no previous ECG for comparison. Chest radiography revealed bilateral ground-glass opacities and computed tomography pulmonary angiogram (CTPA) showed extensive patchy peripheral ground-glass opacification throughout the thorax but no evidence of pulmonary embolism. Echocardiogram revealed a normal left ventricular ejection fraction with no regional wall motion abnormalities or valvular pathology.\n\nThe clinical course in ICU was complicated by shock on day 7 of admission which progressed into multiorgan failure and support requiring continuous renal replacement therapy and hepatic failure as well as elevated troponin level (peak troponin T level was 5003 ng/L). He was also noted to have bradycardia with cardiac telemetry monitoring which revealed a CHB with occasional sinus pause, and the 12-lead ECG showed a CHB (Figure 2). These episodes of AV block alternating with CHB continued with increasing inotropic support. Laboratory investigations for electrolytes and thyroid function were all within normal limits. A balloon flotation temporary pacing wire was inserted successfully using bedside echocardiogram guidance, and he was scheduled for permanent pacemaker implantation. Unfortunately, he developed refractory hypoxic respiratory failure and was deemed not a suitable candidate for Extracorporeal Membrane Oxygenation (ECMO). Successive family conferences resulted in family shifting the focus of care to comfort measures. He passed away on day 10 of admission. A timeline event for this patient is provided in Table 2, Supplementary data.\n\n4. Case 3\n\nPatient 3 is a 36-year-old pregnant female, gravida 2 para 1 (G2P1) with previous Lower Segment Caesarean Section (LSCS) and currently at 38 + 2 weeks pregnant presented with acute onset of shortness of breath for 4-day duration associated with fever, myalgias, and diarrhea for 4-day duration. On arrival to the emergency department, the patient was noted to be febrile with a temperature of 38.8°C, tachycardic with a heart rate of 105 bpm, respiratory rate of 32 breaths per minute, and severely hypoxic with an oxygen saturation of 82% on room air. Her nasopharyngeal swab tested positive for SARS-CoV-2 by polymerase chain reaction and was treated with Tocilizumab and Dexamethasone as per institutional practice. Chest radiography revealed bilateral infiltrates. Initial lab workup revealed mildly elevated white blood cell count with lymphopenia (700 cells/mm3), elevated procalcitonin (6.4 ng/mL), LDH (610 U/L), D-dimer 14000 ng/mL FEU, but normal troponin T < 0.01 ng/mL (Table 1, Supplementary data). ECG on admission (Figure 3(a)) showed sinus tachycardia at 167 bpm, normal intervals, normal axis, and absence of ischemic findings. She was commenced on noninvasive ventilation and had CTPA that showed severe extensive bilateral patchy ground-glass opacification throughout but no evidence of pulmonary embolism. She was intubated for worsening hypoxic respiratory failure and underwent a LSCS with no further complication and was subsequently admitted to ICU.\n\nHer course of admission was complicated by progressive hypoxemia requiring prone ventilation. On day 3, the patient was noted to be in shock requiring inotropic support. Her ECG showed sinus tachycardia with diffuse T wave inversion. Echocardiogram showed global hypokinesia with depressed ejection fraction of 30% but normal septal thickness of 1.2 cm. Her serum CK was elevated at 600 U/L. A diagnosis of myocarditis was made [4], and she was continued on supportive care.\n\nOn day 5 of admission to ICU, intermittent complete heart block was seen on telemetry for less than 24 hours and 12-lead ECG showed a CHB with narrow QRS, suggesting distal AV node focus as origin of escape rhythm (Figure 3(b)). However, she was managed conservatively with vigilant monitoring as she was receiving prone ventilation for refractory hypoxia at the time and she was stable on single, nonescalating inotropic support. Her laboratory investigations for electrolytes and thyroid function were all within normal range. The CHB resolved gradually with improvement in hypoxemia. She was deemed not a suitable candidate for ECMO as the pAO2/FiO2 ratio improved with proning maneuvers. A repeat echocardiography shows improved ejection fraction to 50%. The patient was subsequently discharged to another critical care facility for continuation in management and was stable at the time of writing this report. She was also planned for repeat echocardiography as outpatient cardiology clinic follow-up. A timeline event for this patient is provided in Table 2, Supplementary data.\n\n5. Discussion\n\nThe SARS-CoV-2 virus has caused a worldwide pandemic infecting millions of people, targeting primarily the respiratory system [1–3]. Cardiovascular complications have been reported with varying incidences as one of the manifestations that confer a worse prognosis [4]. Possible etiologies for cardiovascular complications include hypoxemia, electrolyte and metabolic abnormalities, microthrombi, and/or cardiomyopathy from direct invasion to the cardiomyocytes. Cardiac arrhythmias affecting the atrioventricular (AV) node have been reported in association with cardiac injury in critically ill COVID-19 patients [4, 5].\n\nIn our case series, initial and subsequent troponin levels were normal for all the patients. In addition, echocardiography results were not suggestive of underlying cardiomyopathy. This indicates a new onset AV node disease, from either direct infiltration of the AV node, i.e., focused involvement of the AV node, or the AV block being secondary to the critical illness itself. Possible etiologies for new-onset AV node disease include coronary artery disease (CAD); functional, structural, or valvular heart diseases; thyroid disease; medications; and infections [6–8]. Thus, the escape rhythm tended to be narrow, similar to the sinus in morphology, and of adequate rate to support normal hemodynamics without requiring temporary pacing as seen in patient no. 3. The hemodynamic instability requiring temporary pacing in patient 2 is probably contributed by multiple underlying causes rather than the complete heart block alone. Patient 1, meanwhile, has well-documented history of FMF. It has been previously reported that FMF patients are prone to develop CAD, mostly due to increased inflammatory activity and endothelial dysfunction [9]. Several studies and case reports have described the pericardial involvement in FMF patients including acute and recurrent pericarditis, constrictive pericarditis, pericardial effusion, and cardiac tamponade [10]. However, there is no report to suggest a direct correlation between COVID-19 and FMF with cardiac arrhythmia especially CHB and/or acute coronary syndrome.\n\nThe implication of the development of AV block in critically ill COVID-19 patients remains undetermined. In this case series, we have had mixed outcomes from the new onset of AV node disease. The resolution of AV block in patient 3 without further intervention suggests that a temporary or even permanent pacemaker is not required, while patient 2 required immediate temporary pacing wire insertion. Often the prone positioning and clinical status of these exceptional diagnoses make insertion of pacemaker very difficult, which otherwise would be the primary option to treat complete heart block.\n\nWhile in the midst of the pandemic, we have also noted that sinus bradycardia is a very common finding in critically ill COVID-19 patients. However, these cases were not reported due to the fact that sinus bradycardia commonly occurs in patients with mechanical ventilator support and concurrently on high doses of sedatives and NMBA agent.\n\nPrevious publications on cardiovascular manifestation of critically ill COVID-19 mostly focus on acute coronary syndrome and/or myocarditis. To our knowledge, atrioventricular block is a very rare clinical manifestation of COVID-19 patients. Thus, it is important for clinicians to be aware of such a possible severe manifestation with undesirable outcome. We hope that this series will lead to future investigations of the pathophysiology of COVID-19 on the cardiovascular conduction system.\n\n6. Conclusion\n\nCHB can be a clinical manifestation of critically ill COVID-19 patients. Vigilant monitoring and due clinical suspicion are necessary to detect this in a timely manner. The prognosis of the AV node involvement remains unknown and will need future investigations as well as long-term follow-up.\n\nData Availability\n\nRaw data or images were generated at North Middlesex University Hospital. Derived data supporting the findings of this study are available from the corresponding author (FA) on request.\n\nConsent\n\nWritten and informed consent for publication was obtained from the next of kin of the 3 patients described in this case series.\n\nConflicts of Interest\n\nThe authors have no conflict of interest to declare.\n\nSupplementary Materials\n\nSupplementary Materials Table 1: normal reference range for basic laboratory investigations. Table 2: event timeline for patients 1, 2, and 3.\n\nClick here for additional data file.\n\nFigure 1 (a) ECG of patient 1 on day 5 ICU admission showing CHB with ventricular escape rhythm rate approximately 50 bpm. (b) ECG of patient 1 on day 8 admission showing ST elevation in lead AVR and ST depression at leads 1, AVL, II, AVF, V5, and V. (c) ECG of patient 1 on day 8 admission showing ventricular tachycardia and subsequently pulseless electrical activity (not recorded).\n\nFigure 2 ECG for patient 2 on day 7 of admission showing CHB with ventricular rate approximately 35 bpm.\n\nFigure 3 (a) ECG on admission for patient 3 showing sinus tachycardia. (b) ECG for patient 3 on day 5 admission showing complete heart block CHB with narrow QRS, suggesting distal AV node focus as origin of escape rhythm.\n==== Refs\n1 Xu Z. Shi L. Wang Y. Pathological findings of COVID-19 associated with acute respiratory distress syndrome The Lancet Respiratory Medicine 2020 8 4 420 422 10.1016/S2213-2600(20)30076-X 32085846\n2 Wang D. Hu B. Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 32031570\n3 Huang C. L. Wang Y. M. Li W. X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China The Lancet 2020 395 10223 497 506 10.1016/S0140-6736(20)30183-5 31986264\n4 Babapoor-Farrokhran S. Gill D. Walker J. Rasekhi R. T. Bozorgnia B. Amanullah A. Myocardial injury and COVID-19: possible mechanisms Life Sciences 2020 1 p. 253\n5 Eneizat Mahdawi T. Wang H. Y. Haddadin F. I. al-Qaysi D. Wylie J. V. Heart block in patients with coronavirus disease 2019: a case series of 3 patients infected with SARS-CoV-2 HeartRhythm Case Reports 2020 6 9 652 656 10.1016/j.hrcr.2020.06.014 32837907\n6 Gopinathannair R. Merchant F. M. Lakkireddy D. R. COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies Journal of Interventional Cardiac Electrophysiology 2020 59 2 329 336 10.1007/s10840-020-00789-9 32494896\n7 Zoob M. Smith K. S. Aetiology of complete heart-block British Medical Journal 1963 2 5366 1149 1154 10.1136/bmj.2.5366.1149 2-s2.0-0009642232 14060910\n8 Lev M. Anatomic basis for atrioventricular block The American Journal of Medicine 1964 37 5 742 748 10.1016/0002-9343(64)90022-1 2-s2.0-0000901789 14237429\n9 Grimaldi M. P. Candore G. Vasto S. Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population Journal of Leukocyte Biology 2006 79 3 611 615 10.1189/jlb.0705416 2-s2.0-33646092801 16387839\n10 Dabestani A. Noble L. M. Child J. S. Krivokapich J. Schwabe A. D. Pericardial disease in familial Mediterranean fever: an echocardiographic study Chest 1982 81 5 592 595 10.1378/chest.81.5.592 2-s2.0-0020057164 7075279\n\n",
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"title": "Complete Heart Block as a Clinical Feature in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series of Three Cases.",
"title_normalized": "complete heart block as a clinical feature in critically ill coronavirus disease 2019 covid 19 patients a case series of three cases"
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"abstract": "Hematopoietic cell transplantation (HCT) is an increasingly used treatment for hematologic malignancies as well as for nonmalignant diseases. Kidney impairment remains an important early and late post-transplantation complication. Although numerous histopathological changes have been reported, the pathophysiology remains incompletely understood. Furthermore, correlations between clinical findings and morphological changes have not been well studied. Between 2000 and 2016, 17 recipients of allogeneic (n = 12) or autologous (n = 5) HCT underwent kidney biopsy for either proteinuria or deterioration of kidney function at our center. The most common biopsy findings were therapy-related changes with thrombotic microangiopathy (n = 5), calcineurin inhibitor toxicity (n = 4), and membranous glomerulonephritis (n = 3), representing the majority of cases in this category. In addition, kidney findings from 137 autopsies performed between 1995 and March 2017 were analyzed. The most common changes were acute kidney injury (n = 55), most likely due to the patients' premortal deteriorated state, and thrombotic microangiopathy (n = 14). Several cases demonstrated involvement by either infectious agents (n = 6) or tumors (n = 9). Distinct kidney diseases, such as glomerulonephritis, were rare (3% of cases). Uncommon and yet rarely described diagnoses for this patient cohort were IgG4-related tubulointerstitial nephritis and fibrillary nephritis. This study provides a comprehensive overview of the histomorphological findings in kidney biopsy specimens from HCT recipients. Along with treatment-related complications, one putative correlate of chronic GVHD of the kidney could be documented: membranous glomerulonephritis. In contrast, no morphological correlate of acute GVHD of the kidney was identified. Findings at the time of autopsy varied greatly, spanning a wider range than those of indication biopsies.",
"affiliations": "Clinic for Transplantation Immunology and Nephrology, University Hospital of Basel, Basel, Switzerland.;Department of Hematology, University Hospital of Basel, Basel, Switzerland.;Institute of Medical Genetics and Pathology, University Hospital of Basel, Basel, Switzerland.;Clinic for Transplantation Immunology and Nephrology, University Hospital of Basel, Basel, Switzerland.;Institute of Medical Genetics and Pathology, University Hospital of Basel, Basel, Switzerland. Electronic address: Thomas.Menter@usb.ch.",
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"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D064592:Autografts; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies",
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"abstract": "Piperacillin-tazobactam is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. The development of delayed drug hypersensitivity reaction (DHR) has been reported in several cases previously. Here we describe an unusual case of non-immediate DHR due to a prolonged course of piperacillin-tazobactam. We report a 22-year-old man who developed fever, eosinophilia, thrombocytopenia and elevated hepatic enzymes following 17 days of piperacillin-tazobactam for methicillin-sensitive Staphylococcus aureus (MSSA) pneumonia. These adverse reactions were reversed immediately after antibiotic cessation. Our case highlights that clinicians should be aware of delayed adverse effects in patients receiving long-term piperacillin-tazobactam treatment.",
"affiliations": "Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.;Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.;Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.;Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China suxinjs@163.com.",
"authors": "Lv|Jiawen|J|;Wu|Guannan|G|;Zhang|Fang|F|;Su|Xin|X|http://orcid.org/0000-0002-3910-9156",
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"fulltext": "\n==== Front\nEur J Hosp Pharm\nEur J Hosp Pharm\nejhpharm\nejhp\nEuropean Journal of Hospital Pharmacy\n2047-9956\n2047-9964\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33558219\nejhpharm-2020-002575\n10.1136/ejhpharm-2020-002575\nCase Report\n1506\nAn unusual case of piperacillin-tazobactam-induced fever, eosinophilia, thrombocytopenia and liver damage\nLv Jiawen 1\nWu Guannan 1\nZhang Fang 1\nhttp://orcid.org/0000-0002-3910-9156\nSu Xin 123\n1 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China\n2 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China\n3 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southern Medical University, Guangzhou, China\nCorrespondence to Professor Xin Su, Nanjing Jinling Hospital, Nanjing 210002, China; suxinjs@163.com\n3 2022\n8 2 2021\n8 2 2021\n29 e1 e91e94\n22 10 2020\n14 12 2020\n© European Association of Hospital Pharmacists 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.\n2022\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nPiperacillin-tazobactam is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. The development of delayed drug hypersensitivity reaction (DHR) has been reported in several cases previously. Here we describe an unusual case of non-immediate DHR due to a prolonged course of piperacillin-tazobactam. We report a 22-year-old man who developed fever, eosinophilia, thrombocytopenia and elevated hepatic enzymes following 17 days of piperacillin-tazobactam for methicillin-sensitive Staphylococcus aureus (MSSA) pneumonia. These adverse reactions were reversed immediately after antibiotic cessation. Our case highlights that clinicians should be aware of delayed adverse effects in patients receiving long-term piperacillin-tazobactam treatment.\n\ndrug-related side effects and adverse reactions\npulmonary medicine\npharmacy administration\nclinical medicine\nsafety\nhttp://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82070011,81670073 Jiangsu Commission of Health K2019004 “333 project” of Jiangsu Province BRA2019339 special-featureunlocked\n==== Body\npmcBackground\n\nPiperacillin-tazobactam is a combination formulation of an ureidopenicillin and a beta-lactamase inhibitor with a broad spectrum of antibacterial activity.1 2 It is effective for the treatment of patients with polymicrobial infection caused by many Gram-negative, Gram-positive and beta-lactamase-producing bacteria, such as complicated nosocomial and intra-abdominal infections, and also is regarded as empiric therapy for patients who present with fever and neutropenia.3\n\nAs a typical antibiotic, piperacillin-tazobactam is considered safe and well tolerated. However, some adverse reactions have been reported. The most frequent complications include diarrhoea and hepatic dysfunction.4 Eosinophilia with fever and haematological abnormality have been described as severe adverse effects of piperacillin-tazobactam, and are also characteristically regarded as part of the non-immediate drug hypersensitivity reactions (DHRs).5 6 Non-immediate DHRs tend to occur in patients receiving piperacillin-tazobactam therapy over 10 days.7 Here we report an unusual case of a non-immediate DHR reaction to piperacillin-tazobactam.\n\nCase presentation\n\nA previously healthy 22-year-old man presented at our emergency room in January 2020 with high fever (up to 40℃) for a week, accompanied with cough and expectoration. He had 3- year history of smoking without intravenous drug abuse. Physical examination revealed: body temperature 39.5℃; blood pressure 101/54 mmHg and tachypnea of 28 breaths/minute. There were no signs of wounds or skin abscesses. No obvious rhonchi was heard at bilateral lungs and no murmurs were audible in the cardiac valve areas. Initial laboratory tests in the emergency room included: white blood cell count 30.45×109/L, neutrophils 26.95×109/L, platelets 469×109/L, C-reactive protein (CRP) 78 mg/L (normal range 0–8 mg/L) and lactate dehydrogenase (LDH) 657 U/L. Computed tomography (CT) of the chest indicated multiple patchy opacities with cavities. The patient was admitted for further investigation and treatment.\n\nCardiac ultrasound indicated no signs of bacterial endocarditis. Methicillin-sensitive Staphylococcus aureus (MSSA) was isolated from sputum. Repeated blood cultures were negative. HIV and hepatitis B virus tests were negative. Tests for active and latent tuberculosis, including mycobacterium cultures of sputum samples and the interferon-γ release test for tuberculosis infection, were negative. Chest CT showed multiple dense consolidation with cavities at both side of the lungs and also indicated some cavities with gas-liquid level formation inside pulmonary abscesses (figure 1). A small quantity of pleural effusion presented on the scan. No obvious abnormality was found on abdominal CT. A diagnosis was made of S. aureus pneumonia, complicated by pulmonary abscess. Initially the patient empirically received intravenous vancomycin, 1 g twice daily, and imipenem 1 g every 6 hours. Three days later the patient’s body temperature had markedly decreased. Give the presence of MSSA and abnormality of liver function, antimicrobial therapy was switched to intravenous piperacillin-tazobactam 4.5 g every 8 hours per day.\n\nFigure 1 Computed tomography (CT) images of a 22-year-old patient admitted with Staphylococcus aureus pneumonia in January 2020. CT showed multiple patchy opacities with cavities, some of which had gas-liquid level formation inside in the emergency room (A) and after admission (B). During the initiation of vancomycin and imipenem, slightly absorbed parts of inflammatory lesions were revealed on CT (C). Piperacillin-tazobactam treatment improved the CT findings on day 6 following administration (D). No indication of new infection was found after drug-induced fever. (E). No obvious focus was seen on CT scan 3 months after discharge (F).\n\nIntravenous piperacillin-tazobactam apparently further improved the patient's symptoms and CT appearance. His body temperature remained normal for 10 days. However, 17 days after continuous treatment with piperacillin-tazobactam, the patient suddenly developed a high fever with a body temperature of 38.5℃ and did not complain of any other symptoms. Detailed physical examination did not reveal any abnormal findings. Blood samples were taken for culture. Repeated chest CT did not show any deterioration or was suggestive of a new infection for the recurrence of fever. Laboratory analysis indicated reduced platelets (66×109/L) compared with the initial level (figure 2). On the following days, the patient also had eosinophilia (1.36×109/L) and liver function abnormality (alanine aminotransferase (ALT) 78 U/L, aspartate aminotransferase (AST) 223 U/L). Potential viral infection of the upper respiratory tract was excluded.\n\nFigure 2 The development of eosinophilia, thrombocytopenia and liver function test abnormality during the course of piperacillin-tazobactam treatment with normal values for white cell count. Blood counts of eosinophils and platelets returned to normal levels after cessation of piperacillin-tazobactam on day 14 following initiation. Liver parameters returned to normal after 1 week following cessation of piperacillin-tazobactam treatment. PCT, procalcitonin.\n\nThe piperacillin-tazobactam was suspected to be the most likely cause of the recurrent fever, eosinophilia, thrombocytopenia and hepatic abnormalities, and hence was stopped. The fever quickly resolved within 24 hours following the termination of piperacillin-tazobactam treatment and did not recur afterwards. Platelet and eosinophil counts normalised on day 3 and day 7 after cessation of piperacillin-tazobactam, respectively. The parameters of hepatic function declined nearly to normal levels after a week following piperacillin-tazobactam cessation. The patient did not receive any additional medication (including antibiotic therapy) for the recurrent fever until discharge, and underwent supportive treatment without any complications.\n\nInvestigations\n\nThis is an uncommon case of adverse drug response caused by piperacillin-tazobactam. Previous reports have revealed several cases of haematological abnormalities that were suspected as probably being piperacillin-tazobactam-induced side effects, including neutropenia, thrombocytopenia or anaemia.8 9 Other reports showed that eosinophilia with systemic symptoms are regarded as kinds of adverse effects caused by the antibiotics.5 10 In our work, we found a special case of delayed thrombocytopenia and eosinophilia that occurred simultaneously after the use of piperacillin-tazobactam for the treatment of S. aureus pneumonia. The patient’s laboratory and clinical factors did not show evidence of latent infection in other locations. The possibile involvement of the upper respiratory tract was excluded.\n\nTreatment\n\nThe patient' diagnosis was S. aureus pneumonia, complicated by pulmonary abscesses. The use of intravenous piperacillin-tazobactam apparently improved the patient's symptoms and CT appearance. Although the patient developed fever, eosinophilia, thrombocytopenia and liver damage caused by the treatment, the unusual syndromes gradually disappeared after cessation of piperacillin-tazobactama.\n\nOutcome and follow-up\n\nThe fever resolved within 24 hours after stopping piperacillin-tazobactam treatment. The platelet and eosinophil counts both returned to normal after the cessation of piperacillin-tazobactam. The parameters of hepatic function also declined nearly to normal levels following treatment termination.\n\nDiscussion\n\nIn the present case, the patient started to show the side effects of fever, thrombocytopenia and eosinophilia after 17 days of piperacillin-tazobactam treatment. This is similar to previous reports in which drug induced-fever and associated adverse effects occurred from 11 to 17 days after the initiation of piperacillin-tazobactam administration. We have experienced this several times and have described this as the ‘dangerous period’ for piperacillin-tazobactam-induced fever. Consequently we stopped piperacillin-tazobactam therapy immediately without starting any other antibiotics or medication. Fortunately, this patient's fever disappeared within 24 hours of the piperacillin-tazobactam therapy being discontinued. Although the patient's blood CRP and procalcitonin increased in tandem with the fever, they soon declined on day 3 after the termination of piperacillin-tazobactam therapy. Based on the evidence, we believe there is a correlation between the described side effects and piperacillin-tazobactam therapy.\n\nIt has been reported in some cases that piperacillin-tazobactam-induced fever is regarded as a hypersensitivity reaction. Fever, eosinophilia, thrombocytopenia and liver damage are all part of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.5 DRESS syndrome is a life-threatening, rare adverse effect that frequently develops following exposure to antibiotics or antiepileptics, which is characterised by fever, rash, elevated liver enzyme levels, and leukocytosis with eosinophilia.11 The RegiSCAR (European Register of Severe Cutaneous Adverse Reactions) is a scoring system which is most commonly used to categorise cases of DRESS into four groups: no case, possible case, probable case and definite case. Our patient presented several of the described features including fever, eosinophilia and elevated liver enzymes. Typical rash and enlarged lymph nodes were not detected in our patient. Use of the RegiSCAR indicated a possible relationship (score of 3) between our patient’s manifestation of DRESS syndrome and treatment with piperacillin-tazobactam.12\n\nOur patient’s presentation of a fever and an elevated CRP lasting for a transient period evoked a suspicion of latent viral and haematological infection probably after prolonged use of piperacillin-tazobactam. However, no other probable aetiology of eosinophilia could be identified, and the eosinophil abnormality associated with administration of piperacillin-tazobactam resolved soon after the termination of antibiotic therapy. We reasoned that the eosinophilia was probably related to piperacillin-tazobactam as a non-immediate DHR. The mechanism of piperacillin-tazobactam-induced eosinophilia is not entirely understood, but one theory is that activation of interleukin-5 (IL-5) on accumulation of toxic metabolites could cause activation of eosinophils and inflammatory cascades.13 Although there is no accurate diagnostic test or pathognomonic sign, the diagnosis of DRESS syndrome should be considered after exposure to piperacillin-tazobactam for longer than 2 weeks.\n\nBone marrow suppression is a rare and serious adverse effect of piperacillin-tazobactam, and it has been reported that abnormalities occurred after 2 weeks of prolonged antibiotic use.8 The most common abnormality is neutropenia that is often accompanied with thrombocytopenia. Thrombocytopenia rarely develops alone. Thus, we demonstrate an unusual isolated thrombocytopenia after a long course of piperacillin-tazobactam. To our knowledge, isolated thrombocytopenia is thought likely to be due to an immune-mediated reaction induced by drug administration that occurs suddenly and precipitously. Bose et al described a case of abrupt and severe thrombocytopenia within 2 days of piperacillin-tazobactam administration.14 The patient had a positive test for immunoglobulin G (IgG) antiplatelet antibodies to piperacillin-tazobactam therapy, supporting the speculation of immune-related thrombocytopenia. Alzahrani et al reported two cases of possible immune thrombocytopenia that developed rapidly and severely in association with re-exposure to piperacillin-tazobactam.15 Also the platelet count in peripheral blood improved after the discontinuation of piperacillin-tazobactam and the initiation of corticosteroid therapy, suggesting the possibility of immune-mediated thrombocytopenia.\n\nIn our case, the patient developed wild thrombocytopenia without any positive results of auto-immune antibodies or change in complement C3. Since we stopped piperacillin-tazobactam immediately after the side effect occurred, the thrombocytopenia quickly resolved without corticosteroid therapy. It has been suggested that this later-onset thrombocytopenia is dependent on a delayed-type hypersensitivity. Among antibiotics, the beta-lactam antibiotics are a common cause of immune thrombocytopenia, while a beta-lactam-beta-lactamase inhibitor combination, such as piperacillin-tazobactam, has rarely been reported to induce immune-mediated thrombocytopenia. The aetiology of drug-induced immune thrombocytopenia is complex and the mechanism of piperacillin-related thrombocytopenia is possibly associated with hapten-induced antibodies. Some studies have suggested that small molecules like drugs might induce an immune response when linked to macromolecules such as proteins. The combination acts as a hapten and triggers a humoral immune response. On re-exposure to the drug, this leads to platelet destruction and this mechanism may explain the haemolytic anaemia.16 Another report revealed that piperacillin can induce hapten-specific antibodies that are reactive with piperacillin-coated blood cells.17 This similar mechanism may account for the thrombocytopenia that is rarely seen in patients after treatment with piperacillin, but this still needs further confirmation experimentally. An explanation whereby the later-onset thrombocytopenia caused by piperacillin-tazobactam likely occurs as a result of direct toxicity of myeloid precursors should not be excluded.\n\nMoreover, our patient also manifested liver dysfunction, having previously had normal liver function, while the haematological abnormality appeared after the onset of drug-induced fever, and the hepatic value returned to the normal level 1 week after drug cessation. Although hepatic dysfunction has been reported previously in patients on piperacillin-tazobactam therapy, there is no apparent relationship with mortality or progression. Saloojee et al showed that among 225 critically ill patients enrolled in a retrospective study, piperacillin-tazobactam was found to be associated with hepatic dysfunction18. McDonald et al showed there were no significant differences between the high-dose and licensed dose of piperacillin-tazobactam therapy in terms of hepatotoxicity.19 Another report indicates that the beta-lactamantibiotics may induce leucopenia in sever liver dysfunction.20 In the present case, there was no other explanation for this complication except for the exposure to piperacillin-tazobactam as there was no evidence of sepsis, or other responsible drugs. We speculated that the hepatic dysfunction was associated with antibiotic use.\n\nIn conclusion, this is the first description of an unusual case of fever, eosinophilia, thrombocytopenia and liver damage induced by piperacillin-tazobactam. The antibiotic-induced fever may precede bone marrow suppression. Eosinophilia is a rare adverse effect of piperacillin-tazobactam and caution is needed regarding the DRESS syndrome in patients with long duration of piperacillin-tazobactam treatment.\n\nLearning points\n\nThis is an unusual case of adverse effects induced by long-term use of piperacillin-tazobactam that has not been observed previously for methicillin-sensitive Staphylococcus aureus.\n\nEosinophilia is rarely seen following piperacillin-tazobactam treatment, especially accompanying other adverse effects simultaneously.\n\nClinicians should be aware of possible adverse effects in patients receiving long-term antibiotic treatment.\n\nData availability statement\n\nAll data relevant to the study are included in the article.\n\nEthics statements\n\nPatient consent for publication\n\nParental/guardian consent obtained.\n\nContributors: JL: overall manuscript writing and interpretation. GW and FZ: interpretation of results. XS: manuscript modification and submission.\n\nFunding: This study was funded by National Natural Science Foundation of China (82070011, 81670073), Jiangsu Commission of Health (K2019004) and \"333 project\" of Jiangsu Province (BRA2019339).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Lowy FD . Staphylococcus aureus infections. N Engl J Med 1998;339 :520–32. 10.1056/NEJM199808203390806 9709046\n2 Young M , Plosker GL . Piperacillin/tazobactam: a pharmacoeconomic review of its use in moderate to severe bacterial infections. Pharmacoeconomics 2001;19 :1135–75. 10.2165/00019053-200119110-00006 11735679\n3 Gin A , Dilay L , Karlowsky JA , et al . Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev Anti Infect Ther 2007;5 :365–83. 10.1586/14787210.5.3.365 17547502\n4 Perry CM , Markham A . Piperacillin/tazobactam: an updated review of its use in the treatment of bacterial infections. Drugs 1999;57 :805–43. 10.2165/00003495-199957050-00017 10353303\n5 Castellazzi ML , Esposito S , Claut LE , et al . Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis. Ital J Pediatr 2018;44 :93. 10.1186/s13052-018-0535-4 30111350\n6 Shaik S , Kazi HA , Ender PT . Rapid-onset piperacillin-tazobactam induced thrombocytopenia. J Pharm Pract 2015;28 :204–6. 10.1177/0897190014566302 25609660\n7 Demoly P , Adkinson NF , Brockow K , et al . International consensus on drug allergy. Allergy 2014;69 :420–37. 10.1111/all.12350 24697291\n8 He Z-F , Wu X-A , Wang Y-P . Severe bone marrow suppression and hepatic dysfunction caused by piperacillin/tazobactam. Scand J Infect Dis 2013;45 :885–7. 10.3109/00365548.2013.805426 23826789\n9 ElSalem S , Elawad S , Ahmed A , et al . A case of probable piperacillin/tazobactam-induced bone marrow suppression in a pregnant woman. Eur J Hosp Pharm 2019;26 :170–2. 10.1136/ejhpharm-2017-001243 31428326\n10 Cabañas R , Calderon O , Ramirez E , et al . Piperacillin-induced DRESS: distinguishing features observed in a clinical and allergy study of 8 patients. J Investig Allergol Clin Immunol 2014;24 :425–30.\n11 Cacoub P , Musette P , Descamps V , et al . The DRESS syndrome: a literature review. Am J Med 2011;124 :588–97. 10.1016/j.amjmed.2011.01.017 21592453\n12 Kardaun SH , Sidoroff A , Valeyrie-Allanore L , et al . Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156 :609–11. 10.1111/j.1365-2133.2006.07704.x 17300272\n13 Choquet-Kastylevsky G , Intrator L , Chenal C , et al . Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome. Br J Dermatol 1998;139 :1026–32. 10.1046/j.1365-2133.1998.02559.x 9990366\n14 Bose S , Wurm E , Popovich MJ , et al . Drug-induced immune-mediated thrombocytopenia in the intensive care unit. J Clin Anesth 2015;27 :602–5. 10.1016/j.jclinane.2015.06.021 26260647\n15 Alzahrani M , Alrumaih I , Alhamad F , et al . Rapid onset severe thrombocytopenia following reexposure to piperacillin-tazobactam: report of two cases and review of the literature. Platelets 2018;29 :628–31. 10.1080/09537104.2018.1468025 29863943\n16 Garratty G , Petz LD . Drug-induced immune hemolytic anemia. Am J Med 1975;58 :398–407. 10.1016/0002-9343(75)90606-3 1090160\n17 Leger RM , Arndt PA , Garratty G . Serological studies of piperacillin antibodies. Transfusion 2008;48 :2429–34. 10.1111/j.1537-2995.2008.01852.x 18657075\n18 Saloojee A , Skinner DL , Loots E , et al . Hepatic dysfunction: a common occurrence in severely injured patients. Injury 2017;48 :127–32. 10.1016/j.injury.2016.08.017 27599394\n19 McDonald C , Cotta MO , Little PJ , et al . Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients? Minerva Anestesiol 2016;82 :957–65. 27054905\n20 Singh N , Yu VL , Mieles LA , et al . Beta-lactam antibiotic-induced leukopenia in severe hepatic dysfunction: risk factors and implications for dosing in patients with liver disease. Am J Med 1993;94 :251–6. 10.1016/0002-9343(93)90056-U 8452148\n\n",
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"title": "An unusual case of piperacillin-tazobactam-induced fever, eosinophilia, thrombocytopenia and liver damage.",
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"abstract": "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder, seen most often in young adults and children, triggered by tumors or infections. We report a case of cryptococcal meningitis in a patient with sarcoidosis, presenting prominent neuropsychiatric symptoms, electroencephalographic features of autoimmune encephalitis and positive anti-NMDAR antibodies in the cerebrospinal fluid, raising the hypothesis of an infectious immune-mediated mechanism triggering the production of anti-NMDAR antibodies. Since anti-NMDAR encephalitis is potentially fatal and has significant morbidity, further descriptions of its etiological associations are essential to early identification and prompt treatment.",
"affiliations": "Department of Infectious Diseases, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Neurology, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Internal Medicine, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Neurology, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Infectious Diseases, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Infectious Diseases, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.;Department of Infectious Diseases, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal.",
"authors": "Valdoleiros|Sofia R|SR|;Calejo|Margarida|M|;Marinho|António|A|;Martins da Silva|Ana|A|;Vasconcelos|Olga|O|;Gonçalves|Maria João|MJ|;Sarmento E Castro|Rui|R|",
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"fulltext": "\n==== Front\nBrain Behav Immun Health\nBrain Behav Immun Health\nBrain, Behavior, & Immunity - Health\n2666-3546\nElsevier\n\nS2666-3546(20)30001-6\n10.1016/j.bbih.2020.100036\n100036\nShort Communication\nFirst report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis\nValdoleiros Sofia R. sofia.valdoleiros@chporto.min-saude.pt\na∗\nCalejo Margarida mgcalejo@gmail.com\nb\nMarinho António antmarinho@hotmail.com\ncd\nMartins da Silva Ana anamartins.neurologia@chporto.min-saude.pt\nbd\nVasconcelos Olga vasconcelosomgc@yahoo.com\na\nGonçalves Maria João mjoaomsgoncalves@gmail.com\na\nSarmento e Castro Rui rsarmentocastro@netcabo.pt\na\na Department of Infectious Diseases, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal\nb Department of Neurology, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal\nc Department of Internal Medicine, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal\nd Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4099-001, Porto, Portugal\n∗ Corresponding author. sofia.valdoleiros@chporto.min-saude.pt\n09 1 2020\n2 2020\n09 1 2020\n2 10003627 12 2019\n28 12 2019\n3 1 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder, seen most often in young adults and children, triggered by tumors or infections. We report a case of cryptococcal meningitis in a patient with sarcoidosis, presenting prominent neuropsychiatric symptoms, electroencephalographic features of autoimmune encephalitis and positive anti-NMDAR antibodies in the cerebrospinal fluid, raising the hypothesis of an infectious immune-mediated mechanism triggering the production of anti-NMDAR antibodies. Since anti-NMDAR encephalitis is potentially fatal and has significant morbidity, further descriptions of its etiological associations are essential to early identification and prompt treatment.\n\nHighlights\n\n• Cryptococcal meningitis is a rare complication of sarcoidosis and CD4 lymphopenia.\n\n• Anti-NMDAR encephalitis is an autoimmune disorder triggered by tumors or infection.\n\n• A case of concomitant cryptococcosis and anti-NMDAR encephalitis is presented.\n\nKeywords\n\nAnti-N-Methyl-D-Aspartate receptor\nAnti-N-Methyl-D-Aspartate receptor encephalitis\nCryptococcosis\nCryptococcal meningitis\nCryptococcus neoformans\nSarcoidosis\n==== Body\npmc1 Introduction\n\nSarcoidosis is a multisystem granulomatous disease of unknown etiology. Lymphopenia is common (Crouser et al., 2010; Jamilloux et al., 2015; Morell et al., 2002; Yanardag et al., 2002) and T-cell mediated immunity has been shown to be impaired (Adams and Gibson, 2016; Bernard et al., 2013; Dhote et al., 2009; Jamilloux et al., 2015; Leonhard et al., 2016; Miyara, 2006; Ross and Katz, 2002). Albeit infrequent, cryptococcosis is a known complication (Bernard et al., 2013; Jamilloux et al., 2015; Leonhard et al., 2016; Peret et al., 2014), as T-cell immunity is the predominant pathway for protection against infection by Cryptococcus neoformans (Bernard et al., 2013; Riha and Allen, 2004). The frequent administration of immunosuppressive therapy to patients with sarcoidosis, particularly steroids, may potentiate the already present relative susceptibility to cryptococcosis (Baughman and Lower, 2005; Dhote et al., 2009; Mehrany et al., 2002; Peret et al., 2014). Nevertheless, cryptococcal meningitis can develop even in the absence of immunosuppressive therapy (Adams and Gibson, 2016; Girard et al., 2004; Jamilloux et al., 2015; Leonhard et al., 2016; Peret et al., 2014).\n\nAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, an autoimmune disorder, is not uncommon and its frequency has come to rival that of viral encephalitis (Gable et al., 2012). First described in 2007, there is still insufficient understanding of its etiologies and pathogenesis. Whilst mostly associated to neoplasms (Gable et al., 2009; Liu et al., 2017; Lynch et al., 2018; Venkatesan and Adatia, 2017), some infections appear to precede it in a large set of individuals, which pathogenesis is now an active area of investigation (Venkatesan and Benavides, 2015). Mechanisms by which infections may lead to CNS autoimmunity are manifold (Venkatesan and Benavides, 2015). There is significant evidence that herpes simplex can trigger anti-NMDAR encephalitis (Armangue et al., 2013, 2014; Prüss et al., 2012; Venkatesan and Benavides, 2015); there are also reports of possible links to Varicella-Zoster virus (Dalmau et al., 2011; Schabitz et al., 2014), influenza virus, Japanese Encephalitis virus (Ma et al., 2017) and Human Immunodeficiency Virus (HIV) (Arboleya et al., 2016; Patarata et al., 2016), but, to our knowledge, it has not yet been reported any association to fungal infection. Although potentially treatable, anti-NMDAR encephalitis can lead to death if untreated and is associated with significant morbidity (Lynch et al., 2018; Venkatesan and Benavides, 2015). Hence, further understanding of its etiologies is essential to allow early identification and timely treatment.\n\n2 Case report\n\nA previously healthy 39-year-old man received a diagnosis of pulmonary sarcoidosis on September 2016. He was started on prednisolone (40 mg per day) on December 2016, but soon tapering was commenced; on July 2017, he was on 10–15 mg per day on alternate days.\n\nProgressively worsening headaches, accompanied by photophobia and changes in sleep (alternation between insomnia and somnolence/prostration) developed in September 2017 and motivated an increase in prednisone to 40 mg per day for a suspected diagnosis of neurosarcoidosis. At this time, CT scan and MRI of the brain were unremarkable. Four weeks later, changes in behavior and speech, confusion, memory difficulties and visual hallucinations, with periods of psychomotor agitation, without fever, appeared. The patient was medicated with amitriptyline, escitalopram, olanzapine and clonazepam, without improvement. On October 2017, an episode of loss of consciousness, with urinary incontinence and unresponsiveness, without apparent tonic-clonic movements, was described by the patient’s wife. A few days later he was admitted to our hospital. Neurological examination at the Emergency Department (day 0) revealed inattention and disorientation, with psychomotor retardation and no verbal or motor initiative; speech was non-fluent, with hesitations in naming and repeating; myoclonus of the upper limbs, postural tremor and gait ataxia were observed. Meningeal signs were absent.\n\nOn blood panel, C-reactive protein was within normal range (4.68 mg/L) and white blood cells were elevated (15.49 × 109/L), with neutrophilia (14.30 × 109/L) and lymphopenia (0.36 × 109/L). Immunophenotyping of lymphocytes disclosed an absolute CD4+, CD8+ and CD3+ T cells lymphopenia, with 0.066 × 109/L, 0.134 × 109/L and 0.180 × 109/L, respectively. CD19 + B cells lymphopenia was also present (0.053 × 109/L). Natural killer cells were within normal range (0.375 × 109/L). Relative CD4 and CD8 T cells lymphopenia (with no available absolute count) of 5.6% and 21.1%, respectively, were already present in 2016 (before the diagnosis of sarcoidosis and without steroids). HIV serology was negative, immunoglobulins were normal and there was no complement consumption.\n\nNucleocapsular focal hypodensities, without mass effect or hydrocephalus, were seen on the admission CT scan. A lumbar puncture was performed, revealing a cerebrospinal fluid (CSF) opening pressure above 40 cmH2O. CSF analysis disclosed pleocytosis, with polymorphonuclear predominance, glucose consumption and elevated proteinorrachia (Table 1). Angiotensin-converting enzyme (ACE) dosing in CSF was inferior to the detection limit. Amplification of nucleic acids from CSF was negative for Mycobacterium tuberculosis, Cytomegalovirus (CMV), John Cunningham virus (JCV), Epstein-Barr virus (EBV), Herpes-6, Herpes simplex 1 and 2. CSF venereal disease research laboratory (VDRL) was also negative. Detection of Cryptococcus neoformans in the CSF prompted combined therapy with liposomal formulation of amphotericin B and flucytosine. The patient was admitted to the Infectious Diseases’ ward.Table 1 Cerebrospinal fluid cytochemical data of the patient.a\n\nTable 1Hospital Day after Admission\tGlucose (mmol/L)\tProteins (mg/L)\tWhite Cells (x 106/L)\tNeutrophils (x 106/L)\tLymphocytes (x 106/L)\tMonocytes (x 106/L)\t\nDay 0\t0.67\t1860\t330\t257\t53\t20\t\nDay 2\t0.94\t1290\t266\t194\t37\t24\t\nDay 8\t2.72\t920\t140\t48\t65\t24\t\nDay 16\t2.94\t1050\t42\t6\t36 mononuclear cellsb\t\nDay 27\t2.50\t750\t10\t4\t6 mononuclear cellsb\t\nFollow-up (6 months after admission)\t3.00\t770\t25\t13\t12 mononuclear cellsb\t\na Reference ranges: glucose, 2.60–4.51 mmol/L; proteins, 0–400 mg/L; white cell count, 0–5 cells x 106/L.\n\nb Distribution of lymphocytes, monocytes and eosinophils not available.\n\nOn day 1, given the patient’s immunodepression and since there was no evidence of neurosarcoidosis, prednisolone was reduced to 10 mg per day to enhance response against infection. However, despite cytochemical improvement of CSF (Table 1) and normalization of CSF pressure with daily performance of evacuating lumbar punctures, a progressive depression of consciousness was observed since day 7. Brain magnetic resonance imaging (MRI) revealed T1 contrast-enhancing focal areas in the basal ganglia compatible with cryptococcal lesions and small acute ischemic lesions in the subcortical white matter, in possible relation with a vasculitic process (Fig. 1). The patient remained afebrile, but C-reactive protein increased (149 mg/L), without leukocytosis. On day 10, an electroencephalogram (EEG) showed global slowing, with ‘delta brush’ activity and paroxysmal posterior focal activity (Fig. 2A, Supplementary Data). The patient was started on levetiracetam (500 mg twice daily), but his neurological condition showed no improvement. Day 13’s revaluation EEG exhibited slow and monotonous activity, with registration of slow delta bilateral sequences and no paroxysmal activity, congruent with a severe encephalopathic process of non-specific etiology. He also developed sustained hypotension with sinus tachycardia (systolic arterial pressure, 77–90 mmHg; diastolic arterial pressure, 39–55 mmHg; heart rate, 115–138 beats per minute) that did not respond to fluids or hydrocortisone for two days, and required admission to Intermediate Care Unit. IgG anti-NMDAR antibodies, directed to the NR1 subunit, were positive in the CSF (negative in serum). Elevated intrathecal IgG synthesis was registered (1.92 μmol/L to an upper limit of normal of 0.27 μmol/L), and eight CSF-restricted oligoclonal bands were found. Thoraco-abdomino-pelvic CT scan, a testicular ultrasound and a whole-body PET scan were performed, with no evidence of neoplasia.Fig. 1 A, B: Brain MR imaging showing basal ganglia T2 hyperintense (A) and T1 contrast-enhancing areas (B), suggestive of cryptococcal lesions. C, D: Subcortical white matter diffusion weighted imaging (DWI) hyperintensities, possibly related to small vessel vasculitic phenomena. D: Apparent diffusion coefficient (ADC) map showing hypointensity in the splenium of corpus callosum, as previously described in cases of cryptococcal encephalitis.\n\nFig. 1\n\nTreatment for anti-NMDAR encephalitis was instituted. Since it was feared that intensive immunosuppression with intravenous methylprednisolone would further impair response to infection and plasma exchange was considered hazardous due to CD4 T lymphocytes depletion, re-increase of prednisolone to 40 mg per day and immunoglobulin infusion therapy (0.4 mg/kg per day for 5 days) constituted the initial choice. Thereon, the patient slowly improved, and, on day 27, EEG displayed well-structured alpha activity, without paroxysmal activity nor ‘delta brush’ pattern (Fig. 2B, Supplementary Data). Later on, prednisolone was progressively stepped-down, with no clinical worsening. Six weeks of induction therapy were completed and maintenance treatment with fluconazole was initiated given confirmed cultural negativity. The patient was discharged on day 51 with 10 mg of prednisolone per day, with total clinical resolution and imaging improvement.\n\nFour months after discharge, the patient remained neurologically asymptomatic but anti-NMDAR antibodies were still present on CSF (negative in serum), with a high IgG level (1.03 μmol/L) and seven CSF-restricted oligoclonal bands. The patient was re-started on intravenous immunoglobulin (1 g/kg per month). Infliximab was initiated at seven months after discharge, due to sarcoid progression and very low CD4 counts. At 12-months follow-up, the patient displays no neurologic symptoms, with CD4 elevation until 165/mm3, maintaining fluconazole secondary prophylaxis.\n\n3 Discussion and conclusions\n\nWe report a case of concomitant cryptococcal meningitis and anti-NMDAR encephalitis in a sarcoidosis adult patient. Recent experimental studies have shown a significant inflammatory response in cryptococcal CNS disease, particularly in non-HIV cases, driving tissue damage (Neal et al., 2017; Panackal et al., 2015). Hereby, we consider the hypothesis of an infectious immune-mediated mechanism triggering anti-NMDAR antibodies production.\n\nConsidering the patient’s background, there were several initial diagnostic possibilities: in a patient with sarcoidosis, neurological involvement (neurosarcoidosis) must be considered; in a patient under immunosuppression, risk of infection must be carefully addressed. A preliminary diagnosis of neurosarcoidosis determined an increase in steroid dosing, which led to clinical deterioration. Differentiation between cryptococcal meningitis and neurosarcoidosis can be challenging, as they both often present with symptoms of chronic meningitis and can be complicated by hydrocephalus (Leonhard et al., 2016). CSF abnormalities can be similar, with a mild pleocytosis and elevated protein, as well as hypoglycorrachia to some degree (Leonhard et al., 2016). In neurosarcoidosis, any portion of the central or peripheral nervous system can be affected, and the IgG index can be elevated, with presence of oligoclonal bands in CSF, as we saw in our patient. However, for its diagnosis, an intercurrent infection must be excluded. Furthermore, the absence of response to the rise in corticotherapy dosing (on the contrary, the patient deteriorated) makes neurosarcoidosis unlikely.\n\nCryptococcal meningitis is a rare complication of sarcoidosis associated with CD4 lymphopenia, which diagnosis is often delayed or missed (Leonhard et al., 2016). In our patient, cell-mediated immunity was already impaired before steroid treatment. Cryptococcosis alone could not explain this clinical picture; the illness exhibited a biphasic course, which is not typical in cryptococcal meningitis. We postulate that our patient could initially be suffering from chronic meningitis due to cryptococcal infection, as he first presented with characteristic symptoms and aggravated with intensified immunosuppression, and that this infection triggered the production of anti-NMDAR antibodies, leading to the subsequent development of neuropsychiatric symptoms characteristic of this condition. He was medicated with psychotropic drugs, again with no improvement, and it is not unusual to anti-NMDAR encephalitis to be confounded with psychiatric disorders (Dalmau et al., 2008, 2011; Hermans et al., 2017). A clinical response to antifungal treatment can be inferred by CSF cytochemical improvement and normalization of CSF pressure. However, we observed a progressive depression of consciousness under effective therapy. EEG monitoring showed generalized slowing with occasional delta-brush pattern, which is consistent with anti-NMDAR encephalitis (Steriade et al., 2018). The particular ‘extreme delta brush’ pattern, initially described as pathognomonic of this disorder, was not present, but it is usually seen in only 16–33% of patients (Venkatesan and Adatia, 2017). Nonspecific slowing of brain activity is typically seen and focal electrographic seizures can also be present (Dalmau et al., 2011; Fischer et al., 2016; Guasp and Dalmau, 2018; Venkatesan and Adatia, 2017; Zhang et al., 2017). Above all, we only observed neurological improvement after immune therapy and a new rise in corticoid dosing. A diagnosis of anti-NMDAR encephalitis was established based on the diagnostic criteria (Graus et al., 2016): rapid onset (less than 3 months) of abnormal (psychiatric) behavior, cognitive and speech dysfunction, decreased level of consciousness and autonomic dysfunction; EEG showing ‘delta brush’ pattern and focal paroxysmal activity, with slow disorganized activity; CSF with pleocytosis and oligoclonal bands, with the presence of IgG anti-NMDA antibodies specifically directed to the NR1 subunit.\n\nCD4 lymphopenic sarcoidosis phenotype is usually resistant to conventional therapies and responsive to anti-TNF therapy (Crouser et al., 2010). In these patients, infliximab may normalize peripheral CD4 T-cell depletion and improve clinical disease manifestations (Crouser et al., 2010). CD4 counts should be frequently evaluated and prophylaxis prescribed accordingly – primary prophylaxis with cotrimoxazole for Pneumocystis pneumonia and secondary prophylaxis with fluconazole in case of previous cryptococcal meningitis.\n\nLastly, it is of notice that our report has several limitations. First, it does not establish proven causation between infection by Cryptococcus and CNS autoimmunity. Mechanistic studies linking infections with anti-NMDAR encephalitis are lacking (Venkatesan and Benavides, 2015), and the presence of co-incident infection alone with an autoimmune process is not sufficient to establish causality (Venkatesan and Benavides, 2015). Henceforth, studies are needed to firmly establish such a link. Secondly, this study is limited by the absence of a CSF sample from the pre-illness phase or even from the first phase of the illness, in which we speculate there would be no anti-NMDAR antibodies production. Nevertheless, since this autoimmune encephalitis can be fatal and its prognosis can be significantly improved by prompt treatment, the knowledge of new probable triggers is of particular importance to enhance its recognition. Investigation of other related or causal triggers may allow a new understanding of anti-NMDAR encephalitis and facilitate its early diagnosis.\n\nEthical standards\n\nThe patient has agreed to this publication by written consent.\n\nDeclaration of competing interest\n\nNone.\n\nAppendix A Supplementary data\n\nThe following is the supplementary data to this article:Fig. 2 SupplementaryData. A: EEG showing global slowing with occasional inscription of delta waves with superimposed beta activity in a ‘delta brush pattern’ (asterisks*). Occasional posterior paroxystic activity. B: Post-treatment EEG, with normalized, well-structured alpha activity.\n\nFig. 2\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbih.2020.100036.\n==== Refs\nReferences\n\nAdams T.N. Gibson M. Cryptococcal meningitis in a patient with sarcoidosis Proceedings 29 2016 207 208\nArboleya S. Clemente A. Deng S. Bedmar M. Salvador I. Herbera P. Cunill V. Vives-Bauza C. Haro J.M. Canellas F. Julia M.R. Anti-NMDAR antibodies in new-onset psychosis. Positive results in an HIV-infected patient Brain Behav. Immun. 56 2016 56 60 26996305\nArmangue T. Leypoldt F. Malaga I. Raspall-Chaure M. Marti I. Nichter C. Pugh J. Vicente-Rasoamalala M. Lafuente-Hidalgo M. Macaya A. Ke M. Titulaer M.J. Hoftberger R. Sheriff H. Glaser C. Dalmau J. Herpes simplex virus encephalitis is a trigger of brain autoimmunity Ann. Neurol. 75 2014 317 323 24318406\nArmangue T. Titulaer M.J. Málaga I. Bataller L. Gabilondo I. Graus F. Dalmau J. Pediatric Anti-NMDAR encephalitis-Clinical analysis and novel findings in a series of 20 patients J. Pediatr. 162 2013 850 856 e852 23164315\nBaughman R.P. Lower E.E. Fungal infections as a complication of therapy for sarcoidosis QJM : Mon. J. Assoc. Phys. 98 2005 451 456\nBernard C. Maucort-Boulch D. Varron L. Charlier C. Sitbon K. Freymond N. Bouhour D. Hot A. Masquelet A.C. Valeyre D. Costedoat-Chalumeau N. Etienne M. Gueit I. Jouneau S. Delaval P. Mouthon L. Pouget J. Serratrice J. Brion J.P. Vaylet F. Bremont C. Chennebault J.M. Jaffuel S. Broussolle C. Lortholary O. Seve P. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases QJM : Mon. J. Assoc. Phys. 106 2013 523 539\nCrouser E.D. Lozanski G. Fox C.C. Hauswirth D.W. Raveendran R. Julian M.W. The CD4+ lymphopenic sarcoidosis phenotype is highly responsive to anti-tumor necrosis factor-{alpha} therapy Chest 137 2010 1432 1435 20525654\nDalmau J. Gleichman A.J. Hughes E.G. Rossi J.E. Peng X. Lai M. Dessain S.K. Rosenfeld M.R. Balice-Gordon R. Lynch D.R. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies Lancet Neurol. 7 2008 1091 1098 18851928\nDalmau J. Lancaster E. Martinez-Hernandez E. Rosenfeld M.R. Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis Lancet Neurol. 10 2011 63 74 21163445\nDhote R. Abad S. Valeyre D. [The infectious complications of sarcoidosis] Presse Med. 38 2009 317 323 (Paris, France : 1983) 19097746\nFischer C.E. Golas A.C. Schweizer T.A. Munoz D.G. Ismail Z. Qian W. Tang-Wai D.F. Rotstein D.L. Day G.S. Anti N-methyl-D-aspartate receptor encephalitis: a game-changer? Expert Rev. Neurother. 16 2016 849 859 27123777\nGable M.S. Gavali S. Radner A. Tilley D.H. Lee B. Dyner L. Collins A. Dengel A. Dalmau J. Glaser C.A. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis Eur. J. Clin. Microbiol. Infect. Dis. 28 2009 1421 1429 official publication of the European Society of Clinical Microbiology 19718525\nGable M.S. Sheriff H. Dalmau J. Tilley D.H. Glaser C.A. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project Clin. Infect. Dis. 54 2012 899 904 an official publication of the Infectious Diseases Society of America 22281844\nGirard N. Cottin V. Hot A. Etienne-Mastroianni B. Chidiac C. Cordier J.F. [Opportunistic infections and sarcoidosis] Rev. Mal. Respir. 21 2004 1083 1090 15767952\nGraus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. Cortese I. Dale R.C. Gelfand J.M. Geschwind M. Glaser C.A. Honnorat J. Hoftberger R. Iizuka T. Irani S.R. Lancaster E. Leypoldt F. Pruss H. Rae-Grant A. Reindl M. Rosenfeld M.R. Rostasy K. Saiz A. Venkatesan A. Vincent A. Wandinger K.P. Waters P. Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis Lancet Neurol. 15 2016 391 404 26906964\nGuasp M. Dalmau J. Encephalitis associated with antibodies against the NMDA receptor Med. Clín. (Barc) 151 2018 71 79 10.1016/j.medcli.2017.10.015 Epub 2017 Nov 26 29183618\nHermans T. Santens P. Matton C. Oostra K. Heylens G. Herremans S. Lemmens G.M.D. Anti-NMDA receptor encephalitis: still unknown and underdiagnosed by physicians and especially by psychiatrists? Acta Clin. Belg. 2017 1 4\nJamilloux Y. Valeyre D. Lortholary O. Bernard C. Kerever S. Lelievre L. Neel A. Broussolle C. Seve P. The spectrum of opportunistic diseases complicating sarcoidosis Autoimmun. Rev. 14 2015 64 74 25305373\nLeonhard S.E. Fritz D. van de Beek D. Brouwer M.C. Cryptococcal meningitis complicating sarcoidosis Medicine 95 2016 e4587\nLiu C.Y. Zhu J. Zheng X.Y. Ma C. Wang X. Anti-N-Methyl-D-aspartate receptor encephalitis: a severe, potentially reversible autoimmune encephalitis Mediat. Inflamm. 2017 2017 6361479\nLynch D.R. Rattelle A. Dong Y.N. Roslin K. Gleichman A.J. Panzer J.A. Anti-NMDA receptor encephalitis: clinical features and basic mechanisms Adv. Pharmacol. 82 2018 235 260 29413523\nMa J. Zhang T. Jiang L. Japanese encephalitis can trigger anti-N-methyl-D-aspartate receptor encephalitis J. Neurol. 264 2017 1127 1131 28470592\nMehrany K. Kist J.M. Gibson L.E. Cryptococcal infection in sarcoidosis Int. J. Dermatol. 41 2002 773 774 12453001\nMiyara M. The immune paradox of sarcoidosis and regulatory T cells 203 2006 359 370\nMorell F. Levy G. Orriols R. Ferrer J. De Gracia J. Sampol G. Delayed cutaneous hypersensitivity tests and lymphopenia as activity markers in sarcoidosis Chest 121 2002 1239 1244 11948059\nNeal L.M. Xing E. Xu J. Kolbe J.L. Osterholzer J.J. Segal B.M. Williamson P.R. Olszewski M.A. CD4(+) T cells orchestrate lethal immune pathology despite fungal clearance during Cryptococcus neoformans meningoencephalitis mBio 8 2017\nPanackal A.A. Wuest S.C. Lin Y.C. Wu T. Zhang N. Kosa P. Komori M. Blake A. Browne S.K. Rosen L.B. Hagen F. Meis J. Levitz S.M. Quezado M. Hammoud D. Bennett J.E. Bielekova B. Williamson P.R. Paradoxical immune responses in non-HIV cryptococcal meningitis PLoS Pathog. 11 2015 e1004884\nPatarata E. Bernardino V. Martins A. Pereira R. Loureiro C. Moraes-Fontes M.F. Anti-N-Methyl-D-Aspartate receptor encephalitis in HIV infection Case Rep. Neurol. 8 2016 251 257 28101036\nPeret G. Picard A. Corneloup O. Begueret H. Raherison-Semjen C. [Cryptococcal infection and sarcoidosis: a coincidence?] Rev. Pneumol. Clin. 70 2014 164 168 24210157\nPrüss H. Finke C. Höltje M. Hofmann J. Klingbeil C. Probst C. Borowski K. Ahnert-Hilger G. Harms L. Schwab J.M. Ploner C.J. Komorowski L. Stoecker W. Dalmau J. Wandinger K.P. N-Methyl-d-Aspartate receptor antibodies in herpes simplex encephalitis Ann. Neurol. 72 2012 902 911 23280840\nRiha R.L. Allen R.K. Cryptococcosis and sarcoidosis: strange bed-fellows. A report of five cases. Sarcoidosis, vasculitis, and diffuse lung diseases Off. J. WASOG 21 2004 71 76\nRoss J.J. Katz J.D. Cryptococcal meningitis and sarcoidosis Scand. J. Infect. Dis. 34 2002 937 939 12587633\nSchabitz W.R. Rogalewski A. Hagemeister C. Bien C.G. VZV brainstem encephalitis triggers NMDA receptor immunoreaction Neurology 83 2014 2309 2311 25378669\nSteriade C. Hantus S. Moosa A.N.V. Rae-Grant A.D. Extreme delta - with or without brushes: a potential surrogate marker of disease activity in anti-NMDA-receptor encephalitis Clin. Neurophysiol. 129 2018 2197 2204 29580710\nVenkatesan A. Adatia K. Anti-NMDA-receptor encephalitis: from bench to clinic ACS Chem. Neurosci. 8 2017 2586 2595 29077387\nVenkatesan A. Benavides D.R. Autoimmune encephalitis and its relation to infection Curr. Neurol. Neurosci. Rep. 15 2015 3 25637289\nYanardag H. Pamuk G.E. Karayel T. Demirci S. Bone marrow involvement in sarcoidosis: an analysis of 50 bone marrow samples Haematologia 32 2002 419 425 12803116\nZhang Y. Liu G. Jiang M.D. Li L.P. Su Y.Y. Analysis of electroencephalogram characteristics of anti-NMDA receptor encephalitis patients in China Clin. Neurophysiol. 128 2017 1227 1233 official journal of the International Federation of Clinical Neurophysiology 28527387\n\n",
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"journal": "Brain, behavior, & immunity - health",
"keywords": "Anti-N-Methyl-D-Aspartate receptor; Anti-N-Methyl-D-Aspartate receptor encephalitis; Cryptococcal meningitis; Cryptococcosis; Cryptococcus neoformans; Sarcoidosis",
"medline_ta": "Brain Behav Immun Health",
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"title": "First report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis.",
"title_normalized": "first report of concomitant cryptococcal meningitis and anti nmdar encephalitis"
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"abstract": "BACKGROUND\nMucous membrane pemphigoid (MMP) comprises a group of immunobullous diseases involving the mucosa and skin. Potential sequelae include painful mucosal erosions, vision loss and laryngeal stenosis.\n\n\nOBJECTIVE\nTo characterize the features of patients with MMP seen within an Oral Medicine setting, including clinical features, immunofluorescence results and response to treatment.\n\n\nMETHODS\nA retrospective case note analysis was undertaken. Treatment effect was divided into response and nonresponse using predetermined adjective terms.\n\n\nRESULTS\nIn total, 42 cases of MMP were identified (18 men, 24 women), mean age 65 years (range 36-85 years). Oral involvement was most common on the gingivae (n = 38; 90.5%) while the most common extraoral sites involved were ocular (n = 13; 31.0%) and skin (n = 12; 28.6%). Features of MMP were found in 21 of 34 (61.8%) of routine biopsies, 31 of 34 (91.2%) direct immunofluorescence samples and 8 of 25 (32.0%) indirect immunofluorescence samples. Topical corticosteroids provided effective symptom control in 9 of 42 cases (21.4%), while systemic therapy was used in 31 of 42 patients (73.8%). Dapsone was prescribed for 25 patients, of whom 18 (72.0%) responded. Mycophenolate mofetil was used in 13 cases and had a response rate of 46.2%. Overall, 27 of 42 patients (64.3%) achieved a response using a tolerable topical or systemic treatment.\n\n\nCONCLUSIONS\nThis series demonstrates that MMP has a female predominance and is a disease of older age, with a predilection for specific oral sites. Direct immunofluorescence has a high sensitivity in detecting features of MMP. Although some patients achieve adequate symptom control with topical corticosteroids, many require systemic therapy.",
"affiliations": "Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.;Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.;Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.;Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.;Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.;Department of Oral Medicine, Liverpool University Dental Hospital, Liverpool, UK.",
"authors": "Finn|D J|DJ|;Graham|C|C|;Holt|D J|DJ|;Kelly|R|R|;Rajlawat|B P|BP|;Yesudian|P D|PD|",
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"journal": "Clinical and experimental dermatology",
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"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000287:Administration, Topical; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009059:Mouth Diseases; D009061:Mouth Mucosa; D010390:Pemphigoid, Benign Mucous Membrane",
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"publication_types": "D016428:Journal Article",
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"title": "Management of mucous membrane pemphigoid in a joint oral medicine-dermatology clinic.",
"title_normalized": "management of mucous membrane pemphigoid in a joint oral medicine dermatology clinic"
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"abstract": "Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin.\n\n\n\nTreatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72.\n\n\n\nOverall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms.\n\n\n\nFilibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered.",
"affiliations": "Fundación de Investigación and San Juan Bautista School of Medicine, San Juan, Puerto Rico, USA.;University of British Columbia and Vancouver General Hospital, Vancouver, B.C. Canada.;Service d'Hépatologie, Hôpital Beaujon, Université Paris-Diderot, Clichy, France.;Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer.;Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer.;Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer.;Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer.",
"authors": "Rodriguez-Torres|Maribel|M|;Yoshida|Eric M|EM|;Marcellin|Patrick|P|;Srinivasan|Subasree|S|;Purohit|Vivek S|VS|;Wang|Cunshan|C|;Hammond|Jennifer L|JL|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; C550357:PF 00868554; D011753:Pyrones; D012367:RNA, Viral; D011994:Recombinant Proteins; D014230:Triazoles; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
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"title": "A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV.",
"title_normalized": "a phase 2 study of filibuvir in combination with pegylated ifn alfa and ribavirin for chronic hcv"
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"abstract": "From May 2000 to May 2010, we performed 111 simultaneous pancreas-kidney transplants (SPKT) from cadaveric donors, by using enteric drainage and systemic vascular anastomosis. In 26 cases they showed 6 HLA mismatches. Immunosuppression included antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. The patients' mean age was 34 ± 6 years, and mean time from diabetes diagnosis was 23 ± 6 years; 107 patients had been on dialysis for 32 ± 24 months, and 4 had a preemptive status. Acute rejection episodes were detected in 20 patients (18%): in 3 cases they affected both organs, in 9 only the kidney, and in 8 only the pancreas. The incidence of complications needing reoperation was 28.8%. They were mostly pancreas graft-related, including bleeding, thrombosis, and infection. In more recent years, after a slight modification of surgical technique, we noted a decreased rate of complications. Six patients died from: 2 from cardiovascular or cerebrovascular disease, 3 from infection, and 1 from an unknown cause. Pancreas graft loss occurred in 26 and kidney graft loss in 12 patients. Four patients underwent a second pancreas and 5 a second kidney graft. Patients with surviving grafts showed good function: serum creatinine, 1.09 ± 0.23 mg/dL; fasting blood glucose, 79.7 ± 9.8 mg/dL; and HbA(1c), 4.88 ± 0.47%. Patient, kidney, and pancreas survival results were 96%, 96%, and 83% at 1; 94%, 91%, and 75% at 5; and 94%, 62%, and 69% at 10 years, respectively. These good results, compared with larger series and to recent pancreas transplant registry reports, are a strong motivation for the further development of this unique program in Portugal.",
"affiliations": "Nephrology Department, Hospital Santo António, Porto, Portugal. lasalete@clix.pt",
"authors": "Martins|L|L|;Henriques|A C|AC|;Dias|L|L|;Pedroso|S|S|;Almeida|M|M|;Santos|J|J|;Dores|J|J|;Almeida|R|R|;Cabrita|A|A|;Teixeira|M|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2010.12.035",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "43(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002102:Cadaver; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D016035:Pancreas Transplantation; D011174:Portugal",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "205-8",
"pmc": null,
"pmid": "21335189",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "One hundred eleven simultaneous pancreas-kidney transplantations: 10-year experience from a single center in Portugal.",
"title_normalized": "one hundred eleven simultaneous pancreas kidney transplantations 10 year experience from a single center in portugal"
} | [
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"abstract": "A 55-year-old nurse was referred with a 5-month history of right eye corneal abscess. The initial injury occurred when doing lawn work. The infection worsened despite multiple antibiotic, antiviral, and steroid treatments. Visual acuity was limited to hand motion. On examination, there was keratitis, ocular hypertension, and a secondary cataract. Corneal scrapings grew a filamentous fungus, identified as Metarhizium anisopliae (MA). Despite intensive antifungal treatment with topical, intravitreous, and systemic voriconazole, purulent corneal melting and scleritis with endophthalmitis rapidly appeared. An emergency surgical procedure including sclerocorneal transplantation, cataract surgery, a pars plana vitrectomy using temporary keratoprosthesis, and scleral crosslinking was necessary. One year after the surgery, there was no recurrence of infection. Functional outcome remained very poor. This is the first case of sclerokeratitis and endophthalmitis caused by MA ever reported. The infection was successfully treated with an aggressive combination of medical and surgical treatments.",
"affiliations": "Department of Ophthalmology, Strasbourg University Hospital, FMTS, University of Strasbourg, 67000 Strasbourg, France.;Department of Ophthalmology, Strasbourg University Hospital, FMTS, University of Strasbourg, 67000 Strasbourg, France.;Parasitology and mycology laboratory, Strasbourg University Hospital; Institute of Parasitology and Tropical Diseases, Strasbourg University, 67000 Strasbourg, France.;Department of Ophthalmology, Strasbourg University Hospital, FMTS, University of Strasbourg, 67000 Strasbourg, France.;Parasitology and mycology laboratory, Strasbourg University Hospital; Institute of Parasitology and Tropical Diseases, Strasbourg University, 67000 Strasbourg, France.;Parasitology and mycology laboratory, Strasbourg University Hospital; Institute of Parasitology and Tropical Diseases, Strasbourg University, 67000 Strasbourg, France.;Department of Ophthalmology, Strasbourg University Hospital, FMTS, University of Strasbourg, 67000 Strasbourg, France.",
"authors": "Derhy|Dan|D|;Sauer|Arnaud|A|;Sabou|Marcela|M|;Letsch|Jonathan|J|;Candolfi|Ermanno|E|;Letscher-Bru|Valérie|V|;Bourcier|Tristan|T|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_461_16",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 28643721IJO-65-52310.4103/ijo.IJO_461_16Brief CommunicationsSurgical treatment of Metarhizium anisopliae sclerokeratitis and endophthalmitis Derhy Dan Sauer Arnaud Sabou Marcela 12Letsch Jonathan Candolfi Ermanno 12Letscher-Bru Valérie 12Bourcier Tristan Department of Ophthalmology, Strasbourg University Hospital, FMTS, University of Strasbourg, 67000 Strasbourg, France1 Parasitology and mycology laboratory, Strasbourg University Hospital, 67000 Strasbourg, France2 Institute of Parasitology and Tropical Diseases, Strasbourg University, 67000 Strasbourg, FranceCorrespondence to: Dr. Dan Derhy, Department of Ophthalmology, NHC, Strasbourg University Hospital, BP 426, 67091 Strasbourg, France. E-mail: dan.derhy@chru-strasbourg.fr6 2017 65 6 523 526 30 8 2016 18 5 2017 Copyright: © 2017 Indian Journal of Ophthalmology2017This 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 55-year-old nurse was referred with a 5-month history of right eye corneal abscess. The initial injury occurred when doing lawn work. The infection worsened despite multiple antibiotic, antiviral, and steroid treatments. Visual acuity was limited to hand motion. On examination, there was keratitis, ocular hypertension, and a secondary cataract. Corneal scrapings grew a filamentous fungus, identified as Metarhizium anisopliae (MA). Despite intensive antifungal treatment with topical, intravitreous, and systemic voriconazole, purulent corneal melting and scleritis with endophthalmitis rapidly appeared. An emergency surgical procedure including sclerocorneal transplantation, cataract surgery, a pars plana vitrectomy using temporary keratoprosthesis, and scleral crosslinking was necessary. One year after the surgery, there was no recurrence of infection. Functional outcome remained very poor. This is the first case of sclerokeratitis and endophthalmitis caused by MA ever reported. The infection was successfully treated with an aggressive combination of medical and surgical treatments.\n\nEndophthalmitisfungalkeratitisMetarhizium anisopliaescleritis\n==== Body\nFungal keratitis represents one of the most difficult manifestations of microbial keratitis regarding diagnosis and treatment. Risk factors include compromised corneas, topical steroids, contact lens wear, and surgical and external corneal trauma. More than 70 genera of filamentous fungi and yeast have been identified in fungal keratitis.[1] Progression of fungal keratitis to exogenous endophthalmitis, however, is relatively rare.[2]\n\nMetarhizium anisopliae (MA) is an entomopathogenic ubiquitous fungus found in soil. It can act as a parasite in insects. In humans, it is an uncommon cause of fungal keratitis or sclerokeratitis, with only six cases previously described.[3]\n\nWe report a case of MA sclerokeratitis and subsequent endophthalmitis that was successfully treated with an aggressive combination of medical and surgical treatments.\n\nCase Report\nA 55-year-old female nurse from the Lorraine region in northeastern France was referred with a 5-month history of infectious keratitis and ocular hypertension in the right eye (OD). Despite many topical (ciprofloxacin, rifamycin, dexamethasone, and hexamidine) and systemic (valacyclovir) treatments, there was no significant improvement. Corneal scraping initially performed was negative. The patient did not wear contact lenses. She mentioned a vegetal foreign body in her OD after mowing the lawn before the beginning of the infection. Medical history was unremarkable.\n\nShe presented with significant ocular pain and redness in the OD. Visual acuity was limited to hand motions OD and 20/20 left eye. Slit-lamp examination revealed a large central epithelial defect with an underlying deep white 6 mm × 7 mm central suppurative stromal infiltrate, keratic precipitates, and posterior synechiae. Intraocular pressure was 40 mmHg. Corneal scraping of the infiltrate was performed. No bacteria were isolated. Polymerase chain reaction for herpes viruses and Acanthamoeba was negative. After 8 days, two colonies of a fungus appeared on 2% malt extract medium at 27°C [Fig. 1]. The fungus was later identified by double-strand sequencing of the internal transcribed spacer (ITS1 and ITS4 primers) of the ribosomal DNA as MA. Susceptibility testing showed resistance to amphotericin B, itraconazole, and posaconazole, but susceptibility to voriconazole and caspofungin. Topical voriconazole (every hour) and oral voriconazole (200 mg b.i.d) treatment was started. As B-scan ultrasonography showed mild vitritis, two intravitreal injections of voriconazole (100 μg/0.1 ml) were administered 6 days apart. Despite these treatments, the abscess worsened, and purulent corneal melting involving sclera, with massive inflammation in a shallow anterior chamber, and a secondary cataract appeared [Fig. 2]. Visual acuity in the OD was reduced to light perception. A diagnosis of MA endophthalmitis and sclerokeratitis was made. To avoid evisceration, an emergency surgical procedure was performed. The procedure started with an 8-mm trephination of the central cornea. Button and fibrin deposits were then removed from the anterior chamber and iridocorneal angle. Open-sky phacoemulsification and intraocular lens implantation were performed. A temporary Eckardt's keratoprosthesis was then sutured to the recipient cornea, allowing a 25-gauge pars plana vitrectomy to be performed [Fig. 3]. Retinal hemorrhaging and optic nerve atrophy were observed intraoperatively.\n\nFigure 1 (a) Metarhizium anisopliae: Culture grown on 2% malt extract medium at 27°C for 2 weeks. (b) Metarhizium anisopliae: Conidiophores with verticillate branching and cylindrical conidia. Lactophenol cotton blue stain, ×400\n\nFigure 2 Preoperative slit-lamp photography of the right eye showing conjunctival hyperemia, corneal melting involving sclera with massive inflammation in a shallow anterior chamber\n\nFigure 3 Pars plana vitrectomy was performed through the optic of Eckardt's keratoprosthesis. Retinal hemorrhaging and optic nerve atrophy were observed intraoperatively\n\nAfter keratoprosthesis removal, a conjunctival peritomy was performed, and corneal trephination was manually enlarged to a diameter of 13 mm to remove the infected peripheral cornea and adjacent scleral tissues. A 14 mm sclerocorneal graft was manually prepared and sutured with 24 interrupted stitches of 10/0 nylon. At the end of the procedure, a scleral crosslinking was performed (10 mW/cm2 ultraviolet A [UVA] lamp and riboflavin, Horus, Saint-Laurent du Var, France) on the donor–recipient junction. Procedure time was 2 h and 45 min. Pathologic examination of the excised cornea showed the presence of septate hyphae. Postoperative medications included topical and oral voriconazole, oral acetazolamide, and topical cyclosporine 2% t.i.d. Topical dexamethasone was started 2 months after surgery. Antifungal treatment was discontinued after 4 months due to elevated liver enzymes.\n\nOne year after the surgery, there was no recurrence of the infection [Fig. 4]. However, the sclerocorneal graft was rejected after 6 months, and persistent ocular hypertension required diode laser cyclophotocoagulation. Visual acuity was reduced to light perception.\n\nFigure 4 Slit-lamp photograph of the right eye 1 year after surgery revealing graft edema, mydriasis, but no sign of inflammation or infection\n\nDiscussion\nMA is a fungus first described under the name Entomophthora anisoplia as a pathogen of the wheat cockchafer. It is an uncommon cause of cutaneous necrosis, chronic sinusitis, disseminated infection, and there were six published cases of keratitis or sclerokeratitis worldwide (Colombia, the USA, Australia, Japan, and France).[3456] Three cases of keratitis were cured by topical natamycin eye drops alone or in combination with silver sulfadiazine 1% soluble cream,[4] bacitracin, and ciprofloxacin,[5] while the three other patients had sclerokeratitis. They were initially treated medically, but then underwent a therapeutic corneal graft.[36] Visual prognosis was poor for all cases, and we confirm that functional outcome is poor with this first case of sclerokeratitis and subsequent endophthalmitis. This may be due to retinal damage caused by inflammation and infection or might also be attributed to prolonged secondary glaucoma and subsequent optic neuropathy.\n\nThe main triggering incident found in our patient was the initial corneal trauma after lawn work. Apart from the history of trauma with vegetative matter, excessive usage of antibiotics and antivirals in combination with topical steroids might well have contributed to the destruction of local microflora, reduction in local immunity, and to epithelial toxicity, all of which might have predisposed to fungal infection.\n\nThe patient was treated with topical, intravitreal, and systemic voriconazole, the only molecule that was shown to be efficient on the isolate. Natamycin was not tested in our case. As the corneal infection progressed to the sclera and posterior segment, an emergency surgical intervention was decided. The procedure combined five steps: sclerocorneal allograft, cataract extraction, intraocular lens implantation, pars plana vitrectomy through temporary keratoprosthesis, and scleral crosslinking. As in previous cases, surgery was a decisive step in the management of the infection. It is now admitted that therapeutic keratoplasty or sclerokeratoplasty has a definitive role in the management of progressive microbial keratitis refractory to medical therapy.[2] The primary aim of the procedure is to eliminate infected tissues, especially when infection progresses to the peripheral cornea, limbus, and anterior sclera. The diameter of the trepanation was chosen to leave a 1-mm infection-free scleral margin. Riboflavin/UVA corneal collagen crosslinking has already been shown experimentally and clinically to be an interesting adjuvant treatment of advanced nonresponsive microbial keratitis.[7] Recently, collagen crosslinking of the sclera has been shown to increase the biomechanical strength of rabbit sclera without side effects on the retina or retinal pigment epithelium.[8] This new crosslinking method is considered to be a possible sclera-based treatment for progressive myopia. We suggest that scleral crosslinking could also be useful in the management of infectious scleritis. Experimental investigations are needed to confirm the anti-infectious and anti-inflammatory properties of the procedure in the scleral tissue. Finally, we were able to use Eckardt's temporary keratoprosthesis, a reusable device, which provided a clear view and watertight eye after corneal trephination. Its large optical diameter allowed the visualization of the peripheral fundus.\n\nConclusion\nThis is the first case of sclerokeratitis and endophthalmitis caused by MA ever reported. The patient's infection was successfully treated by an aggressive combination of medical and surgical treatments.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Thomas PA Fungal infections of the cornea Eye (Lond) 2003 17 852 62 14631389 \n2 Wang MX Shen DJ Liu JC Pflugfelder SC Alfonso EC Forster RK Recurrent fungal keratitis and endophthalmitis Cornea 2000 19 558 60 10928778 \n3 Eguchi H Toibana T Hotta F Miyamoto T Mitamura Y Yaguchi T Severe fungal sclerokeratitis caused by Metarhizium anisopliae : A case report and literature review Mycoses 2015 58 88 92 25590990 \n4 De García MC Arboleda ML Barraquer F Grose E Fungal keratitis caused by Metarhizium anisopliae var. anisopliae J Med Vet Mycol 1997 35 361 3 9402530 \n5 Jani BR Rinaldi MG Reinhart WJ An unusual case of fungal keratitis: Metarhizium anisopliae Cornea 2001 20 765 8 11588434 \n6 Dorin J Debourgogne A Zaïdi M Bazard MC Machouart M First unusual case of keratitis in Europe due to the rare fungus Metarhizium anisopliae Int J Med Microbiol 2015 305 408 12 25813244 \n7 Vajpayee RB Shafi SN Maharana PK Sharma N Jhanji V Evaluation of corneal collagen cross-linking as an additional therapy in mycotic keratitis Clin Exp Ophthalmol 2015 43 103 7 25070527 \n8 Wollensak G Iomdina E Long-term biomechanical properties of rabbit sclera after collagen crosslinking using riboflavin and ultraviolet A (UVA) Acta Ophthalmol 2009 87 193 8 18803623\n\n",
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"issue": "65(6)",
"journal": "Indian journal of ophthalmology",
"keywords": null,
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D003315:Cornea; D003316:Corneal Diseases; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D007634:Keratitis; D052981:Metarhizium; D008875:Middle Aged; D013508:Ophthalmologic Surgical Procedures; D015423:Scleritis; D014792:Visual Acuity",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "523-526",
"pmc": null,
"pmid": "28643721",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25070527;11588434;18803623;10928778;14631389;25813244;9402530;25590990",
"title": "Surgical treatment of Metarhizium anisopliae sclerokeratitis and endophthalmitis.",
"title_normalized": "surgical treatment of metarhizium anisopliae sclerokeratitis and endophthalmitis"
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"abstract": "Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.\n\n\n\nFrom May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.\n\n\n\nAmong 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months.\n\n\n\nThe value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.\n\n\n\nThis retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.",
"affiliations": "Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy silvia.stacchiotti@istitutotumori.mi.it.;Cancer Medicine, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.;Cancer Medicine, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.;Medical Oncology, University Campus Bio-Medico, Rome, Italy.;N.N. Blokhin Russian Cancer Research, Moscow, Russian Federation.;Monter Cancer Center, Northwell Health, Lake Success, New York, USA.;Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.;Cancer Medicine, Centre Léon Bérard, Lyon, France.;Cancer Medicine, Centre Léon Bérard, Lyon, France.;Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Medical Oncology, Biomedicine Research Institute (IBIS), University Hospital Virgen del Rocio, Sevilla, Spain.;Department of Medical Oncology, Biomedicine Research Institute (IBIS), University Hospital Virgen del Rocio, Sevilla, Spain.;Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.;Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.;Institut Bergonié, Bordeaux, France.;Service d'Oncologie Médicale Chu la Timone, Marseille, France.;Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center, Tokyo, Japan.;Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center, Tokyo, Japan.",
"authors": "Stacchiotti|Silvia|S|;Mir|Olivier|O|;Le Cesne|Axel|A|;Vincenzi|Bruno|B|;Fedenko|Alexander|A|;Maki|Robert G|RG|;Somaiah|Neeta|N|;Patel|Shreyaskumar|S|;Brahmi|Mehedi|M|;Blay|Jean Y|JY|;Boye|Kjetil|K|;Sundby Hall|Kirsten|K|;Gelderblom|Hans|H|;Hindi|Nadia|N|;Martin-Broto|Javier|J|;Kosela|Hanna|H|;Rutkowski|Piotr|P|;Italiano|Antoine|A|;Duffaud|Florence|F|;Kobayashi|Eisuke|E|;Casali|Paolo G|PG|;Provenzano|Salvatore|S|;Kawai|Akira|A|",
"chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000077606:Trabectedin",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(1)",
"journal": "The oncologist",
"keywords": "Alveolar soft part sarcoma; Chemotherapy; Pazopanib; Sarcoma; Trabectedin",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011743:Pyrimidines; D012189:Retrospective Studies; D018234:Sarcoma, Alveolar Soft Part; D013449:Sulfonamides; D015996:Survival Rate; D000077606:Trabectedin",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "62-70",
"pmc": null,
"pmid": "28754721",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "19652065;20456972;22868503;22595799;24714778;27716285;19188185;19451427;25453902;17327610;21242589;20593242;25795406;26371143;19097774;11244503;12855256;23630200;23410977;12837977;26970174;22749255;23894721;24074204;27792052;26666647",
"title": "Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma.",
"title_normalized": "activity of pazopanib and trabectedin in advanced alveolar soft part sarcoma"
} | [
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"abstract": "Human adenovirus type 34 (HAdV-34) infection is a recognized cause of transplant-associated hemorrhagic cystitis and, in rare cases, tubulointerstitial nephritis. The source of such infections is often difficult to assess, that is, whether acquired as a primary infection, exposure to a pathogen in the transplanted organ, or reactivation of an endogenous latent infection. We present here 2 cases of likely transplant-acquired HAdV-34 infection from the same organ donor, manifesting as tubulointerstitial nephritis in 1.",
"affiliations": "University of Rochester Medical Center, Rochester, New York.;University of Rochester Medical Center, Rochester, New York.;University of Rochester Medical Center, Rochester, New York.;University of Rochester Medical Center, Rochester, New York.;University of Rochester Medical Center, Rochester, New York.;University of Rochester Medical Center, Rochester, New York.;Wadsworth Center, New York State Department of Health, Albany, New York.;US Centers for Disease Control and Prevention, Atlanta, Georgia.;US Centers for Disease Control and Prevention, Atlanta, Georgia.;University of Rochester Medical Center, Rochester, New York.",
"authors": "Pettengill|Matthew A|MA|;Babu|Tara M|TM|;Prasad|Paritosh|P|;Chuang|Sally|S|;Drage|Michael G|MG|;Menegus|Marilyn|M|;Lamson|Daryl M|DM|;Lu|Xiaoyan|X|;Erdman|Dean|D|;Pecora|Nicole|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofy354",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n30882008\n10.1093/ofid/ofy354\nofy354\nBrief Report\nProbable Donor-Derived Human Adenovirus Type 34 Infection in 2 Kidney Transplant Recipients From the Same Donor\nPettengill Matthew A 12 Babu Tara M 1 Prasad Paritosh 1 Chuang Sally 1 Drage Michael G 1 Menegus Marilyn 1 Lamson Daryl M 3 Lu Xiaoyan 4 Erdman Dean 4 Pecora Nicole 1 1 \nUniversity of Rochester Medical Center, Rochester, New York\n\n2 \nThomas Jefferson University, Philadelphia, Pennsylvania\n\n3 \nWadsworth Center, New York State Department of Health, Albany, New York\n\n4 \nUS Centers for Disease Control and Prevention, Atlanta, Georgia\n\nCorrespondence: N. Pecora, MD, PhD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642 (nicole_pecora@urmc.rochester.edu).Deceased\n\n\n3 2019 \n26 12 2018 \n26 12 2018 \n6 3 ofy35418 9 2018 21 12 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This 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.comAbstract\nHuman adenovirus type 34 (HAdV-34) infection is a recognized cause of transplant-associated hemorrhagic cystitis and, in rare cases, tubulointerstitial nephritis. The source of such infections is often difficult to assess, that is, whether acquired as a primary infection, exposure to a pathogen in the transplanted organ, or reactivation of an endogenous latent infection. We present here 2 cases of likely transplant-acquired HAdV-34 infection from the same organ donor, manifesting as tubulointerstitial nephritis in 1.\n\nadenovirusHAdV-34kidney transplanttubulointerstitial nephritisHealth Research Incorporated\n==== Body\nTransplant recipients and other immunocompromised patients are particularly susceptible to severe disease or death due to infection with human adenoviruses (HAdVs), which can affect almost any organ system [1–3]. In stem cell transplant patients, severe lymphopenia is associated with disseminated HAdV infection [3, 4]. Kidney transplant recipients may develop serious infections, commonly manifesting as hemorrhagic cystitis, though tubulointerstitial nephritis has rarely been reported [5–9]. Patients develop clinical disease 1 to 3 months after transplant [10]. The most common types of HAdV associated with serious renal infections are from species B (types 7, 11, 34, and 35) [1, 4, 8, 11, 12]. Although establishing an etiology of these infections is difficult, their propensity to occur not long after the time of transplant and to affect the kidneys and urinary tract has raised the possibility of a donor-derived infection. This report describes clinical and laboratory findings from a donor and 2 kidney transplant recipients who evidenced transmission of infection with HAdV-34 after transplantation.\n\nDONOR\nThe donor was a 31-year-old male with a history of a seizure disorder who presented to an outside hospital after a seizure and head trauma complicated by cardiac and respiratory arrest. No respiratory illness was noted; however, a computed tomography (CT) head scan did demonstrate mucosal thickening in the ethmoid sinuses and air fluid levels in the sphenoid sinuses, which could suggest recent viral infection. Chest x-ray (CXR) on admission noted patchy opacity in the right upper lobe; this was improved on repeat CXR on hospital day 2, and CT of the chest on hospital day 5 demonstrated only atelectasis. His kidneys were transplanted into 2 patients in 1 medical center reported on here. The heart, lungs, and liver were all available from this donor for transplant. The liver was rejected on biopsy for unknown reasons. The heart and lungs were transplanted at other medical centers and, at the date of writing, recipient patients were doing well without evidence of adenovirus infection. Note that, to the best of our knowledge, serologic tests have not been performed on these patients. In addition, the center that transplanted this donor’s lungs routinely screens for adenovirus species B/E and C when they perform pre- and post-transplant bronchoscopies (3 of the latter) as part of their routine care (HAdV-34 is a serotype of adenovirus B). No specimens tested positive for adenovirus. Both centers (heart and lungs) were notified of the potential adenovirus transmission and continue to monitor those patients.\n\nPATIENT 1\nPatient 1 was a 36-year-old male with end-stage renal disease due to sclerosing glomerulonephritis, for which he underwent an uncomplicated deceased donor kidney transplant (donor CMV IgG negative, recipient CMV IgG positive). He received antithymocyte globulin induction. One month after his transplant, he presented to the hospital with 3 days of allograft tenderness, hematuria, fever, dysuria, and urinary retention. At that time, he was on valganciclovir, trimethoprim/sulfamethoxazole, and fluconazole prophylaxis. His immunosuppressive regimen consisted of tacrolimus 6 mg daily, mycophenolate mofetil 1000 mg twice daily, and prednisone 20 mg daily.\n\nOn admission, the patient had a low-grade fever and was hemodynamically stable. His physical exam demonstrated significant tenderness to palpation over his allograft. Admission laboratory values revealed a white blood cell count (WBC) of 5.9 THOU/uL with lymphopenia, a hemoglobin (Hgb) of 10.7 g/dL, and a platelet count of 166 THOU/uL. His creatinine (Cr) was elevated at 1.69 mg/dL (1.15 mg/dL 1 month prior, the lowest since transplant). His liver function tests were normal. Urine studies showed 660 red blood cells (RBCs) and 61 WBCs. Computerized tomography abdominal imaging on admission showed perinephric stranding consistent with allograft pyelonephritis.\n\nThe patient was started on empiric antibiotic therapy for presumed bacterial allograft pyelonephritis while the microbiologic testing was pending. He initially improved; however, on day 3 of hospitalization, he had worsening allograft tenderness and high-grade fevers up to 40°C. Repeat CT abdominal imaging showed progressive perinephric stranding and allograft edema. Urine and blood cultures were negative. Serum was submitted for quantitative HAdV nucleic acid testing (~5 weeks post-transplantation), which was positive at a level of 6 × 106 HAdV genome copies/mL. HAdV molecular typing was performed by polymerase chain reaction (PCR) amplification and sequence analysis of a partial region of the HAdV hexon gene and was determined to be HAdV-34 (nucleotide sequence similarity score = 99% compared with reference sequence KF268196) [13].\n\nCore biopsy of the allograft kidney revealed sharply demarcated zones of tubular necrosis in a pauci-inflammatory background. High-powered examination revealed residual tubular epithelium with textureless “smudge” chromatin and intraluminal necrotic debris. The histologic findings were characteristic of HAdV infection and were confirmed by immunohistochemistry (Figure 1A and B). The patient was treated with cidofovir (dosed at 1 mg/kg 3 times per week) and probenecid, and immunosuppression was concurrently decreased. With treatment, the adenovirus viremia cleared up in 29 days (Table 1). Cidofovir therapy was well tolerated for 5 weeks and was stopped when his viral load became undetectable. His Cr at treatment completion was 1.5 mg/dL, and no protein was isolated from his urine. The patient had rapid resolution of his symptoms and improvement in renal function.\n\nFigure 1. Patient 1 kidney biopsy sections stained with hematoxylin and eosin (A) or adenovirus immunohistochemistry (B).\n\nTable 1. Human Adenovirus PCR and Serum Neutralization Test Results of Transplant Donor and Recipients\n\n\tDonor\tRecipient (Patient 1)a\tRecipient (Patient 2)\t\nTime Frame\tHAdV PCR, GC/mL\tHAdV-34 Nt, Titer\tHAdV PCR, GC/mL\tHAdV-34 Nt, Titer\tHAdV PCR, GC/mL\tHAdV-34 Nt, Titer\t\nPretransplant \tNeg\tPos (320)\tN/A\tNeg (<10)\tN/A\tNeg (<10)\t\nPost-transplant\t\nWeek 1 \tN/A\tN/A\tNeg\tN/A\tN/A\tN/A\t\nWeek 2\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\nWeek 3\tN/A\tN/A\tPos (4.3×104)\tN/A\tN/A\tN/A\t\nWeek 4\tN/A\tN/A\tPos (2.8×105)\tPos (160)\tN/A\tN/A\t\nWeek 5\tN/A\tN/A\tPos (6.0×106)\tN/A\tN/A\tN/A\t\nWeek 6 \tN/A\tN/A\tPos (4.6×106)\tN/A\tN/A\tN/A\t\nWeek 7\tN/A\tN/A\tPos (7.6×103)\tPos (640)\tN/A\tN/A\t\nWeek 8\tN/A\tN/A\tPos (2.8×103)\tN/A\tN/A\tPos (80)\t\nWeek 9\tN/A\tN/A\tPos (236)\tPos (1280)\tN/A\tN/A\t\nWeek 10\tN/A\tN/A\tNeg\tN/A\tN/A\tN/A\t\nWeek 11\tN/A\tN/A\tNeg\tN/A\tN/A\tN/A\t\nWeek 12\tN/A\tN/A\tN/A\tN/A\tNeg\tN/A\t\nAbbreviations: GC/mL, genome copies per milliliter; N/A, not available; Neg, negative; Nt, serum neutralization titer; Pos, positive.\n\n\naTransplant recipient 1 was symptomatic during weeks 5–7 and received cidofovir treatment during weeks 7–10. \n\nPATIENT 2\nThe recipient of the donor’s other kidney was a 40-year-old male with end-stage renal disease secondary to type 1 diabetes mellitus. He received basiliximab induction (CMV IgG donor negative, CMV IgG recipient negative). His clinical course was complicated by grade 1A cellular rejection, for which he received antithymocyte globulin therapy. He presented to the hospital 3 months after transplantation with 2 days of fever, chills, and malaise. On admission, he was on acyclovir, dapsone, and fluconazole prophylaxis. His immunosuppression at that time included tacrolimus 5 mg daily, mycophenolate mofetil 750 mg twice daily, and prednisone 10 mg daily.\n\nOn admission, the patient had fever, rigors, and tachycardia. His physical exam was unremarkable. Admission laboratory tests revealed a WBC of 11.7 THOU/uL with 22% bandemia, a Hgb of 7.1 g/dL, and a platelet count of 249 THOU/uL. His Cr was elevated from baseline to 1.99 mg/dL. His liver function tests were normal. Urine studies showed 9 WBCs and <1 RBC. Blood cultures and urine culture were positive for Escherichia coli. He improved with targeted antibiotic therapy for urosepsis and concurrent decrease in immunosuppression. Given the known history of Patient 1, a serum specimen from Patient 2 was submitted to a commercial laboratory for HAdV nucleic acid testing, which was negative.\n\nHADV SERUM NEUTRALIZATION TEST RESULTS\nUsing pre- and post-transplant serum specimens, it was possible to evaluate the timing of Patient 1’s exposure to HAdV-34. Serum HAdV-34–neutralizing antibodies were measured against the HAdV-34 prototype strain Compton using a laboratory-developed test based on a standard serum neutralization protocol [14] that had been modified for this study to use another cell type (A549). Neutralizing antibodies were considered positive with titers of 10 or greater. Serum from Patient 1 was negative for neutralizing antibodies both 6 months and 1 day before transplant (Table 1). However, by 4 weeks after transplant, he seroconverted to HAdV-34, consistent with the PCR findings and indicating that his HAdV-34 infection occurred at the time of transplant, either through the donated kidney or as a de novo infection.\n\nAs serum was available from both the donor and the second kidney recipient pre- and post-transplant, it was possible to differentiate between these possibilities. Donor serum collected 1 day before transplant was positive for neutralizing antibodies (titer 320) to HAdV-34, indicating prior HAdV-34 infection. Serum collected 1 day before transplant from Patient 2 was seronegative. However, a serum specimen from Patient 2 collected 8 weeks after transplant was positive, indicating seroconversion to HAdV-34 (Table 1). These findings indicate that both Patient 1 and Patient 2 were infected with HAdV-34 either at the time of transplant via a donor organ–derived infection or shortly thereafter (independently, as a de novo infection). Serum from the donor was submitted for quantitative HAdV nucleic acid testing but was negative, indicating that the donor was not HAdV viremic at the time of organ harvest, although latent infection and viremia below the limit of detection could not be ruled out. Tissue was not available to assess the presence of virus in the transplanted organs.\n\nDISCUSSION\nHAdV-34 was first isolated in 1972 from a 17-year-old male patient who developed fever after receiving a kidney transplant [15]. Multiple reports followed of systemic HAdV-34 infections among renal transplant recipients and other immunocompromised patients [8, 16, 17], as well as rare reports of acute conjunctivitis [18, 19] in immunocompetent persons. To our knowledge, there are no reports that directly document HAdV latency in the kidneys. Latency has been documented in lymphatic tissues of the oro-gastrointestinal tract for other hAdV types, and hAdV-34 infection with persistent shedding in the urine of recipients of kidney transplants has has been widely documented. Case reports of hAdV-34 infection in patients receiving donor kidneys have led to speculation that the virus was latent in donor kidneys, becoming active in the recipient as a consequence of immunological impairment. In preparation for organ transplantation, donors are tested for a variety of infectious diseases (such as hepatitis B, hepatitis C, and HIV) that could be transmitted to recipients. However, HAdV testing is not required by the Organ Procurement and Transplantation Network (OPTN) [20]. The source of an HAdV infection in a transplant patient can be difficult to determine, and de novo infection or reactivation of latent disease may be the most likely explanations. In this instance, 1 of the 2 kidney recipients (Patient 1) had disease suggestive of HAdV infection within a few weeks after transplantation, which prompted testing that confirmed HAdV tubulointerstitial nephritis and disseminated viremia. The United Network for Organ Sharing (UNOS) was contacted, and the health status of the other 2 recipients was ascertained from the respective transplant centers. In addition to the kidneys, the donor heart and lungs were also transplanted to separate patients, neither of whom developed symptomatic HAdV-related disease or required HAdV diagnostic testing. The confirmed adenovirus infection in the first patient was reported to the OPTN at the time it was diagnosed. The second kidney recipient at our institution did not have symptoms specifically suggestive of HAdV infection but was tested for HAdV due to the known positive results of Patient 1. Retrospective testing found that the deceased organ donor had serological evidence of prior exposure to HAdV-34.\n\nAs both kidney recipients were initially seronegative for HAdV-34 before transplant and then seroconverted a few weeks later, a possible route of HAdV-34 transmission was from the donor to both organ recipients. As the absence of specimens positive for HAdV from both the donor and Patient 2 makes it impossible to strengthen the connection with sequencing data, it does remain possible that both recipients contracted HAdV-34 infection independent from the environment. Although to our knowledge there are limited data available on hAdV-34 seroprevelance, seropositivity to hAdV-35, a closely related virus that shows a similar clinical/epidemiological profile to hAdV-34, was found to be uncommon in an international study [21]. At least 1 epidemiological survey has indicated that HAdV-34 is uncommon in the general population [22], making the possibility of acquisition from the environment somewhat less likely. The kidney recipient patients did not share a room during their hospital stay, but they were seen at separate times by some common health care providers. No other cases of HAdV disease were diagnosed in other patients in the hospital wards occupied by the kidney transplant patients described here in the 6 months preceding or in the 6 months after their hospital stay. Interestingly, the clinical courses of the 2 patients were quite different, which may reflect differences in infectious doses from each kidney or differences in host resistance to infection. It is also possible that differing cross-protection from prior infections with other adenovirus serotypes could have contributed to the difference in clinical courses between recipients, but this is poorly understood for adenoviruses.\n\nAlthough donor-derived HAdV infections are rare, testing for HAdV should be considered in transplant recipients with culture-negative pyelonephritis and those who demonstrate hemorrhagic cystitis or tubulointerstitial nephritis within a few months of transplant.\n\nAcknowledgments\nThe authors would like to acknowledge the Wadsworth Center’s Applied Genomics Technologies Core for performing the dideoxy sequencing and Eileen Schneider (Centers for Disease Control and Prevention) for helpful discussion and feedback.\n\n\nAuthor contributions. Marilyn Menegus initiated this study, and all authors agree that she met the definition of authorship. Marilyn passed away on March 20, 2017, and to the best of our knowledge, she did not have any conflicts of interest related to this work, but due to her passing before the study completion, a conflict of interest (COI) form for Marilyn is not available. Marilyn was a remarkable and productive educator, mentor, and scientist with a special interest in clinical virology.\n\n\nDisclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.\n\n\nFinancial support. Nicole Pecora is supported by funding through the Emerging Infections Program, sponsored by Health Research Incorporated. No other authors have funding to disclose.\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nHierholzer JC \nAdenoviruses in the immunocompromised host\n. Clin Microbiol Rev 1992 ; 5 :262 –74\n.1323383 \n2. \nIson MG \nAdenovirus infections in transplant recipients\n. Clin Infect Dis 2006 ; 43 :331 –9\n.16804849 \n3. \nLion T \nAdenovirus infections in immunocompetent and immunocompromised patients\n. Clin Microbiol Rev 2014 ; 27 :441 –62\n.24982316 \n4. \nChakrabarti S , Mautner V , Osman H , et al. \nAdenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery\n. Blood 2002 ; 100 :1619 –27\n.12176880 \n5. \nBarraclough K , Oliver K , Playford EG , et al. \nLife-threatening adenovirus infection in a kidney transplant recipient\n. NDT Plus 2009 ; 2 :250 –3\n.25984003 \n6. \nKim SS , Hicks J , Goldstein SL \nAdenovirus pyelonephritis in a pediatric renal transplant patient\n. Pediatr Nephrol 2003 ; 18 :457 –61\n.12736808 \n7. \nTomoe H , Onitsuka S , Nishino S , et al. \nAdenovirus-induced kidney graft pyelonephritis following renal transplantation\n. Hinyokika Kiyo 1994 ; 40 :1005 –8\n.7832071 \n8. \nKeller EW , Rubin RH , Black PH , et al. \nIsolation of adenovirus type 34 from a renal transplant recipient with interstitial pneumonia\n. Transplantation 1977 ; 23 :188 –91\n.189468 \n9. \nDawood US , Nelson A , Wu D , et al. \nDisseminated adenovirus infection in kidney transplant recipient\n. Nephrology (Carlton) 2014 ; 19 (Suppl 1 ):10 –3\n.24460584 \n10. \nWatcharananan SP , Avery R , Ingsathit A , et al. \nAdenovirus disease after kidney transplantation: course of infection and outcome in relation to blood viral load and immune recovery\n. Am J Transplant 2011 ; 11 :1308 –14\n.21449944 \n11. \nFlorescu MC , Miles CD , Florescu DF \nWhat do we know about adenovirus in renal transplantation?\nNephrol Dial Transplant 2013 ; 28 :2003 –10\n.23493328 \n12. \nRady K , Walters G , Brown M , Talaulikar G \nAllograft adenovirus nephritis\n. Clin Kidney J 2014 ; 7 :289 –92\n.25852891 \n13. \nOkada M , Ogawa T , Kubonoya H , et al. \nDetection and sequence-based typing of human adenoviruses using sensitive universal primer sets for the hexon gene\n. Arch Virol 2007 ; 152 :1 –9\n.16957827 \n14. \nHierholzer JC , Bingham PG \nVero microcultures for adenovirus neutralization tests\n. J Clin Microbiol 1978 ; 7 :499 –506\n.670375 \n15. \nHierholzer JC , Atuk NO , Gwaltney JM Jr \nNew human adenovirus isolated from a renal transplant recipient: description and characterization of candiate adenovirus type 34\n. J Clin Microbiol 1975 ; 1 :366 –76\n.170313 \n16. \nMori T , Aisa Y , Shimizu T , et al. \nHemorrhagic cystitis caused by adenovirus type 34 after allogeneic bone marrow transplantation\n. Transplantation 2005 ; 79 :624 .15753860 \n17. \nde Jong PJ , Valderrama G , Spigland I , Horwitz MS \nAdenovirus isolates from urine of patients with acquired immunodeficiency syndrome\n. Lancet 1983 ; 1 :1293 –6\n.6134092 \n18. \nUchio E , Matsuura N , Takeuchi S , et al. \nAcute follicular conjunctivitis caused by adenovirus type 34\n. Am J Ophthalmol 1999 ; 128 :680 –6\n.10612502 \n19. \nSaitoh-Inagawa W , Tanaka K , Uchio E , et al. \nGenome typing of adenovirus type 34 isolated in two cases of conjunctivitis in Sapporo, Japan\n. J Clin Microbiol 2001 ; 39 :4187 –9\n.11682557 \n20. \nFischer SA , Avery RK ; AST Infectious Disease Community of Practice \nScreening of donor and recipient prior to solid organ transplantation\n. Am J Transplant 2009 ; 9 (Suppl 4 ):S7 –18\n.20070698 \n21. \nBarouch DH , Kik SV , Weverling GJ , et al. \nInternational seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations\n. Vaccine 2011 ; 29 :5203 –9\n.21619905 \n22. \nGray GC , McCarthy T , Lebeck MG , et al. \nGenotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004–2006\n. Clin Infect Dis 2007 ; 45 :1120 –31\n.17918073\n\n",
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"issue": "6(3)",
"journal": "Open forum infectious diseases",
"keywords": "HAdV-34; adenovirus; kidney transplant; tubulointerstitial nephritis",
"medline_ta": "Open Forum Infect Dis",
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"references": "10612502;11682557;12176880;12736808;1323383;15753860;16804849;16957827;170313;17918073;189468;20070698;21449944;21619905;23493328;24460584;24982316;25852891;25984003;6134092;670375;7832071",
"title": "Probable Donor-Derived Human Adenovirus Type 34 Infection in 2 Kidney Transplant Recipients From the Same Donor.",
"title_normalized": "probable donor derived human adenovirus type 34 infection in 2 kidney transplant recipients from the same donor"
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"abstract": "Retinal pigment epithelial (RPE) tear has been described to occur spontaneously, after laser photocoagulation and in recent times, after intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents. In the latter case, the rapid contraction of the choroidal vascular membrane underneath a serous RPE detachment is believed to be the underlying cause. Preservation of good visual acuity after the occurrence of RPE tear with continued use of intravitreal VEGF agents has been reported. In this case report, we describe the occurrence of multiple RPE tears with the use of intravitreal bevacizumab and also correlate the preservation of visual acuity with features seen on spectral domain optical coherence tomography.",
"affiliations": "Department of Ophthalmology, University of Florida-College of Medicine, Jacksonville, FL, USA. kchalam@jax.ufl.edu",
"authors": "Chalam|Kakarla V|KV|;Murthy|Ravi K|RK|;Gupta|Shailesh K|SK|;Brar|Vikram S|VS|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
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"fulltext": "\n==== Front\nIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications India IJO-59-472115707210.4103/0301-4738.73712Brief CommunicationsSpectral domain optical coherence tomography features of multiple subfoveal retinal pigment epithelial tears after intravitreal bevacizumab Chalam Kakarla V Murthy Ravi K Gupta Shailesh K Brar Vikram S Department of Ophthalmology, University of Florida-College of Medicine, Jacksonville, FloridaCorrespondence to: Dr. K. V. Chalam, Department of Ophthalmology, University of Florida, Jacksonville, 580 West Eighth St, Jacksonville, FL-322 09. E-mail: kchalam@jax.ufl.eduJan-Feb 2011 59 1 47 48 06 1 2009 02 7 2009 © Indian Journal of Ophthalmology2011This 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.Retinal pigment epithelial (RPE) tear has been described to occur spontaneously, after laser photocoagulation and in recent times, after intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents. In the latter case, the rapid contraction of the choroidal vascular membrane underneath a serous RPE detachment is believed to be the underlying cause. Preservation of good visual acuity after the occurrence of RPE tear with continued use of intravitreal VEGF agents has been reported. In this case report, we describe the occurrence of multiple RPE tears with the use of intravitreal bevacizumab and also correlate the preservation of visual acuity with features seen on spectral domain optical coherence tomography.\n\nBevacizumabretinal pigment epithelial tearspectral domain optical coherence tomography\n==== Body\nRetinal pigment epithelial (RPE) tear is an infrequent complication of pigment epithelial detachment in the elderly, and occurs either spontaneously or after laser photocoagulation.[12] Recently, RPE tears have been described after intravitreal bevacizumab injection, due to rapid contraction of the underlying choroidal neovascular membrane (CNVM).[3] The diagnosis is based on typical clinical appearance and fundus fluorescein angiography.[23] Retracted RPE after the rip generates increased reflectivity on low-resolution optical coherence tomography (OCT).[4]\n\nSpectral-domain OCT (SD-OCT), a novel imaging technology provides high-resolution cross-sectional images of the retina with high point to point correlation with the fundus picture.[5] We describe SD-OCT features in a patient who developed multiple RPE tears after intravitreal bevacizumab injection.\n\nCase Report\nA 70-year-old female with clinical features of advanced exudative age-related macular degeneration presented with bilateral decreased vision. Her best-corrected visual acuities were 20/400 and 20/30 in the right and left eye, respectively. Fundus evaluation revealed a disciform scar involving the macula in the right eye and a serous RPE detachment with an occult CNVM in her left eye for which she received intravitreal bevacizumab, 1.25 mg/ml. One month after the injection, the patient developed a juxtafoveal RPE tear [Fig. 1A]. OCT evaluation with Stratus showed an area devoid of RPE reflectivity corresponding to the tear with an adjoining area of high reflectivity indicating the scrolled up margin of the RPE [Fig. 1B]. Over the next 11 months, four intravitreal injections of bevacizumab were administered to stabilize the CNVM. One year into the follow-up, a new RPE tear was noted, extending from the superior border of the first tear (Fig. 2A, area within blue arrows represents the first RPE tear and the area within the red arrows represents the second tear). Visual acuity in the left eye was maintained at 20/30. SD-OCT (Heidelberg Engineering, Vista, CA / Germany), of the left eye revealed an elevated RPE corresponding to the scrolled margin of the tear [Fig. 2B, 2D]. Fibrovascular membrane beneath the outer segments was seen as hyporeflective, due to the lack of RPE layer. The margin of the rip was subfoveal with elevation of the corresponding area.\n\nFigure 1 (A) Fundus photograph of the left eye showing the presence of a juxtafoveal retinal pigment epithelial (RPE) tear. (B) Stratus OCT scan of the left eye showing an area devoid of RPE reflectivity with adjoining area of high reflectivity corresponding to the scrolled margin of the RPE tear\n\nFigure 2 (A) Fundus photograph of the left eye showing the occurrence of a new RPE tear. (B) Spectral-domain OCT of the left eye showing the scrolled up margins of the RPE tear and the fibrovascular membrane lying adjacent to it (area within the blue arrows) (C) Histological picture from a surgical sample showing the corresponding areas of the scrolled up margin of the tear and the fibrovascular membrane (black arrows) (Lafaut et al.[6] (D) Spectral-domain OCT of the left eye outlining the second RPE tear (area within the red arrows)\n\nDiscussion\nThe pathogenesis of RPE tear is not completely understood. While some believe that CNVMs play only a minor role in the formation of RPE tears, others consider these membranes to be instrumental in the tearing process.[67] Evidence is now in favor of the hydraulic theory, which attributes the development of RPE detachment to the presence of a hydrophobic Bruch’s membrane.[8] It is believed that RPE detachments that are destined to tear tend to become progressively larger and highly detached, generating sufficient tangential stress to cause a rupture. An increase in the incidence of RPE tears is observed after the use of anti-vascular endothelial growth factor (VEGF) agents. This has been attributed to the rapid contraction of the regressing neovascular membrane resulting in tangential traction of the RPE.[3]\n\nThe actual composition of RPE tears is not well established. Histological study of the surgically removed RPE tear has revealed that the torn RPE margin rolls up and the bare area of the tear is covered by a thin fibrovascular tissue which covers the remains of the outer segment.[8]\n\nOCT, a useful complementary tool in the clinical assessment of RPE tears reveals high reflectivity signal in the area of the bare choroid and a flattened appearance of the associated pigment epithelial detachment.[4] SD-OCT, also known as Fourier domain OCT collects data 100 times faster than conventional time-domain OCT (TD-OCT), resulting in improved resolution of the B-scan images.[5] The Spectralis, one of the commercially available SD-OCT, also incorporates the Trutrack™technology, which provides reliable point to point correlation between the OCT and the fundus images, thereby allowing repeat scans of identical locations over time. In our patient, SD-OCT showed additional features. The margin of the tear was underneath the subfoveal area with elevation of the corresponding area. The presence of an intact photoreceptor layer overlying the rip margin corresponded to the good visual acuity seen in our patient. In the area devoid of RPE, a raised area with hyporeflectivity was seen corresponding to the fibrous scar.\n\nWe used the SD-OCT to define the two features described histopathologically from a surgically excised RPE tear[8] [Fig. 2C]. The scrolled up RPE margin is seen as a hyperintense area with a shadowing underneath. Fibrovascular membrane beneath the outer segments is seen as hyporeflective, due to lack of RPE layer.\n\nThe treatment of underlying CNVM after the occurrence of RPE tear is not well established. Continuation of anti-VEGF therapy has been reported to stabilize the visual acuity.[3] In our case, repeated use of bevacizumab may have caused a continued contraction of the fibrovascular membrane with shearing effect resulting in the occurrence of a new tear.\n\nIn conclusion, we report formation of multiple RPE tears after repeated use of anti-VEGF therapy for treatment of the underlying CNVM. In addition we correlate the preservation of good visual acuity in the presence of a subfoveal RPE tear with features seen on SD-OCT.\n==== Refs\n1 Hoskins A Bird AC Sehmi K Tears of detached RPE Br J Ophthalmol 1981 65 417 22 7260013 \n2 Gass JD Retinal pigment epithelial during krypton red photocoagulation Am J Ophthalmol 1984 98 700 6 6507541 \n3 Chang LK Sarraf D Tears of the retinal pigment epithelium: an old problem in a new era Retina 2007 27 523 34 17558312 \n4 Giovannini A Amato G Mariotti C Scassellati-Sforzolini B Optical coherence tomography in the assessment of retinal pigment epithelial tear Retina 2000 20 37 40 10696745 \n5 Wojtkowski M Srinivasan V Fujimoto JG Ko T Schuman JS Kowalczyk A Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography Ophthalmology 2005 112 1734 46 16140383 \n6 Gass JD Pathogenesis of the tears of the RPE Br J Ophthalmol 1984 68 513 9 6204685 \n7 Shiraki K Kohno T Ataka S Abe K Inoue K Miki T Thinning and small holes at an impending tear of a retinal pigment epithelial detachment Graefes Arch Clin Exp Ophthalmol 2001 239 430 6 11561791 \n8 Lafaut BA Aisenbrey S Vanden Broecke C Krott R Jonescu-Cuypers CP Reynders S Clinicopathological correlation of retinal pigment epithelial tears in exudative age related macular degeneration: Pretear, tear, and scarred tear Br J Ophthalmol 2001 85 454 60 11264137\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0301-4738",
"issue": "59(1)",
"journal": "Indian journal of ophthalmology",
"keywords": null,
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D005260:Female; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D012167:Retinal Perforations; D041623:Tomography, Optical Coherence; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "47-8",
"pmc": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10696745;16140383;11264137;17558312;6507541;7260013;6204685;11561791",
"title": "Spectral domain optical coherence tomography features of multiple subfoveal retinal pigment epithelial tears after intravitreal bevacizumab.",
"title_normalized": "spectral domain optical coherence tomography features of multiple subfoveal retinal pigment epithelial tears after intravitreal bevacizumab"
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"abstract": "Within the text we describe a 66-year-old male with a history of prostate cancer (PCa), incidentally found to have left-sided hydronephrosis and a left ureteral lesion. Ureteroscopy was employed to visualize the lesion, a biopsy was taken, and a double J stent was placed. The lesion was of prostatic origin and the patient was subsequently started on androgen deprivation therapy (ADT). 6 months following the procedure, the patient's PSA had decreased and his hydronephrosis had resolved. We are the first to report treating a ureteral metastasis from PCa and its associated hydronephrosis solely with ADT and double J stenting, respectively.",
"affiliations": "F. Edward Hébert School of Medicine; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, United States.;Division of Urology, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, United States.;Department of Pathology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, United States.;F. Edward Hébert School of Medicine; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, United States.",
"authors": "Janatpour|Zachary C|ZC|;Shanmuga|Santosh|S|;Gandia|Edwin|E|;Rosner|Inger L|IL|",
"chemical_list": null,
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"doi": "10.1016/j.eucr.2021.101780",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00220-5\n10.1016/j.eucr.2021.101780\n101780\nOncology\nUreteral metastasis from locally invasive, castrate-resistant prostate cancer: A Case report\nJanatpour Zachary C. zachary.janatpour@usuhs.edu\na∗\nShanmuga Santosh santosh_shanmuga@yahoo.com\nb\nGandia Edwin edwin.gandia.mil@mail.mil\nc\nRosner Inger L. inger.l.rosner.mil@mail.mil\nabd\na F. Edward Hébert School of Medicine; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, United States\nb Division of Urology, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, United States\nc Department of Pathology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889, United States\nd Department of Urology, Inova Fairfax Hospital, 8081 Innovation Park Dr, Fairfax, VA 22031, USA\n∗ Corresponding author. 1901 Connecticut Ave NW, Washington, DC 20009, USA. zachary.janatpour@usuhs.edu\n13 7 2021\n11 2021\n13 7 2021\n39 10178021 6 2021\n13 7 2021\nPublished by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nWithin the text we describe a 66-year-old male with a history of prostate cancer (PCa), incidentally found to have left-sided hydronephrosis and a left ureteral lesion. Ureteroscopy was employed to visualize the lesion, a biopsy was taken, and a double J stent was placed. The lesion was of prostatic origin and the patient was subsequently started on androgen deprivation therapy (ADT). 6 months following the procedure, the patient's PSA had decreased and his hydronephrosis had resolved. We are the first to report treating a ureteral metastasis from PCa and its associated hydronephrosis solely with ADT and double J stenting, respectively.\n\nKeywords\n\nProstate cancer\nUreteral metastasis\nMetastatic prostate cancer\nCastrate-resistant prostate cancer\nNephroureterectomy\n==== Body\nIntroduction\n\nAs the incidence of metastasis to the ureters remains exceedingly rare, disease management for patients with ureteral metastases is often guided by the few published experiences of others. Thus, it is imperative that additional cases be documented in a public domain. The following Case describes an incidence of ureteral metastasis from locally invasive, castrate-resistant prostate cancer that was managed without resection.\n\nCase presentation\n\nThe patient is a 66-year-old male who presented to clinic for an elevated PSA (3.79 ng/mL in 2014 to 14.95 ng/mL in 2015). Transrectal ultrasound guided prostate biopsy revealed high volume, high-risk disease with 11 of 12 cores positive and a Gleason score of 5 + 5 = 10. He underwent robot-assisted radical prostatectomy that was complicated by a 4 mm rectal laceration. Final pathological staging was pT4N0R1 with positive margins and rectal invasion. The patient was subsequently started on androgen deprivation therapy (ADT) with leuprolide acetate administered every 3 months, and his PSA dropped to a nadir of 1.33mg/mL.\n\nSurveillance MRI in 2016 revealed a T2-intense nodular region at the posterior inferior bladder. Additionally, PET scan revealed radiotracer accumulation within a single vertebral body. However, concerns for bony malignancy were low at that time due to the solitary nature of the finding. In late 2017 the patient developed castrate resistant disease due to increasing PSA with a PSA doubling time of 5.6 months. MRI performed in 2018 revealed enlargement of the previously mentioned T2-intense nodular region at the posterior inferior bladder. In late 2018 the patient was referred for enrollment in the NIH Clinical protocol NCT 03315871 for treatment of combination immunotherapy involving vaccines (Prostvac and CV301) and MSB0011359C [an anti-PD-L1 antibody (avelumab) with TGF beta-Trap molecule].\n\nIn early 2020, a computerized tomography (CT) revealed development of left hydroureteronephrosis (Fig. 1) that traced to the level of an enhancing lesion in the left distal ureter, as well as the presence of enlarging sclerotic vertebral lesions; both concerning for metastasis. The patient was started on Apalutamide in addition to depot goserelin, and scheduled for diagnostic ureteroscopy.Fig. 1 Computed tomography (CT) of the abdomen and pelvis. Cross-sectional imaging using computed tomography (CT) of the abdomen and pelvis with IV contrast shows marked left hydroureteronephrosis and an enhancing ureteral mass in the distal left ureter.\n\nFig. 1\n\nCystoscopy was notable for post-prostatectomy changes and a bladder neck mass consistent with his recurrent prostate cancer. Retrograde pyelogram of the left ureter revealed marked hydroureteronephrosis and a torturous ureter. Left ureteroscopy revealed a bulbous mass in the left distal ureter (Fig. 2A and B), with normal ureter observed distally and dilated ureter observed proximally (Fig. 2C and D). Biopsies were taken using ureteral cold cup biopsy forceps. A left ureteral 6Fr x 28cm double J stent was placed successfully.Fig. 2 Diagnostic ureteroscopy. Intra-operative images from the left diagnostic ureteroscopy show a bulbous ureteral mass (A, B), with normal, dilated ureter proximal to the mass (C). A post-biopsy image of the mass (D) is also shown.\n\nFig. 2\n\nThis biopsy specimen consisted of multiple small tissue fragments characterized by the presence of a cell infiltrate with severe crush artifact. Evaluation of morphology and architecture was precluded by the presence of this severe crush artifact (Fig. 3A). An immunohistochemical panel of PSA, NKX3.1, CD45, SOX-10, synaptophysin and chromogranin with appropriately reactive controls was performed on the submitted biopsy material. CD45 highlighted the background inflammatory cells. PSA showed mild to moderate immunoreactivity, while NKX3.1 showed strong immunoreactivity in the cells of interest (Fig. 3B and C). Chromogranin, synaptophysin and SOX-10 were negative. The immunohistochemical profile was consistent with the diagnosis of metastatic carcinoma of prostatic origin.Fig. 3 Histopathologic analysis suggest prostatic origin of ureteral biopsy. A) Hematoxylin and Eosin (H&E) stain at of the biopsy material showing a prominent cell infiltrate with severe cautery artifact. B) Prostate specific antigen (PSA) immunohistochemical stain of ureteral biopsy. Note the patchy, moderate to strong immunoreactivity in the cells of interest. C) NKX3.1 immunohistochemical stain. The cells show strong, diffuse immunoreactivity. PSA and NKX3.1 immunoreactivity favors metastatic carcinoma of prostatic origin.\n\nFig. 3\n\n6 months following ADT and double J stenting, the patient remained asymptomatic, the patient's PSA showed a substantial decrease, and repeat CT showed no hydroureteronephrosis.\n\nDiscussion\n\nOccurrence of ureteral metastasis from prostate cancer remains exceedingly rare, with approximately 50 cases documented over the last century. Gandaglia et al. assessed distribution of metastasis in a cohort of 74,826 patients with metastatic PCa and described the most common metastatic sites as bone (84%), distant lymph nodes (10.6%), liver (10.2%), and thorax (9.1%).1 For PCa patients with bone metastases, the most common sites of secondary metastases were liver (39.1%), thorax (35.2%), distant lymph nodes (24.6%), and brain (12.4%).1 In fact, the most common source of ureteral metastasis are breast cancer, gastric cancer, and colorectal cancer; rather than PCa.2 Due to the infrequent occurrence of ureteral metastasis from PCa, a paucity of literature exists with regard to understanding risk factors and pathophysiology that contribute to acquiring ureteral metastasis.\n\nAmong patients presenting with a ureteral mass, it is common for surgeons to perform nephroureterectomy (NU) rather than diagnostic ureteroscopy with biopsy. Ureteroscopy is often difficult in patients with ureteral strictures, and nephroureterectomy allows for both reduction of disease burden and biopsy to occur within one step. However, as in our Case, we were able to easily access the ureter via ureteroscopy which allowed for visualization both proximal and distal to the lesion, and easy acquisition of a biopsy. Similar to case reports by Gupal et al., in 2009, Schneider et al., in 2012, and Munshi et al., in 2019, we decided against nephroureterectomy due to concerns of post-surgical complications in a patient with extensive extra-prostatic disease burden.3, 4, 5 Unlike any of the aforementioned cases, we placed 6Fr x 28cm double J stent to relieve the patient's hydronephrosis, rather than performing a nephrostomy, and did not resect the lesion.\n\nConclusion\n\nAs best we can tell, we are the first to report treating a ureteral metastasis from PCa and its associated hydronephrosis solely with ADT and double J stenting, respectively.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDoD disclaimer\n\nThe opinions and assertions contained herein are the private opinions of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences, the U.S. Department of Defense, or the U.S. Department of the Army.\n\nAuthor contribution\n\nAll authors have made substantial contributions to the acquisition of data, the interpretation of data, and both drafting and revising the article critically for important intellectual content. All authors have granted approval of the final version to be submitted.\n\nDeclaration of competing interest\n\nNone.\n==== Refs\nReferences\n\n1 Gandaglia G. Abdollah F. Schiffmann J. Distribution of metastatic sites in patients with prostate cancer: a population-based analysis: sites of Metastases in PCa Patients Prostate 74 2 2014 210 216 10.1002/pros.22742 24132735\n2 Haddad F.S. Metastases to the ureter. Review of the world literature, and three new Case reports J Med Liban 47 4 1999 265 271 10641458\n3 Singh G. Tiong H.Y. Kalbit T. Liew L. Urothelial metastasis in prostate adenocarcinoma Ann Acad Med Singapore 38 2 2009\n4 Schneider S. Popp D. Denzinger S. Otto W. A rare location of metastasis from prostate cancer: hydronephrosis associated with ureteral metastasis Adv Urol. Published online 2012 10.1155/2012/656023\n5 Munshi F. Shinder B. Sadimin E. Mayer T. Singer E. Metastatic prostate cancer to the renal pelvis and proximal ureter: a case report and review of the literature Cancer Stud Ther 4 4 2019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2214-4420",
"issue": "39()",
"journal": "Urology case reports",
"keywords": "Castrate-resistant prostate cancer; Metastatic prostate cancer; Nephroureterectomy; Prostate cancer; Ureteral metastasis",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101780",
"pmc": null,
"pmid": "34345592",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": "24132735;10641458;32148662;19271050;21912541",
"title": "Ureteral metastasis from locally invasive, castrate-resistant prostate cancer: A Case report.",
"title_normalized": "ureteral metastasis from locally invasive castrate resistant prostate cancer a case report"
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"abstract": "BACKGROUND\nAlthough thrombotic microangiopathy (TMA) is recognized as one of the poor-prognosis factors after liver transplantation, the precise outcome of TMA is unclear. We sought to elucidate the factors affecting the outcome of TMA after liver transplantation in Japan, based on the data from a nationwide survey.\n\n\nMETHODS\nOne hundred cases of post-transplant TMA were accumulated from 17 Japanese centers of which two cases were excluded because the cause of death was obviously not related to TMA (recurrence of original diseases as primary sclerosing cholangitis and hepatocellular carcinoma), and the remaining 98 cases were enrolled in this study. The patient survival after the development of TMA and the factors that affected the patients' outcomes were retrospectively analyzed.\n\n\nRESULTS\nAll cases were living-donor liver transplant cases, and the 1-, 3-, and 5-year patient survival rates after transplantation were 66.9%, 64.6%, and 62.2%, respectively. In a multivariate analysis, the requirement of renal replacement therapy during TMA treatment was the only factor that was significantly related to poor outcome after the development of TMA.\n\n\nCONCLUSIONS\nThe outcomes of TMA were generally poor. The progression of renal dysfunction despite intensive treatment might be the only factor related to the poor prognosis after the development of TMA.",
"affiliations": "Department of Digestive and General Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.;Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan.",
"authors": "Takatsuki|Mitsuhisa|M|https://orcid.org/0000-0002-0819-3156;Eguchi|Susumu|S|https://orcid.org/0000-0002-7876-0152;Yamamoto|Masakazu|M|;Yamaue|Hiroki|H|;Takada|Yasutsugu|Y|;|||",
"chemical_list": null,
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"delete": false,
"doi": "10.1002/jhbp.1032",
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"journal": "Journal of hepato-biliary-pancreatic sciences",
"keywords": "liver transplantation; living donor; thrombotic microangiopathy",
"medline_ta": "J Hepatobiliary Pancreat Sci",
"mesh_terms": null,
"nlm_unique_id": "101528587",
"other_id": null,
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"pmc": null,
"pmid": "34355533",
"pubdate": "2021-08-06",
"publication_types": "D016428:Journal Article",
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"title": "The outcomes of thrombotic microangiopathy after liver transplantation: A nationwide survey in Japan.",
"title_normalized": "the outcomes of thrombotic microangiopathy after liver transplantation a nationwide survey in japan"
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"abstract": "Pulmonary veno-occlusive disease (PVOD) is a rare, almost universally fatal complication of chemotherapy and bone marrow transplantation with few treatment options. A 19-month-old boy with stage 4 neuroblastoma with fatal PVOD following high-dose chemotherapy with autologous peripheral blood stem cell rescue is described here. A comprehensive literature review revealed 40 case reports of PVOD in oncology patients. Various therapeutic modalities were attempted, with four survivors. PVOD should be considered in patients with dyspnea and cardiomegaly. Less invasive diagnostic methods and more effective therapies are needed.",
"affiliations": "Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Children's Hospital of Denver, Colorado, USA.",
"authors": "Trobaugh-Lotrario|Angela D|AD|;Greffe|Brian|B|;Deterding|Robin|R|;Deutsch|Gail|G|;Quinones|Ralph|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00043426-200305000-00011",
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"issue": "25(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009367:Neoplasm Staging; D009447:Neuroblastoma; D011668:Pulmonary Veno-Occlusive Disease; D014182:Transplantation, Autologous",
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"pages": "405-9",
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"pubdate": "2003-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: case report and literature review.",
"title_normalized": "pulmonary veno occlusive disease after autologous bone marrow transplant in a child with stage iv neuroblastoma case report and literature review"
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"abstract": "Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection with a difficult diagnosis, rapid progression, high mortality rate and poor prognosis. The primary treatment and prevention of PCP is trimethoprim/sulfamethoxazole (TMP/SMZ). However, there are many cases of intolerance or resistance to the drug, so the convenient and effective alternatives are deficient.\nA 66-year-old woman who took an immunosuppressive agent for a long time was diagnosed with PCP. Poor compliance of treatment was found out after monitoring TMP/SMZ plasma concentrations in this patient. She stopped taking the drug herself because of nausea. As a result of intolerance to TMP/SMZ, caspofungin combined with clindamycin were chosen to continue anti-PCP treatment in this patient. She finally improved and discharged from hospital.\nThe new combination of caspofungin and clindamycin may be beneficial for patients with PCP who have failed treatment or are intolerant of TMP/SMZ. In addition, the trend of β-glucan levels can be a predictor of therapeutic efficacy in PCP.",
"affiliations": "Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.;Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.;Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.;Department of Pharmacy, Zhejiang Hospital, No. 12 Lingyin Road, Hangzhou, 310007, China.;Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.",
"authors": "Yang|Di-Hong|DH|;Xu|Yuan|Y|;Hong|Lu|L|;Song|Zhou-Ye|ZY|;Ge|Wei-Hong|WH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2018.12.003",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30281-810.1016/j.rmcr.2018.12.003Case ReportEfficacy of caspofungin combined with clindamycin for Pneumocystis jirovecii pneumonia in a systemic lupus erythematosus patient: A case report and literature review Yang Di-hong abXu Yuan aHong Lu abSong Zhou-ye cGe Wei-hong 6221230@sina.coma∗a Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Chinab School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Jiangning District, Nanjing, 211198, Chinac Department of Pharmacy, Zhejiang Hospital, No. 12 Lingyin Road, Hangzhou, 310007, China∗ Corresponding author. Department of Pharmacy, The Affiliated Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China. 6221230@sina.com08 12 2018 2019 08 12 2018 26 108 111 7 9 2018 3 12 2018 4 12 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nPneumocystis jirovecii pneumonia (PCP) is an opportunistic infection with a difficult diagnosis, rapid progression, high mortality rate and poor prognosis. The primary treatment and prevention of PCP is trimethoprim/sulfamethoxazole (TMP/SMZ). However, there are many cases of intolerance or resistance to the drug, so the convenient and effective alternatives are deficient.\n\nCase presentation\nA 66-year-old woman who took an immunosuppressive agent for a long time was diagnosed with PCP. Poor compliance of treatment was found out after monitoring TMP/SMZ plasma concentrations in this patient. She stopped taking the drug herself because of nausea. As a result of intolerance to TMP/SMZ, caspofungin combined with clindamycin were chosen to continue anti-PCP treatment in this patient. She finally improved and discharged from hospital.\n\nConclusion\nThe new combination of caspofungin and clindamycin may be beneficial for patients with PCP who have failed treatment or are intolerant of TMP/SMZ. In addition, the trend of β-glucan levels can be a predictor of therapeutic efficacy in PCP.\n\nKeywords\nCaspofunginClindamycinPneumocystis jirovecii pneumonia\n==== Body\nAbbreviations list\nPCPPneumocystis jirovecii pneumonia\n\nTMPTrimethoprim\n\nSMZsulfamethoxazole\n\nCTCAEthe National Cancer Institute common terminology criteria for adverse events\n\nLDHlactate dehydrogenase\n\nGMSGrocott' Methenamine silver\n\nBALstaining of bronchoalveolar lavage fluid\n\n1 Introduction\nPneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection disease. The strategy of trimethoprim (TMP) 15–20 mg/kg/day and sulfamethoxazole (SMZ) 75–100mg/kg/day administered in three or four doses has long been standard treatment of PCP [1]. In a retrospective cohort study [2], a total of 67 adverse events (≥grade 3) were recorded according to the National Cancer Institute common terminology criteria for adverse events (CTCAE) version 4.03, and 6% patients discontinued TMP/SMX therapy because of severe adverse events. Dermatological and haematological toxicity are Commonly causes of a change of treatment [3].\n\nTherapeutic drug monitoring of TMP/SMZ is necessary in individuals. It is recommended that the more satisfactory therapeutic effects and lower incidence of adverse events can be achieved within a target steady peak concentration of 5–8 ng/ml for TMP, 100-200 μg/ml for SMZ [1]. For patients with PCP who require large doses of TMP/SMZ, serum concentrations should be detected to prevent excessive levels.\n\nFurthermore, evidence [4] shows that mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii will decrease the efficacy of TMP/SMZ. Adverse drug reactions also occur more frequent in patients with DHPS mutations. Thus we cannot ignore the possibility of TMP/SMZ resistance despite the lack of reports on the mutation rates in China. The most important thing is to find safer and more effective alternatives for patients who are intolerant or resistant to TMP/SMZ.\n\nThe purpose of this case is to discuss the significance of monitoring TMP/SMZ concentrations in patients with PCP, demonstrate the efficacy of caspofungin combined with clindamycin in patients with TMP/SMZ intolerance or resistance and summarize 21 previously reported cases and our case.\n\n2 Case presentation\nA 66-year-old woman who was diagnosed with systemic lupus erythematosus because of multiple joint pain 5 years ago, has been long-term immunosuppressive therapy with methylprednisolone (2mg-4mg/d) and hydroxylamine sulfate (0.1g-0.2g/d). Approximately 20 days ago, the patient appeared intermittent fever after catching cold, and the temperature peak was about 38.0 °C. Blood gas analysis at admission showed an oxygen partial pressure of 106 mmHg, an oxygenation index of 500, a CD4 cell count of 0.074 × 109/L, a β-glucan of 984.6 pg/ml, and a lactate dehydrogenase (LDH) of 1084 U/L. On the 4th day of admission, the patient presented with abrupt chest tightness and shortness of breath. Her urgent blood gas analysis (oxygen 5L/min) showed: oxygen partial pressure 76 mmHg, oxygen Index 173. Chest CT with obvious diffuse ground glass opacity suggested a serious infection of both lungs (Fig. 1). She was diagnosed as PCP by Grocott' Methenamine silver (GMS) staining of bronchoalveolar lavage fluid (BAL), and immediately received the combination strategy including TMP/SMZ (160/800mg tid)、carboplatin (50mg qd with 70mg on day 1), clindamycin (0.6g q12h) and methylprednisolone (40mg q12h) to against Pneumocystis jirovecii. Hydroxylamine sulfate was discontinued at the same time.Fig. 1 High resolution CT scan of the chest on days 1 (A: April 24, 2017), 10 (B: May 3, 2017), 22 (C: May 15, 2017) from left to right. Column A shows obvious diffuse ground glass opacities in both lungs. Column B shows the absorbtion of the diffuse ground glass in both lungs. C column CT image displays a remarkable improvement after 22 days of the combined therapy.\n\nFig. 1\n\nThe steady-state peak concentrations of SMZ and TMP were monitored on the 4th day after administration, with a SMZ of 43.1 μg/ml and a TMP of 8.1 μg/ml. Unfortunately, these results are not credible because we found out that she had stopped taking TMP/SMZ by herself for 2 days. The patient complained nausea after using TMP/SMZ and refused to take the drug anymore. Therefore, the anti-Pneumocystis jirovecii treatment with caspofungin (50mg qd) and clindamycin (0.6g q12h) was continued.\n\nAt 4 days of the treatment, the patient's temperature returned to normal, chest tightness and shortness of breath were significantly improved. The patient's LDH decreased to 877 U/L on day 8, and chest CT scan demonstrated that the lung lesions had decreased in size (Fig. 1) on day 10. A follow-up chest CT scan showed a remarkable improvement after 22 days of the combined therapy (Fig. 1). She was finally in good condition with her β-glucan decreased to 89.0 pg/ml, LDH to 691 U/L before she was discharged from hospital (Fig. 2).Fig. 2 Trends of two indicators before and after treatment. Both LDH and β-glucan decreased after 25 days of treatment, indicating that the therapy was effective.\n\nFig. 2\n\n3 Discussion\nPneumocystis jirovecii, originally found in an animal infected with Trypanosoma cruzi, was considered to be a form of life cycle of the Trypanosoma cruzi. Subsequently, it was realized that this microorganism was different from Trypanosoma cruzi as as the cysts of the spores were found in the lungs of the non-Trypanosoma-cruzi-infected rats. Until 1952, researchers found that there was a correlation between Pneumocystis jirovecii and plasma cell pneumonia in preterm infant, which confirmed for the first time that Pneumocystis jirovecii is pathogenic in humans [5]. Pneumocystis jirovecii was classified as protozoa 1980s ago due to the similar morphology and treatment to protozoa. However, with the progress of molecular biology techniques, the nucleotide sequence of Pneumocystis jirovecii was found to be more closely related to fungi [6,7], and the similarity was 60%, compared with only 20% of protozoa [8]. Therefore, it is generally considered that Pneumocystis jirovecii should be attributed to fungi.\n\nThe combination therapy of low-dose TMP/SMZ and antifungal drug caspofungin can effectively eliminate Pneumocystis jirovecii and reduce the burden of the pathogens as an improved PCP treatment regimen [9]. In this case, the initial therapy comprised low-dose TMP/SMZ (160/800mg tid), while the steady-state peak concentration of SMZ at this dose was lower than 65.7 μg/ml reported in the literature, and TMP is significantly higher than 2.3 μg/ml [10]. The patient stopped taking her own TMP/SMZ resulting in lower concentration of SMZ. As for TMP, individual differences could not be excluded. On the other hand, there are few reports related to blood concentrations of TMP/SMZ in the Chinese population, so the drug's metabolism may be racially differentiated. The patient with a creatinine clearance rate of only 30 ml/min also suffered from lupus nephritis so that the drug excreted by the kidney such as TMP/SMZ will accumulate in her body, which resulted in higher blood concentration. However, the target concentrations in combined treatment regimen of low-dosage of compound sulfamethoxazole are not yet clear and remain to be further studied.\n\nThis patient was unable to tolerate the TMP/SMZ due to nausea. According to the recommendation [1], we could choose primaquine (30 mg/d) combined with clindamycin (0.6 g q8h) or single-strength pentamidine treatment (4 mg/Kg/day) as second line options. While primaquine and pentamidine related adverse events cause frequently, and they are not available in most hospitals in China. It is recommended that Caspofungin combined with clindamycin as an alternative in patients with treatment failure or intolerance to TMP/SMZ may achieve satisfactory therapeutic effects [11].\n\nAlthough the efficacy of caspofungin in the treatment of PCP has been confirmed, the current reports are limited to case studies. Including our patient, there have been a total of 22 cases to date (Table 1). Most of combined regimens can significantly improve the treatment effect of PCP, either as primary or salvage therapies. Caspofungin inhibits the synthesis of β(1,3)-D-glucan in cysts wall as well as cytokinesis and karyokinesis of the trophozoites preventing the development of Pneumocystis jirovecii in hosts [24]. With the widespread recognition that Pneumocystis jirovecii should be attributed to fungi and the discovery that β-glucan is an important component of the cell wall, serum β-glucan levels are increasingly being used to support presumptive diagnosis of PCP. In this case, the initial β-glucan up to 984.6 pg/ml, highly suspected of fungal infection. It dropped to 89 pg/ml after 24 days of admission, indicating the success of treatment. On the other hand, serum β-glucan levels could be a predictor of therapeutic efficacy of caspofungin for PCP.Table 1 Caspofungin cases summarized.\n\nTable 1First author\tAge\tGender\tFundam-ental disease\tFirst line treatment\tSecond line treatment\tThird line treatment\tTime to caspofungin from other regimens (days)\tDuration of Caspofun-gin (days)\tOutcome\t\nBeltz K [12]\t5\tMale\tALL\tT/S + Ca\t/\t/\t0\t22\tRecover\t\nJiang XQ [13]\t46\tMale\tDLBCL\tCa\t/\t/\t0\tNA\tRecover\t\nTu GW [14]\t61\tMale\tRT\tT/S\tT/S + Ca\t/\t3\t14\tFail\t\nTu GW [14]\t35\tMale\tRT\tT/S\tT/S + Ca\t/\t10\t14\tRecover\t\nTu GW [14]\t43\tMale\tRT\tT/S + Ca\t/\t/\t0\t14\tRecover\t\nKim T [15]\t1\tMale\tID\tT/S\tCa + A + Pr\t/\t25\t26\tFail\t\nKim T [15]\t63\tMale\tLT\tT/S\tT/S + Ca\t/\t9\t4\tFail\t\nKim T [15]\t57\tMale\tKT\tT/S\tT/S + Cl + P\tT/S + Ca\t17\t11\tFail\t\nKim T [15]\t46\tMale\tLT\tT/S\tT/S + Ca\t/\t5\t7\tRecover\t\nCeballos ME [16]\t39\tMale\tHIV\tT/S\tT/S + Cl\tT/S + Ca\t28\tNA\tRecover\t\nAnnaloro C [17]\t45\tMale\tTLL\tT/S\tT/S + Ca\tCa\t45\t43\tRecover\t\nHof H [18]\t60\tMale\tWD\tCa\t/\t/\t0\t21\tRecover\t\nUtili R [19]\t57\tFemale\tRT\tT/S + Ca\t/\t/\t0\t14\tRecover\t\nUtili R [19]\t28\tMale\tRT\tT/S\tT/S + Cl\tT/S + Ca\t7\t16\tRecover\t\nUtili R [19]\t59\tMale\tHT\tT/S\tT/S + Ca\t/\t6\t7\tRecover\t\nUtili R [19]\t58\tFemale\tHT\tT/S + Ca\t/\t/\t0\t14\tRecover\t\nLee WS [20]\t46\tMale\tHIV\tT/S\tCa\t/\t7\t14\tRecover\t\nZhang JC [21]\t93\tMale\tCOPD\tT/S\tCa\t/\t16\t40\tRecover\t\nLee N [22]\t54\tFemale\tHIV\tT/S\tCa + Cl + P\t/\t5\tNA\tRecover\t\nLi H [11]\t46\tMale\tIN\tT/S\tCa + Cl\t/\t7\t21\tRecover\t\nYao Z [23]\t44\tMale\tHIV\tCa + Cl\tT/S\t/\t0\t14\tRecover\t\nCurrent Case\t66\tFemale\tSLE\tT/S + Ca + Cl\tCa + Cl\t/\t0\t24\tRecover\t\nALL: acute lymphoblastic leukemia; T/S: TMP/SMZ; Ca: Caspofungin; DLBCL: diffused large-B cell lymphoma; NA: not available; RT: renal transplant; A: atovaquone; ID:immune deficiency; Pr: proguanil; LT: liver transplant; KT: kidney transplant; Cl: clindamycin; P: primaquine; HIV: human immunodeficiency virus; TLL: T-lymphoblastic leukemia; WD: wegener's disease; HT: heart transplant; COPD: chronic obstructive pulmonary disease; IN: IgA nephropathy; SLE: systemic lupus erythematosus.\n\n\n\nHowever, the number of cases alone using caspofungin is small and the efficacy remains uncertain, we can only attempted a new strategy of caspofungin combined with clindamycin as this patient was intolerant of TMP/SMZ and primaquine was not available in Chinese hospitals. There were only 2 cases [11、23] reported about the new combination of caspofungin and clindamycin, and 1 case [22] of caspofungin、clindamycin and primaquine at present. One of the cases was successfully treated with two drug's combination, and another failed. Nevertheless, the efficacy of the new strategy is still uncertain. The patient could not tolerate TMP/SMZ because of nausea in our case, but she finally recovered after the two drugs' therapy. It is suggested that the new combination of caspofungin and clindamycin might be effective for PCP. But further research is needed for which group of patients are effective and which are not.\n\n4 Conclusion\nIn summary, the new strategy of caspofungin combined with clindamycin as a salvage therapy is effective for PCP. Monitoring blood concentrations of drugs not only prevents the occurrence of adverse reactions, but also observes patients' adherence. It is necessary for patients with severe, fatal diseases such as PCP to monitor blood concentrations. β-glucan levels can be used to support presumptive diagnosis of PCP, it is also a predictor of therapeutic efficacy in patients with PCP.\n\nFunding source\nThis research was supported by Jiangsu Pharmaceutical Association - Tianqing Hospital Pharmaceutical Foundation (Q2018019).\n\nConflicts of interest\nThere are none.\n==== Refs\nReferences\n1 Maschmeyer G. Helweg-Larsen J. Pagano L. ECIL guidelines for treatment of Pneumocystis jirovecii pneumonia in non-HIV-infected haematology patients J. Antimicrob. Chemother. 71 2016 2405 2413 27550993 \n2 Ice L.L. Barreto J.N. Dao B.D. Relationship of sulfamethoxazole therapeutic drug monitoring to clinical efficacy and toxicity: a retrospective cohort study Ther. Drug Monit. 38 2016 319 326 26836809 \n3 Helweg-Larsen J. Benfield T. Atzori C. Miller R.F. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study J. Antimicrob. Chemother. 64 2009 1282 1290 19858161 \n4 Ponce C.A. Chabé M. George C. High prevalence of pneumocystis jirovecii dihydropteroate synthase gene mutations in patients with a first episode of pneumocystis pneumonia in Santiago, Chile, and clinical response to trimethoprim-sulfamethoxazole therapy Antimicrob. Agents Chemother. 61 2017 \n5 Vanek J. Jirovec O. Parasitic pneumonia. Interstitial plasma cell pneumonia of premature, caused by pneumocystis carinii Zentralbl. Bakteriol. Parasitenkd. Infektionskr. Hyg. 158 1952 120 127 \n6 Edman J.C. Kovacs J.A. Masur H. Santi D.V. Elwood H.J. Sogin M.L. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi Nature 334 1988 519 522 2970013 \n7 Liu Y. Rocourt M. Pan S. Liu C. Leibowitz M.J. Sequence and variability of the 5.8S and 26S rRNA genes of Pneumocystis carinii Nucleic Acids Res. 20 1992 3763 3772 1641341 \n8 Pixley F.J. Wakefield A.E. Banerji S. Hopkin J.M. Mitochondrial gene sequences show fungal homology for Pneumocystis carinii Mol. Microbiol. 5 1991 1347 1351 1664905 \n9 Lobo M.L. Esteves F. de Sousa B. Therapeutic potential of caspofungin combined with trimethoprim-sulfamethoxazole for pneumocystis pneumonia: a pilot study in mice PLoS One 8 2013 \n10 Amsden G.W. Foulds G. Thakker K. Pharmacokinetic study of azithromycin with fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole) in healthy volunteers Clin. Drug Invest. 20 2000 135 142 \n11 Li H. Huang H. He H. Successful treatment of severe Pneumocystis pneumonia in an immunosuppressed patient using caspofungin combined with clindamycin: a case report and literature review BMC Pulm. Med. 16 2016 144 27835947 \n12 Beltz K. Kramm C.M. Laws H.J. Schroten H. Wessalowski R. Göbel U. Combined trimethoprim and caspofungin treatment for severe Pneumocystis jiroveci pneumonia in a five year old boy with acute lymphoblastic leukemia Klin. Pädiatr. 218 2006 177 179 16688676 \n13 Jiang X.Q. Fang L. Mei X.D. Wang X.J. Bao M.H. Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma after Rituximab-containing regimen: two cases of report and literature review J. Thorac. Dis. 5 2013 E162 E166 23991330 \n14 Tu G.W. Ju M.J. Xu M. Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients Nephrology (Carlton) 18 2013 736 742 24571744 \n15 Kim T. Hong H.L. Lee Y.M. Is caspofungin really an effective treatment for Pneumocystis jirovecii pneumonia in immunocompromised patients without human immunodeficiency virus infection? Experiences at a single center and a literature review Scand. J. Infect. Dis. 45 2013 484 488 23317167 \n16 Ceballos M.E. Ortega M. Andresen M. Wozniak A. García P. Balcells M.E. Successful treatment with echinocandin in an HIV-infected individual failing first-line therapy for Pneumocystis jirovecii pneumonia AIDS 25 2011 2192 2193 22019819 \n17 Annaloro C. Della Volpe A. Usardi P. Lambertenghi Deliliers G. Caspofungin treatment of Pneumocystis pneumonia during conditioning for bone marrow transplantation Eur. J. Clin. Microbiol. Infect. Dis. 25 2006 52 54 16365723 \n18 Hof H. Schnülle P. Pneumocystis jiroveci pneumonia in a patient with Wegener's granulomatosis treated efficiently with caspofungin Mycoses 1 2008 65 67 \n19 Utili R. Durante-Mangoni E. Basilico C. Mattei A. Ragone E. Grossi P. Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients Transplantation 84 2007 685 688 17893600 \n20 Lee W.S. Hsueh P.R. Hsieh T.C. Chen F.L. Ou T.Y. Jean S.S. Caspofungin salvage therapy in Pneumocystis jirovecii pneumonia J. Microbiol. Immunol. Infect. 50 2017 547 548 27094385 \n21 Zhang J.C. Dai J.Y. Fan J. Wu X.P. The treatment of pneumocystis Carinii pneumonia with caspofungin in elderly patients: a case report and literature review Zhonghua Jiehe He Huxi Zazhi 29 2006 463 465 17045046 \n22 Lee N. Lawrence D. Patel B. Ledot S. HIV-related Pneumocystis jirovecii pneumonia managed with caspofungin and veno-venous extracorporeal membrane oxygenation rescue therapy BMJ Case Rep. 2017 bcr2017221214, PMCID: PMC5652506, PMID: 28978595 \n23 Yao Z. Hua Z. Jun X. Chan W. Xiao-jun M. Lack of response in severe pneumocystis pneumonia to combined caspofungin and clindamycin treatment: a case report Chin. Med. Sci. J. 26 2011 246 248 22218054 \n24 Wyder M.A. Johnston L.Q. Kaneshiro E.S. Evidence for DNA synthesis in Pneumocystis carinii trophozoites treated with the beta-1,3-glucan synthesis inhibitor pneumocandin L-693,989 J. Eukaryot. Microbiol. 57 2010 447 448 20738464\n\n",
"fulltext_license": "CC BY-NC-ND",
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"keywords": "Caspofungin; Clindamycin; Pneumocystis jirovecii pneumonia",
"medline_ta": "Respir Med Case Rep",
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"nlm_unique_id": "101604463",
"other_id": null,
"pages": "108-111",
"pmc": null,
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"pubdate": "2019",
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"title": "Efficacy of caspofungin combined with clindamycin for Pneumocystis jirovecii pneumonia in a systemic lupus erythematosus patient: A case report and literature review.",
"title_normalized": "efficacy of caspofungin combined with clindamycin for pneumocystis jirovecii pneumonia in a systemic lupus erythematosus patient a case report and literature review"
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"abstract": "Mutations in the KIAA2022 gene have been implicated in non-syndromic X-linked intellectual disability. Thus far, all carrier females reported have been unaffected and genotype-phenotype correlations have not been described. Herein, we report a de novo KIAA2022 nonsense mutation in a 17-year-old female with short stature, microcephaly, severe intellectual disability, poor speech, epilepsy, and autistic behavior. X-inactivation pattern is normal suggesting that the mutation is causing the phenotype. This report contests the current view that KIAA2022 mutations only affect males, which has implications for testing and genetic counseling.",
"affiliations": "Division of Medical Genetics, Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas.;Division of Medical Genetics, Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas.",
"authors": "Farach|Laura S|LS|;Northrup|Hope|H|",
"chemical_list": "D018389:Codon, Nonsense; C000598871:NEXMIF protein, human; D009419:Nerve Tissue Proteins",
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"journal": "American journal of medical genetics. Part A",
"keywords": "KIAA2022; X-inactivation; X-linked; autism; epilepsy; intellectual disability",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000293:Adolescent; D018389:Codon, Nonsense; D004392:Dwarfism; D004827:Epilepsy; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability; D009419:Nerve Tissue Proteins; D010641:Phenotype",
"nlm_unique_id": "101235741",
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"pages": "703-6",
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"pmid": "26576034",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "KIAA2022 nonsense mutation in a symptomatic female.",
"title_normalized": "kiaa2022 nonsense mutation in a symptomatic female"
} | [
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"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2016-015461",
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"abstract": "We report two patients with refractory epilepsy who developed unilateral painful gynecomastia and lower extremity pain (one of them localized and the other one diffuse), shortly after receiving Pregabalin (PGB). Neither of them had previous endocrinologic problems or complaints about pain on their medical history. PGB was stopped in one patient and reduced in the other one, with complete disparition of the symptoms in the following weeks in both patients. This supports the hypothesis that gynecomastia could be a drug-induced and easy to manage secondary effect of PGB, with a higher incidence than observed on previous clinical trials.",
"affiliations": "Department of Pediatric Neurology, Hospital Universitario Sant Joan de Deu, Barcelona, Spain. imalaga@hsjdbcn.org",
"authors": "Málaga|Ignacio|I|;Sanmarti|Francesc X|FX|",
"chemical_list": "D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1528-1167.2006.00713.x",
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"issn_linking": "0013-9580",
"issue": "47(9)",
"journal": "Epilepsia",
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"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D004487:Edema; D004827:Epilepsy; D006177:Gynecomastia; D006801:Humans; D007085:Ilium; D035002:Lower Extremity; D008279:Magnetic Resonance Imaging; D008297:Male; D010146:Pain; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "2983306R",
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"pages": "1576-9",
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"pmid": "16981876",
"pubdate": "2006-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of painful gynecomastia and lower extremity pain in association with pregabalin therapy.",
"title_normalized": "two cases of painful gynecomastia and lower extremity pain in association with pregabalin therapy"
} | [
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"companynumb": "ES-LUNDBECK-DKLU3023815",
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{
"abstract": "Neuronal intranuclear inclusion disease is a rare hereditary neurodegenerative disease characterized by localized eosinophilic intracytoplasmic inclusion bodies in cells of the nervous system and internal organs. This disorder is frequently missed or misdiagnosed, as there is significant heterogeneity of its clinical presentation. Recently, genetic sequencing has revealed complex links between neuronal intranuclear inclusion disease and other neurodegenerative diseases, potentially explaining the diversity of clinical manifestations. Herein, we describe the case of a 68-year-old male Chinese patient who was initially diagnosed with Parkinson's disease based on classic symptomatology and ¹²³I-metaiodobenzylguanidine scintigraphy results and was subsequently treated with oral methyldopa for 3 years. He developed a paroxysmal tic before he presented to our hospital for treatment after a convulsive seizure. Brain magnetic resonance imaging identified signal hyperintensity at the corticomedullary junction on diffusion-weighted imaging. Skin biopsy results and genetic testing confirmed a revised diagnosis of neuronal intranuclear inclusion disease. This report highlights that patients clinically diagnosed with Parkinson's disease may actually be in the early stages of neuronal intranuclear inclusion disease, suggesting that patients with suspected Parkinson's disease should also be screened for this disease.",
"affiliations": "Department of Neurology and Neuroscience, The First Hospital of Jilin University, Changchun 130021, China.;Department of Neurology and Neuroscience, The First Hospital of Jilin University, Changchun 130021, China.;Department of Neurology and Neuroscience, The First Hospital of Jilin University, Changchun 130021, China.;Department of Neurology, Peking University First Hospital, Beijing 100000, China.;Department of Neurology, Peking University First Hospital, Beijing 100000, China.;Department of Neurology and Neuroscience, The First Hospital of Jilin University, Changchun 130021, China.",
"authors": "Wang|Zi-Yi|ZY|;Guo|Jiao-Jiao|JJ|;Wang|Meng|M|;Wang|Zhao-Xia|ZX|;Hong|Dao-Jun|DJ|;Yu|Xue-Fan|XF|",
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"issn_linking": "0172-780X",
"issue": "41(4)",
"journal": "Neuro endocrinology letters",
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"medline_ta": "Neuro Endocrinol Lett",
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"nlm_unique_id": "8008373",
"other_id": null,
"pages": "155-161",
"pmc": null,
"pmid": "33307649",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adult-onset neuronal intranuclear inclusion disease mimicking Parkinson's disease in a Chinese patient: a case report and literature reviews.",
"title_normalized": "adult onset neuronal intranuclear inclusion disease mimicking parkinson s disease in a chinese patient a case report and literature reviews"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-273044",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drug... |
{
"abstract": "Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.",
"affiliations": "College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Medical Oncology, Allan Blair Cancer Centre, Regina, Saskatchewan, Canada.;Section of Nephrology, Department of Medicine, Regina General Hospital, Regina, Saskatchewan, Canada bprasad@sasktel.net.",
"authors": "Gordon|Lexis|L|;Dokouhaki|Pouneh|P|;Hagel|Kimberly|K|;Prasad|Bhanu|B|http://orcid.org/0000-0002-1139-4821",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D013256:Steroids",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; chemotherapy; renal system; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008545:Melanoma; D009395:Nephritis, Interstitial; D012878:Skin Neoplasms; D013256:Steroids",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31653633",
"pubdate": "2019-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25605845;23400564;10623706;26715621;27282937;28881921;25324356;20525992;18173375;6375363;29762725;27113507;28467867;28076863;25399552;12091876;28889792;22437870;30775635;16943303;29959196;19587352",
"title": "Acute kidney injury from immune checkpoint inhibitor use.",
"title_normalized": "acute kidney injury from immune checkpoint inhibitor use"
} | [
{
"companynumb": "CA-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-110771",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VITAMINS"
},
"drugaddit... |
{
"abstract": "A substantial fraction of patients demonstrate resistance to immune checkpoint inhibitors, which limits their use. Use of radiation concurrently with checkpoint inhibitors has been shown to boost immune responsiveness, resulting in significant tumor regression in patients with metastatic melanoma. However, it is unknown whether radiation could play a role in reversing the inherent resistance to checkpoint inhibition in certain tumor types. Most trials testing this concurrent approach exclude such modestly responsive tumors and pursue checkpoint inhibition using anti-cytotoxic T-lymphocyte-associated protein 4 antibody (anti-CTLA-4, ipilimumab). The efficacy of anti-programmed-death-1 (anti-PD-1) therapy when used concurrently with radiation is less known but remains an attractive option due to less autoimmune toxicity compared with CTLA-4 inhibition. In this first reported experience, we have safely and effectively combined anti-PD-1 therapy (nivolumab) concurrently with radiation to treat two patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma. Both patients experienced a dramatic response that was durable.",
"affiliations": "Department of Hematology and Oncology, Lehigh Valley Health Network, Allentown, Pennsylvania, USA drsameertolay@gmail.com.;The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Radiation Oncology, Lehigh Valley Health Network, Allentown, Pennsylvania, USA.;Department of Radiation Oncology, Lehigh Valley Health Network, Allentown, Pennsylvania, USA.;Department of Hematology and Oncology, Lehigh Valley Health Network, Allentown, Pennsylvania, USA.",
"authors": "Tolay|Sameer|S|;Nair|Ranjit|R|;McIntosh|Alyson F|AF|;Sopka|Dennis M|DM|;Nair|Suresh G|SG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(1)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D002454:Cell Differentiation; D006801:Humans; D008297:Male; D012509:Sarcoma",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e49-e52",
"pmc": null,
"pmid": "30104290",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27660705;28794805;26148880;26307625;29437535;22397654;28889792;25754329;27393506;26755520",
"title": "Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation.",
"title_normalized": "dramatic response to concurrent anti pd 1 therapy and radiation in resistant tumors with sarcomatoid differentiation"
} | [
{
"companynumb": "PHHY2019US036181",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 73-year-old Caucasian female with a history of obesity status post Roux-en-Y gastric bypass (RYGB) surgery presented with generalized weakness and was found to have acute kidney injury (AKI) with a creatinine peak of 9.1 mg/dL above her baseline of 1.2 mg/dL, and anemia with hemoglobin 5.7 g/dl. Kidney biopsy revealed oxalate nephropathy likely related to gastric bypass surgery four years prior. RYGB is a strong risk factor for hyperoxaluria, nephrolithiasis, and oxalate nephropathy which often progresses to end-stage renal disease (ESRD). Meaningful treatment strategies for this disease entity are lacking. We present a case in which dietary and pharmacological management without the use of renal replacement therapy resulted in stabilization of chronic kidney disease (CKD) stage 5 for seven years at the time of this writing.",
"affiliations": "Department of Medicine, Kettering Medical Center, Dayton, Ohio. Electronic address: tony.kamel@ketteringhealth.org.;Department of Medicine, Kettering Medical Center, Dayton, Ohio; Department of Medicine, Boonshoft School of Medicine Wright State University, Dayton, Ohio; Renal Physicians Inc., Dayton, Ohio. Electronic address: natallia.maroz@wright.edu.",
"authors": "Kamel|Tony H|TH|;Maroz|Natallia|N|",
"chemical_list": "D010070:Oxalates",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2020.10.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "361(4)",
"journal": "The American journal of the medical sciences",
"keywords": "Enteric hyperoxaluria; Roux-en-y gastric bypass; Secondary oxalate nephropathy; end stage renal disease",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000368:Aged; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D006959:Hyperoxaluria; D009765:Obesity; D010070:Oxalates; D011183:Postoperative Complications; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "517-521",
"pmc": null,
"pmid": "33187632",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Medical Management of Advanced Oxalate Nephropathy Secondary to Gastric Bypass Surgery.",
"title_normalized": "medical management of advanced oxalate nephropathy secondary to gastric bypass surgery"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-105168",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"d... |
{
"abstract": "Patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome have high rates of psychiatric illness. The effective management of these psychiatric conditions can improve a patient's quality of life and may improve antiretroviral adherence. Care providers for patients with HIV infection frequently encounter clinical situations in which psychotropic medications are needed or are being used. Those clinical situations require familiarity with the broad category of medications termed \"psychotropic.\" That familiarity should include a basic understanding of indications, adverse effects, and drug interactions. In particular, it is very important to recognize the many potential interactions based on cytochrome P450 metabolism, which is common to many psychotropics, the protease inhibitors, and the nonnucleoside reverse-transcriptase inhibitors. In a brief review of the use of psychotropic medications in patients with HIV infection, we discuss indications, adverse effects, and drug interactions for commonly used antidepressants, mood stabilizers, anxiolytics, antipsychotics, psychostimulants, and drugs of abuse.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.",
"authors": "Thompson|Alex|A|;Silverman|Benjamin|B|;Dzeng|Liz|L|;Treisman|Glenn|G|",
"chemical_list": "D019380:Anti-HIV Agents; D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1086/501454",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "42(9)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D019380:Anti-HIV Agents; D004347:Drug Interactions; D015658:HIV Infections; D006801:Humans; D001523:Mental Disorders; D011619:Psychotropic Drugs",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1305-10",
"pmc": null,
"pmid": "16586391",
"pubdate": "2006-05-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Psychotropic medications and HIV.",
"title_normalized": "psychotropic medications and hiv"
} | [
{
"companynumb": "US-ABBVIE-03P-163-0227906-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess the safety and effectiveness of bis-chloroethylnitrosourea (BCNU) wafers in elderly patients with recurrent glioblastoma (GBM).\n\n\nMETHODS\nPatients with recurrent GBM operated on between 2007 and 2014 were divided into 3 groups: >65 years with BCNU wafer implantation, >65 years without BCNU wafer implantation, and ≤65 years with BCNU wafer implantation. We compared survival and complications.\n\n\nRESULTS\nA total of 79 patients were identified: 24 in the older BCNU group (median age 68.2 years, 33.3% with a methylated MGMT promoter), 16 in the older non-BCNU group (median age 68.6 years, 31.3% with a methylated MGMT promoter), and 39 in the younger BCNU group (median age 56.8 years). Survival after progression was 9.2 months in the elderly BCNU group and 7.6 months in the elderly non-BCNU group (p = 0.34); overall survival was 17.2 and 15.9 months, respectively (p = 0.35). We found a tendency toward a higher rate of seizures and pneumonia in the older BCNU group.\n\n\nCONCLUSIONS\nBCNU wafer implantation after resection of recurrent GBM is a reasonably safe treatment in patients aged >65 years. Seizures and systemic infections may occur more frequently, but the trade-off is still favorable as survival may be influenced positively. Higher age should not be regarded as a contraindication for BCNU wafers.",
"affiliations": "Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.",
"authors": "Klein|Johann|J|;Juratli|Tareq A|TA|;Radev|Yordan|Y|;Daubner|Dirk|D|;Soucek|Silke|S|;Schackert|Gabriele|G|;Krex|Dietmar|D|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000464464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "93(1)",
"journal": "Oncology",
"keywords": "Bis-chloroethylnitrosourea; Carmustine; Chemotherapy; Elderly; Glioblastoma; Wafers",
"medline_ta": "Oncology",
"mesh_terms": "D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D002330:Carmustine; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "43-50",
"pmc": null,
"pmid": "28395288",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and Effectiveness of Bis-Chloroethylnitrosourea Wafer Chemotherapy in Elderly Patients with Recurrent Glioblastoma.",
"title_normalized": "safety and effectiveness of bis chloroethylnitrosourea wafer chemotherapy in elderly patients with recurrent glioblastoma"
} | [
{
"companynumb": "DE-EMCURE PHARMS-2017HTG00240",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARMUSTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Noncirrhotic portal hypertension (NCPH) represents a relatively infrequent group of conditions that causes portal hypertension in the absence of cirrhosis. An association between NCPH and patients infected with human immunodeficiency virus (HIV) has been reported. Six consecutive patients with HIV infection and NCPH were the subject of this series. Case histories, including medication lists, liver biopsy and laboratory data were reviewed. Age at diagnosis was 43 +/- 3 years (range, 37-47). Liver disease was diagnosed 12 +/- 4 years (range, 8-18) after initiation of antiretroviral therapy (ART). All patients developed esophageal varices, 5 patients presented at least one bleeding episode and 2 required TIPS. Serum liver tests showed a mean total bilirubin of 1.4 +/- .7 mg/dL (range, .5-2.5) and INR was 1.2 +/- .14 (range, 1.0-1.4). CD4 count was 326 +/- 124 cells/mL (range, 198-467) and all patients presented HIV viral load < 75 copes/mL. Didanosine (ddl) was the most common ART drug being used by 4 patients. Portal vein thrombosis was diagnosed in 2 patients. Hepatic portal sclerosis (HPS) alone was observed in 1 patient, nodular regenerative hyperplasia (NRH) alone in 2 patients and combined HPS/NRH in 3 patients. In conclusion, NCPH should be included in the differential diagnosis of HIV-individuals presenting with clinical manifestations of portal hypertension and well preserved liver synthetic function. Prolonged exposure to ART, specially ddl, can play a pathogenic role. Rarely, liver synthetic function is sufficiently severe to warrant liver transplantation.",
"affiliations": "Department of Gastroenterology, University of Pennsylvania, Philadelphia, USA. mmendiza@cas.austral.edu.ar",
"authors": "Mendizabal|Manuel|M|;Craviotto|Soledad|S|;Chen|Terina|T|;Silva|Marcelo O|MO|;Reddy|K Rajender|KR|",
"chemical_list": "D044966:Anti-Retroviral Agents; D016049:Didanosine",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "8(4)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D016049:Didanosine; D005260:Female; D015658:HIV Infections; D006801:Humans; D006975:Hypertension, Portal; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "390-5",
"pmc": null,
"pmid": "20009143",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Noncirrhotic portal hypertension: another cause of liver disease in HIV patients.",
"title_normalized": "noncirrhotic portal hypertension another cause of liver disease in hiv patients"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-099436",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIDANOSINE"
},
"drugadd... |
{
"abstract": "BACKGROUND\nHydroxychloroquine and chloroquine have been used for hospitalized coronavirus disease 2019 patients because of their antiviral and anti-inflammatory function. However, little research has been published on the impact of the immunomodulatory effect of (hydroxy)chloroquine on humoral immunity.\n\n\nMETHODS\nWe report a case of symptomatic severe acute respiratory syndrome coronavirus 2 reinfection, diagnosed 141 days after the first episode, in a 56-year-old man of Black African origin treated with hydroxychloroquine for lupus erythematosus. No anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies could be detected 127 days after the initial episode of coronavirus disease 2019.\n\n\nCONCLUSIONS\nThe treatment with hydroxychloroquine probably explains the decreased immune response with negative serology and subsequent reinfection in our patient. As humoral immunity is crucial to fight a severe acute respiratory syndrome coronavirus 2 infection, the use of (hydroxy)chloroquine is likely to have a detrimental effect on the spread of the virus. This case emphasizes that more needs to be learned about the role of antibodies in protecting against severe acute respiratory syndrome coronavirus 2 (re)infection and the role of (hydroxy)chloroquine on humoral immunity.",
"affiliations": "Department of Microbiology and Infection Control, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium. astrid.muyldermans@uzbrussel.be.;Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.;Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, KU Leuven, Rega Institute for Medical Research, Leuven, Belgium.;Department of Emergency Medicine, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.;Department of Emergency Medicine, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.;Department of Emergency Medicine, Centre Hospitalier Universitaire Saint-Pierre (CHUSP), Brussels, Belgium.;Department of Microbiology and Infection Control, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium.;Department of Microbiology and Infection Control, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire Bruxelles-Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Microbiology and Infection Control, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090, Brussels, Belgium.",
"authors": "Muyldermans|Astrid|A|http://orcid.org/0000-0002-3043-5051;Maes|Piet|P|;Wawina-Bokalanga|Tony|T|;Anthierens|Tine|T|;Goldberg|Olivier|O|;Bartiaux|Magali|M|;Soetens|Oriane|O|;Wybo|Ingrid|I|;Van den Wijngaert|Sigi|S|;Piérard|Denis|D|",
"chemical_list": "D000998:Antiviral Agents; D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03159-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3159\n10.1186/s13256-021-03159-9\nCase Report\nSymptomatic severe acute respiratory syndrome coronavirus 2 reinfection in a lupus patient treated with hydroxychloroquine: a case report\nhttp://orcid.org/0000-0002-3043-5051\nMuyldermans Astrid astrid.muyldermans@uzbrussel.be\n\n1\nMaes Piet 2\nWawina-Bokalanga Tony 2\nAnthierens Tine 3\nGoldberg Olivier 3\nBartiaux Magali 4\nSoetens Oriane 1\nWybo Ingrid 1\nVan den Wijngaert Sigi 5\nPiérard Denis 1\n1 grid.8767.e 0000 0001 2290 8069 Department of Microbiology and Infection Control, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium\n2 grid.415751.3 Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, KU Leuven, Rega Institute for Medical Research, Leuven, Belgium\n3 grid.8767.e 0000 0001 2290 8069 Department of Emergency Medicine, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium\n4 grid.50545.31 0000000406089296 Department of Emergency Medicine, Centre Hospitalier Universitaire Saint-Pierre (CHUSP), Brussels, Belgium\n5 Department of Microbiology, Laboratoire Hospitalier Universitaire Bruxelles-Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium\n26 11 2021\n26 11 2021\n2021\n15 57213 1 2021\n19 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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\nHydroxychloroquine and chloroquine have been used for hospitalized coronavirus disease 2019 patients because of their antiviral and anti-inflammatory function. However, little research has been published on the impact of the immunomodulatory effect of (hydroxy)chloroquine on humoral immunity.\n\nCase presentation\n\nWe report a case of symptomatic severe acute respiratory syndrome coronavirus 2 reinfection, diagnosed 141 days after the first episode, in a 56-year-old man of Black African origin treated with hydroxychloroquine for lupus erythematosus. No anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies could be detected 127 days after the initial episode of coronavirus disease 2019.\n\nConclusions\n\nThe treatment with hydroxychloroquine probably explains the decreased immune response with negative serology and subsequent reinfection in our patient. As humoral immunity is crucial to fight a severe acute respiratory syndrome coronavirus 2 infection, the use of (hydroxy)chloroquine is likely to have a detrimental effect on the spread of the virus. This case emphasizes that more needs to be learned about the role of antibodies in protecting against severe acute respiratory syndrome coronavirus 2 (re)infection and the role of (hydroxy)chloroquine on humoral immunity.\n\nKeywords\n\nSARS-CoV-2\nCOVID-19\nReinfection\nHydroxychloroquine\nLupus\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\n(Hydroxy)chloroquine has been used for decades as prophylaxis and treatment of malaria and autoimmune diseases such as lupus erythematosus. In March 2020, the US Food and Drug Administration (FDA) allowed the use of hydroxychloroquine and chloroquine for certain hospitalized coronavirus disease 2019 (COVID-19) patients as an emergency use authorization (EUA). Possible beneficial effects may be attributed to its antiviral and anti-inflammatory function [1, 2]. In June 2020, this EUA was revoked as the known and potential benefits no longer outweighed the known and potential risks, including serious cardiac adverse events. However, little research has been published on the impact of the immunomodulatory effect of (hydroxy)chloroquine on humoral immunity [1, 3].\n\nCase presentation\n\nOn 9 April 2020, a 56-year-old obese man (BMI 35) of Black African origin with discoid lupus erythematosus (treated with hydroxychloroquine 200 mg twice a day) presented at the emergency department (ED) of the Centre Hospitalier Universitaire Saint-Pierre (CHUSP) with dyspnea for 2 weeks, dry cough, chest pain, myalgia, headache, ageusia, and diarrhea. One week earlier he had returned from the Democratic Republic of Congo (DRC) where he resided for 2 months. Malaria prophylaxis (atovaquone/proguanil) was taken correctly. Upon admission, a nasopharyngeal swab was taken and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected by real-time reverse transcription polymerase chain reaction (RT-PCR) (RealStar® SARS-CoV-2 RT-PCR Kit 1.0, Altona Diagnostics GmbH, Hamburg, Germany; targeting E-gene and S-gene) with a crossing point (Cp) of 36, but no abnormalities were observed on a chest computed tomography (CT) (Fig. 1) and oxygen saturation was 100%. His body temperature was 37.1 ℃ and the following laboratory parameters were within normal limits: C-reactive protein (CRP; 1.0 mg/L), leukocytes (4.3 × 103/μL), lymphocytes (1.8 × 103/μL), neutrophils (1.8 × 103/μL), platelets (214 × 103/μL), and hemoglobin (14.7 g/dL). The patient was placed in home quarantine for 2 weeks.Fig. 1 Chest computed tomography and radiograph images during the disease course. A–B, chest computed tomography (CT) without abnormalities; C bedside chest radiograph without alveolar consolidations; D CT pulmonary angiogram showing pulmonary embolism (arrow); E chest CT showing peripheral ground-glass opacities and pleural effusion in the right lower lobe\n\nOn 28 April he presented himself to Universitair Ziekenhuis Brussel's (UZB’s) ED with chest pain, abdominal pain, and diarrhea for a week. The imaging was repeated, but again no abnormalities were observed on a chest CT (Fig. 1). However, cardiac troponin T was slightly elevated (0.011 μg/L), suggesting the diagnosis of pericarditis. Aspirin (1000 mg four times a day) was prescribed and the patient was discharged.\n\nOn 4 June, SARS-CoV-2 RT-PCR (RealStar®) was performed prior to a planned 1-day hospitalization in UZB for gastroscopy because of postprandial bloating. This test was negative. No abnormalities were found by the gastroscopy, and the patient decided to discontinue hydroxychloroquine on his own initiative as gastrointestinal discomfort can be a side effect of the drug.\n\nA serological analysis (LIAISON® SARS-CoV-2 S1/S2 IgG, Diasorin, Saluggia, Italy) performed 127 days after the initial episode (14 August) could not detect anti-SARS-CoV-2 IgG antibodies against spike protein.\n\nOn 28 August (141 days after the initial episode), the patient presented at UZB’s ED with dyspnea, productive cough, malaise, fever, dysosmia, and dysgeusia for 3 days. A nasopharyngeal swab was taken showing a strong positive result for SARS-CoV-2 (Cp 14) (RealStar®). Moreover, laboratory analysis showed a mild leukopenia (3.2 × 103/μL) and lymphocytopenia (0.9 × 103/μL), however CRP (1.8 mg/L), neutrophils (1.6 × 103/μL), platelets (168 × 103/μL), and hemoglobin (13.2 × g/dL) were within normal limits. No abnormalities were observed on a bedside chest radiograph (Fig. 1). The patient was placed in home quarantine, but presented himself again 4 days later (1 September) because of persistent complaints with decreased oxygen saturation (93.9%). He was hospitalized and oxygen therapy was started (2 L/min). The oxygen could be stopped after 12 hours (oxygen saturation 99%) and he stayed in the hospital for 1 week with symptomatic treatment. An evaluation for humoral immune deficiency was performed, however no general antibody deficiency was observed by measurement of serum immunoglobulin levels (IgG, IgA, IgM). Only 4 days after his hospital discharge, the patient presented at CHUSP’s ED with dyspnea, productive cough, and chest pain. Laboratory results showed an elevation of D-dimer (4183 ng/mL) and CRP 32 mg/L. The following parameters were within normal limits: leukocytes (8.3 × 103/µL), lymphocytes (1.9 × 103/µL), neutrophils (5.4 × 103/µL), platelets (314 × 103/µL), and hemoglobin (13.0 g/dL). A CT pulmonary angiogram was performed showing pulmonary embolism and ground-glass opacities compatible with viral pneumonia (Fig. 1). Serological analysis performed 158 days after the first episode (14 September), showed the presence of anti-SARS-CoV-2 IgG antibodies to spike protein (130 AE/mL, Diasorin). Anticoagulation by tinzaparin sodium was initiated (followed by rivaroxaban after 14 days, 15 mg twice a day), as well as empirical antibiotic therapy by ceftriaxone (2 g daily for 7 days). No antiviral therapy or supplemental oxygen was started. On 29 September he was discharged, 173 days after the initial episode.\n\nGenome sequencing was performed on nasopharyngeal swabs from the first and second episode with a MinION (Oxford Nanopore Technologies, Oxford, United Kingdom) using the ARTIC network nCoV-2019 sequencing protocols and analytic pipeline by Josh Quick [4]. From the sample of the initial episode, taken 2 weeks after the first symptoms, only a fragmented genome (6028 out of 29903 bps) could be determined, most likely due to a low viral load of the nasopharyngeal swab (Cp 36). A full-length sequence of the second episode could be determined, revealing a lineage B.1. SARS-CoV-2 [5].\n\nSeven mutations were identified across the genome of the two strains (Table 1). Especially the key block mutation at positions 28881 to 28883 (AAC to GGG) in the nucleocapsid phosphoprotein region resulting in an amino acid change (lysine-arginine to arginine-glycine), indicates that the patient suffered from a reinfection [6]. The coverage for this triplet region was 121-fold for the first episode and 1586-fold for the second episode (with presence of the mutation in 100% of the reads).Table 1 Observed mutations between the genomes of the first and second episode\n\nPosition (bp)\tBase change\tGene\t\n241\tC to T\tORF1a\t\n28831\tC to T\tNucleocapsid phosphoprotein\t\n28854\tC to T\tNucleocapsid phosphoprotein\t\n28881–28883\tAAC to GGG\tNucleocapsid phosphoprotein\t\n29034\tA to C\tNucleocapsid phosphoprotein\t\n\nDiscussion and conclusions\n\nThe patient was likely initially infected in the DRC, which counted 134 confirmed cases in the beginning of April 2020, as he already had symptoms during his stay [7]. The viral load tested on his return to Belgium was low. The patient experienced only mild symptoms during this first episode. At that moment, the patient was treated with hydroxychloroquine because of lupus. Since the EUA from FDA for (hydroxy)chloroquine for hospitalized COVID-19 patients, an increasing number of studies have been published with conflicting results about its effectivity [2, 8, 9]. However, little research has been published on the impact of the immunomodulatory effect of (hydroxy)chloroquine on humoral immunity [1, 3]. Chloroquine has been shown to suppress the antibody responses to vaccines against rabies, tetanus, and diphtheria [3]. This can be attributed to the fact that (hydroxy)chloroquine affects functions of proteins involved in antigen-presenting pathways and B-cell activation [3]. In a study of patients with Chikungunya virus infection, it was shown that the adaptive immune response was delayed due to chloroquine treatment in the acute phase [10]. So, hydroxychloroquine treatment may impair host immunity in response to SARS-CoV-2, however the effects on immune cell function have not been extensively examined [11]. As humoral immunity is crucial to fight a SARS-CoV-2 infection, the use of (hydroxy)chloroquine is likely to have a detrimental effect on the spread of the virus [1].\n\nOur patient was treated with hydroxychloroquine for lupus, probably explaining the decreased immune response with negative serology (IgG) 127 days after the initial episode of COVID-19, and subsequent reinfection. At the time of reinfection, the use of hydroxychloroquine was discontinued and an IgG antibody response was detected 158 days after the initial episode. It has been shown that the IgG antibody response after a COVID-19 infection can wane with possible reinfection [12–14]. However, to conclude, our case emphasizes the need for trials about the role of COVID-19 treatment in general, and (hydroxy)chloroquine in particular, on the (humoral) immunity response [3].\n\nAbbreviations\n\nFDA Food and Drug Administration\n\nEUA Emergency use authorization\n\nED Emergency department\n\nDRC Democratic Republic of Congo\n\nSARS-CoV-2 Severe acute respiratory syndrome coronavirus 2\n\nRT-PCR Reverse transcription polymerase chain reaction\n\nCp Crossing point\n\nCT Computed tomography\n\nCOVID-19 Coronavirus disease 2019\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAM: interpretation of laboratory results and writing of the manuscript. OS, IW, SVDW, DP: interpretation of laboratory results. PM and TWB: analysis and interpretation of genome sequencing. TA, OG, MB: clinical care of patient. All authors read and approved the final manuscript.\n\nFunding\n\nThe authors did not receive support from any organization for the submitted work.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was obtained from the Medical Ethics Committee UZ Brussel - VUB (B.U.N. 1432020000310). Written informed consent was obtained from the patient included in the study.\n\nConsent for publication\n\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-in-Chief of this journal.\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. Li X Wang Y Agostinis P Rabson A Melino G Carafoli E Is hydroxychloroquine beneficial for COVID-19 patients? Cell Death Dis 2020 11 7 512 10.1038/s41419-020-2721-8 32641681\n2. Geleris J Sun Y Platt J Zucker J Baldwin M Hripcsak G Observational study of hydroxychloroquine in hospitalized patients with Covid-19 N Engl J Med 2020 382 25 2411 2418 10.1056/NEJMoa2012410 32379955\n3. de Miranda Santos IKF Costa CHN Impact of hydroxychloroquine on antibody responses to the SARS-CoV-2 Coronavirus Front Immunol 2020 11 1739 10.3389/fimmu.2020.01739 32849619\n4. Protocols.io. nCoV-2019 sequencing protocol. https://www.protocols.io/view/ncov-2019-sequencing-protocol-v3-locost-bh42j8ye. Accessed 15 Oct 2020.\n5. Rambaut A Holmes EC O'Toole Á Hill V McCrone JT Ruis C A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology Nat Microbiol 2020 5 11 1403 1407 10.1038/s41564-020-0770-5 32669681\n6. Nextstrain. Genomic epidemiology of novel coronavirus—global subsampling. https://nextstrain.org/ncov/global. Accessed 15 Oct 2020.\n7. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report–74. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200403-sitrep-74-covid-19-mp.pdf?sfvrsn=4e043d03_14. Accessed 1 Sept 2020.\n8. Lammers AJJ Brohet RM Theunissen REP Koster C Rood R Verhagen DWM Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients Int J Infect Dis 2020 101 283 289 10.1016/j.ijid.2020.09.1460 33007454\n9. Horby P Mafham M Linsell L Bell JL Staplin N Emberson JR Effect of hydroxychloroquine in hospitalized patients with Covid-19 N Engl J Med 2020 383 21 2030 2040 10.1056/NEJMoa2022926 33031652\n10. Roques P Thiberville SD Dupuis-Maguiraga L Lum FM Labadie K Martinon F Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection Viruses 2018 10 5 268 10.3390/v10050268\n11. Devarajan A Vaseghi M Hydroxychloroquine can potentially interfere with immune function in COVID-19 patients: mechanisms and insights Redox Biol 2021 38 101810 10.1016/j.redox.2020.101810 33360293\n12. To KK Hung IF Ip JD Chu AW Chan WM Tam AR COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing Clin Infect Dis 2020 10.1093/cid/ciaa1275 32472679\n13. To KK Hung IF Chan KH Yuan S To WK Tsang DN Serum antibody profile of a patient with Coronavirus Disease 2019 reinfection Clin Infect Dis 2021 72 10 e659 e662 10.1093/cid/ciaa1368 32966566\n14. Van Elslande J Vermeersch P Vandervoort K Wawina-Bokalanga T Vanmechelen B Wollants E Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain Clin Infect Dis 2021 73 2 354 356 10.1093/cid/ciaa1330 32887979\n\n",
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"journal": "Journal of medical case reports",
"keywords": "COVID-19; Case report; Hydroxychloroquine; Lupus; Reinfection; SARS-CoV-2",
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"title": "Symptomatic severe acute respiratory syndrome coronavirus 2 reinfection in a lupus patient treated with hydroxychloroquine: a case report.",
"title_normalized": "symptomatic severe acute respiratory syndrome coronavirus 2 reinfection in a lupus patient treated with hydroxychloroquine a case report"
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"abstract": "We report the case of a 62-year-old woman with a history of bilateral hearing impairment, who developed mitochondrial cardiomyopathy after chemotherapy. The patient underwent postoperative cisplatin chemotherapy after the surgical treatment of cervical cancer. The systolic function of her left ventricle decreased significantly. A tissue examination of the left ventricle revealed mitochondrial cardiomyopathy. Genetic testing revealed mutations in mitochondrial 3,243 A→G. Nine hundred fifty-five individual mutations were identified by next-generation sequencing. Since cardiovascular complications are the second leading cause of morbidity and mortality in patients undergoing cancer treatment, mitochondrial cardiomyopathy should be considered a potential cause of heart failure.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.",
"authors": "Yamasaki|Takashi|T|;Yanishi|Kenji|K|;Tateishi|Shuhei|S|;Nakanishi|Naohiko|N|;Zen|Kan|K|;Nakamura|Takeshi|T|;Yamano|Tetsuhiro|T|;Shiraishi|Hirokazu|H|;Shirayama|Takeshi|T|;Matoba|Satoaki|S|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2856659810.2169/internalmedicine.56.8076Case ReportLate-onset Mitochondrial Cardiomyopathy Triggered by Anticancer Treatment Yamasaki Takashi 1Yanishi Kenji 1Tateishi Shuhei 1Nakanishi Naohiko 1Zen Kan 1Nakamura Takeshi 1Yamano Tetsuhiro 1Shiraishi Hirokazu 1Shirayama Takeshi 1Matoba Satoaki 11 Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, JapanCorrespondence to Dr. Kenji Yanishi, yanishi@koto.kpu-m.ac.jp\n\n1 6 2017 56 11 1357 1361 30 7 2016 25 9 2016 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/).We report the case of a 62-year-old woman with a history of bilateral hearing impairment, who developed mitochondrial cardiomyopathy after chemotherapy. The patient underwent postoperative cisplatin chemotherapy after the surgical treatment of cervical cancer. The systolic function of her left ventricle decreased significantly. A tissue examination of the left ventricle revealed mitochondrial cardiomyopathy. Genetic testing revealed mutations in mitochondrial 3,243 A→G. Nine hundred fifty-five individual mutations were identified by next-generation sequencing. Since cardiovascular complications are the second leading cause of morbidity and mortality in patients undergoing cancer treatment, mitochondrial cardiomyopathy should be considered a potential cause of heart failure. \n\nmitochondrial cardiomyopathychemotherapymutationp53\n==== Body\nIntroduction\nAlthough various mitochondrial diseases such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, myoclonic epilepsy with ragged-red fibers, chronic progressive external ophthalmoplegia, and Leigh’s encephalopathy have been described, each of these conditions displays a variety of symptoms. Mitochondrial cardiomyopathy is often one of several symptoms in patients with mitochondrial diseases. The heart primarily relies on the energy produced through aerobic respiration and is one of the organs that is most affected by mitochondrial disease. In general, myocardial hypertrophy is observed to accompany a diminished left ventricular function, cardiac arrhythmias, left ventricular collapse, and heart failure in patients with these conditions. The severity of these conditions is thought to be directly linked to the mutation load, and numerous cases involving the onset of heart-related symptoms in childhood in conjunction with mitochondrial 3,243 A→G mutations have been reported. In addition, cardiotoxic drugs, such as anticancer drugs, can damage the myocardial mitochondria by altering matrix metalloproteases by enhancing the production of reactive oxygen species (ROS), which induces apoptosis.\n\nIn the present case, although mutations of the mitochondrial 3,243 A→G gene were detected by genetic testing, the patient presented no symptoms for approximately 60 years. The turning point was the development of heart failure with anticancer drug therapy. This led to a definitive diagnosis of mitochondrial cardiomyopathy. Late onset cases of mitochondrial cardiomyopathy have not previously been reported. Furthermore, next-generation sequencing revealed several other mitochondrial DNA mutations. We report this case and discuss future challenges.\n\nCase Report\nThe patient was a 62-year-old woman with a history of bilateral hearing impairment. The symptoms had appeared 5 years previously-the cause was unknown. The patient had no family history of sudden death or hearing impairment; however, she had a history of tobacco use for approximately 40 years. Electrocardiogram abnormalities were observed during the preoperative insertion of an applicator, which was performed as a part of a treatment for cervical cancer (stage IV). Diffuse left ventricular hypertrophy and a mildly diminished left ventricular systolic function (ejection fraction [EF]: 47%) were observed on cardiac ultrasonography.\n\nThe patient was determined to be able to safely tolerate surgery, and first underwent surgery for cervical cancer as per the treatment guidelines. The patient underwent postoperative cisplatin chemotherapy after cervical cancer surgery. Following the completion of 5 courses of chemotherapy, dyspnea at rest and edema in both lower extremities were observed. A chest X-ray film revealed marked pulmonary congestion and cardiac ultrasonography indicated a significant decline in the left ventricular systolic function (EF: 22%). In addition, the patient’s brain natriuretic peptide level was markedly elevated at 2,253 pg/mL, and her condition was diagnosed as an acute exacerbation of chronic heart failure. Consequently, she was admitted to the Department of Cardiovascular Medicine for treatment. Diuretics and dobutamine were administered to treat the patient’s heart failure. The excessive extracellular fluid that was present during chemotherapy was considered to have triggered the acute exacerbation of her heart condition.\n\nThe patient’s heart condition improved on the 14th day after admission because of the drug therapy. Thereafter, she was started on beta-blockers, angiotensin-converting enzyme inhibitors, and pimobendan. The patient was discharged on the 40th day after admission with no recurrence of heart failure after cardiac ultrasonography on the 36th day of hospitalization, indicating the improvement of the left ventricular systolic function (EF: 46%). The echocardiogram findings showed the improvement of the left ventricular function, while the examination findings showed the improvement in her class of heart failure (according to the New York Heart Association (NYHA) classification, her brain natriuretic peptide (BNP) level, and the chest X-ray findings; Table 1). Furthermore, there were no findings of increased eosinophilia during the clinical course.\n\nTable 1. The Progression of the Echocardiographic Data and the Examination Findings..\n\nAlthough cardiac magnetic resonance imaging (MRI), drug stress myocardial scintigraphy, and coronary angiography were conducted as part of a close examination to determine the cause of the patient’s diminished left ventricular systolic function, no clear cause was identified. Cardiac MRI showed diffuse hypertrophy in the left ventricular wall (Fig. 1A, B). Late gadolinium enhancement was seen in the basal- to mid-inferolateral wall of the left ventricular subepicardial myocardium (Fig. 1C). Diffuse cardiac hypertrophy was also observed via cardiac ultrasonography, and α-galactosidase activity levels were measured to test for cardiac Fabry disease. Although the patient’s α-galactosidase activity levels were within the normal range, as the patient was female, we were unable to eliminate the possibility of hetero-phenotypic Fabry disease. A myocardial tissue biopsy was taken from the inferior posterior wall of the left ventricle in order to reach a definitive diagnosis. Light microscopy of hematoxylin and eosin-stained sections revealed a lack of myofibrillar disarray, clear cellular reticula, and ceramide deposition within the cellular reticula (Fig. 2A). Although other staining methods were applied, there were no significant findings (Fig. 2B, C, D). In addition, electron microscopy revealed the enargement of the mitochondrial cells (1.0-2.5 μm in diameter), which exhibited abnormal hyperplasia, central core lysis in the cristae, and abnormal concentric circular lamination (Fig. 3). Cerebral white matter lesions and global brain atrophy were observed on cranial MRI, along with bilateral sensorineural hearing impairment. Based on these findings as well as the left ventricular biopsy findings, the patient was definitively diagnosed with MELAS syndrome. Subsequent genetic testing revealed mutations in the mitochondrial 3,243 A→G and 8,348 A→G genes. Next-generation sequencing indicated 955 individual mutations (Table 2). According to the mitochondrial abnormality observed in the left ventricular biopsy specimen and the results of the subsequent genetic testing, we hypothesize that the patient’s pathological condition developed due to compensated mitochondrial cardiomyopathy, which was exacerbated by decompensated heart failure with the administration of cisplatin and chemotherapy.\n\nFigure 1. Cardiac magnetic resonance imaging (MRI). A and B: Perfusion images. C: Delayed gadolinium enhancement.\n\nFigure 2. Light micrographs of a left ventricular endomyocardial biopsy specimen. A: Hematoxylin and Eosin staining (×100). B: Elastica van Gieson staining (×100). C: Periodic acid-Schiff staining (×100). D: Congo red staining (×100).\n\nFigure 3. Electron micrographs of a left ventricular endomyocardial biopsy specimen. Electron microscopy revealed enlarged mitochondrial cells of 1.0-2.5 μm in diameter, which exhibited abnormal hyperplasia, central core lysis in the cristae, and abnormal concentric circular lamination. Scale bars: 2 µm.\n\nTable 2. Subsequent Genetic Testing and Next-generation Sequencing.>\n\nNo.\tChromosome\tStart\tEnd\tReference\tAlternative\tZygosity\tMutation\tDisease\tLiterature\t\n1\tMitochondria\t1,643\t1,643\tA\tG\tHeteroplasmy\t1,643 A→G\tLate infantile onset\t(17)\t\n2\tMitochondria\t3,243\t3,243\tA\tG\tHeteroplasmy\t3,243 A→G\tMELAS\t(18)\t\n3\tMitochondria\t4,833\t4,833\tA\tG\tHeteroplasmy\t4,833 A→G\tDiabetes mellitus\t(19)\t\n4\tMitochondria\t8,348\t8,348\tA\tG\tHeteroplasmy\t8,348 A→G\tCardiomyopathy\t(20)\t\n5\tMitochondria\t9,185\t9,185\tT\tC\tHeteroplasmy\t9,285 T→C\tLeigh’s disease\t(21)\t\n6\tMitochondria\t11,084\t11,084\tA\tG\tHeteroplasmy\t11,084 A→G\tMELAS\t(22)\t\n7\tMitochondria\t12,770\t12,770\tA\tG\tHeteroplasmy\t12,770 A→G\tMELAS\t(23)\t\n8\tMitochondria\t14,693\t14,693\tA\tG\tHeteroplasmy\t14,693 A→G\tMELAS\t(24)\t\nThe major mitochondrial mutations among 955 individual mutations indicated by subsequent genetic testing.\n\nDiscussion\nMELAS syndrome is caused by the most common mitochondrial 3,243 A→G mutation; it is transmitted maternally. The mitochondria are the main producers of adenosine triphosphate (ATP), which supplies the energy for various cellular processes (1). Thus, MELAS syndrome patients present a various conditions of the heart and the brain with a high amount of energy. As a cardiac condition, MELAS syndrome presents ventricular hypertrophy, systolic and diastolic dysfunction, and conduction disturbance (2, 3). The cardiac involvement is progressive and an independent predictor of mortality in patients with mitochondrial disease (4). The mitochondrial function is a key to maintaining the heart function. The homeostasis of the mitochondria is regulated by their fusion, fission, and autophagy, which contribute to the maintenance of the energy production capacity (5, 6). Fission is the separation of the damaged mitochondria and is important during autophagy (7, 8). In addition, autophagy plays a critical role in maintaining myocardial homeostasis and the response to stressors (9). However, recent studies have revealed that these functions diminish with age (6-8). The failure of the mitochondrial function can result from the restriction of these fission and autophagy processes in the damaged mitochondria of aging cardiac tissue (10). Abnormal mitochondrial proliferation and the suppression of mitochondrial decomposition can be confirmed by electron microscopy (10).\n\nCisplatin produces an antitumor effect by inducing p53-dependent apoptosis. Although cisplatin is a first-line drug that is used in the treatment of various cancers, such as uterine, testicular, and prostate cancer, its use is limited because of its side effects, which include the disruption of transcription, the induction of cell cycle arrest, and the induction of ROS production leading to apoptosis (11, 12). ROS production is particularly important with respect to apoptotic pathways. Matrix metalloproteases are altered by the enhanced ROS production, which damages the respiratory chain and induces apoptosis. Cisplatin rapidly accumulates in the mitochondria, resulting in oxidative stress and damaging mitochondrial DNA. As such, the accumulation of cisplatin is thought to result in ROS production in the mitochondria. Previous studies have reported that the accumulation of cisplatin in the mitochondria and the subsequent enhacement of ROS production resulted in damage to the mitochondria as well as toxicity to other cells (13-15). In the present case, cisplatin might have caused the increase in ROS production, which might have increased the mitochondrial damage. Although under normal conditions, the damaged mitochondria are broken down via fission and autophagy, abnormal mitochondrial proliferation was observed by electron microscopy. The existing decline in mitochondrial function may become further pronounced in cases involving mutations in the mitochondrial 3,243 A→G and 8,348 A→G genes. As such, in cases where the mitochondrial function is diminished, the use of drugs that are reported to exhibit cardiotoxic effects and aging can trigger the onset of mitochondrial cardiomyopathy. In the present case, regardless of the mutations that were observed in the mitochondrial 3,243 A→G and 8,348 A→G genes in the cardiomyocytes, the patient displayed no symptoms for 60 years. Numerous cases involving mitochondrial 3,243 A→G gene mutations and the onset of heart conditions in childhood have been reported (16); in the present case, a putative myocardial protection factor may have been responsible. Nine hundred fifty-five individual mutations were identified by next-generation sequencing. These should be further evaluated in future studies.\n\nIn cases involving mitochondrial dysfunction, even drugs with low cardiotoxicity such as cisplatin can lead to the onset of mitochondrial damage-related heart failure. Considering the increase in the number of cancer survivors, the underlying mitochondrial dysfunction caused by oxidative stress or genetic mitochondrial mutations should be considered as a cause of cardiovascular complications in patients undergoing cancer treatment.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nLimongelli G , Masarone D , D'Alessandro R , Elliott PM \nMitochondrial diseases and the heart: an overview of molecular basis, diagnosis, treatment and clinical course . Future Cardiol \n8 : 71 -88 , 2012 .22185447 \n2. \nDi Donato S \nMultisystem manifestations of mitochondrial disorders . J Neurol \n56 : 693 -710 , 2009 .\n3. \nScaglia F , Towbin JA , Craigen WJ , et al \nClinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease . Pediatrics \n114 : 925 -931 , 2004 .15466086 \n4. \nHolmgren D , Wahlander H , Eriksson BO , Oldfors A , Holme E , Tulinius M \nCardiomyopathy in children with mitochondrial disease: clinical course and cardiological findings . Eur Heart J \n24 : 280 -288 , 2003 .12590906 \n5. \nYoule RJ , van der Bliek AM \nMitochondrial fission, fusion, and stress . Science \n337 : 1062 -1065 , 2012 .22936770 \n6. \nSeo AY , Joseph AM , Dutta D , Hwang JCY , Aris JP , Leeuwenburgh C \nNew insights into the role of mitochondria in aging: mitochondrial dynamics and more . J Cell Sci \n123 : 2533 -2542 , 2010 .20940129 \n7. \nRubinsztein DC , Marino G , Kroemer G \nAutophagy and aging . Cell \n146 : 682 -695 , 2011 .21884931 \n8. \nWang K , Klionsky DJ \nMitochondria removal by autophagy . Autophagy \n7 : 297 -300 , 2011 .21252623 \n9. \nIkeda Y , Sciarretta S , Nagarajan N , et al \nNew insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart . Oxid Med Cell Longev \n2014 (Epub ahead of print).\n10. \nHoshino A , Mita Y , Okawa Y , et al \nCytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart . Nat Commun \n4 : 2308 , 2013 .23917356 \n11. \nXu EY , Perlina A , Vu H , et al \nIntegrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model nephrotoxicants . Chem Res Toxicol \n21 : 1548 -1561 , 2008 .18656965 \n12. \nAlborziia H , Can S , Holenya P , et al \nReal-time monitoring of cisplatin-induced cell death . PLoS One \n6 : e19714 , 2011 .21603599 \n13. \nMukhopadhyay P , Horvath B , Zsengeller Z , et al \nMitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy . Free Radic Biol Med \n52 : 497 -506 , 2012 .22120494 \n14. \nSo H , Kim H , Lee JH , et al \nCisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB . J Assoc Res Otolaryngol \n8 : 338 -355 , 2007 .17516123 \n15. \nHamers FP , Brakkee JH , Cavalletti E , et al \nReduced glutathione protects against cisplatin-induced neurotoxicity in rats . Cancer Res \n53 : 544 -549 , 1993 .8425186 \n16. \nTerasaki F , Tanaka M , Kawamura K , et al \nA case of cardiomyopathy showing progression from the hypertrophic to the dilated form . Jpn Circ J \n65 : 691 -694 , 2001 .11446509 \n17. \nDel Mar O'Callaghan M , Emperador S , López-Gallardo E , et al \nNew mitochondrial DNA mutations in tRNA associated with three severe encephalopamyopathic phenotypes: neonatal, infantile, and childhood onset . Neurogenetics \n13 : 245 -250 , 2012 .22638997 \n18. \nRajasimha HK , Chinnery PF , Samuels DC \nSelection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A→G mutation in blood . Am J Hum Genet \n82 : 333 -343 , 2008 .18252214 \n19. \nOhkubo E , Aida K , Chen J , et al \nA patient with type 2 diabetes mellitus associated with mutations in calcium sensing receptor gene and mitochondrial DNA . Biochem Biophys Res Commun \n278 : 808 -813 .11095989 \n20. \nTerasaki F , Tanaka M , Kawamura K , et al \nA case of cardiomyopathy showing progression from the hypertrophic to the dilated form: association of Mt8348A-->G mutation in the mitochondrial tRNA (Lys) gene with severe ultrastructural alterations of mitochondria in cardiomyocytes . Jpn Circ J \n65 : 691 -694 , 2001 .11446509 \n21. \nBannwarth S , Procaccio V , Lebre AS , et al \nPrevalence of rare mitochondrial DNAmutations in mitochondrial disorders . J Med Genet \n50 : 704 -714 , 2013 .23847141 \n22. \nLevin L , Zhidkov I , Gurman Y , et al \nFunctional recurrent mutations in the human mitochondrial phylogeny: dual roles in evolution and disease . Genome Biol Evol \n5 : 876 -890 , 2013 .23563965 \n23. \nLiolitsa D , Rahman S , Benton S , et al \nIs the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? . Ann Neurol \n53 : 128 -132 , 2003 .12509858 \n24. \nTzen CY , Thajeb P , Wu TY , et al \nMELAS with point mutations involving tRNALeu (A3243 G) and tRNAGlu (A14693 g) . Muscle Nerve \n28 : 575 -581 , 2003 .14571459\n\n",
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"abstract": "Idiopathic hyperammonemia is a rare but potentially fatal complication occurring in patients with acute leukemia or bone marrow transplantation. The role of some specific anticancer drugs may be discussed, but the etiology of hyperammonemia is often multifactorial. We report the case of a 40-year-old woman who developed fatal idiopathic hyperammonemia two weeks after induction chemotherapy with idarubicin-aracytine for acute myeloid leukemia. Despite intensive care management and extrarenal epuration, the patient was declared brain dead two days after hyperammonemia onset.",
"affiliations": "Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.;Department of Clinical Chemistry, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.;Department of Pathology, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.;Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.;Department of Hematology, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.;Department of Hematology, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.",
"authors": "Angelo|Christophe|C|;Vincent|Marie-Françoise|MF|https://orcid.org/0000-0002-8217-0657;Komuta|Mina|M|;Hantson|Philippe|P|https://orcid.org/0000-0003-4409-3352;Straetmans|Nicole|N|;Boulet|Edwige|E|",
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"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi 10.1155/2020/3136074Case ReportFatal Idiopathic Hyperammonemia after Induction Chemotherapy for Acute Myeloid Leukemia Angelo Christophe \n1\nhttps://orcid.org/0000-0002-8217-0657Vincent Marie-Françoise \n2\nKomuta Mina \n3\nhttps://orcid.org/0000-0003-4409-3352Hantson Philippe philippe.hantson@uclouvain.be\n1\n\n4\nStraetmans Nicole \n5\nBoulet Edwige \n5\n\n1Department of Intensive Care, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium\n2Department of Clinical Chemistry, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium\n3Department of Pathology, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium\n4Louvain Centre of Toxicology and Applied Pharmacology, Université Catholique de Louvain, 1200 Brussels, Belgium\n5Department of Hematology, Cliniques St-Luc, Université Catholique de Louvain, 1200 Brussels, BelgiumAcademic Editor: Vincent Ribrag\n\n2020 8 2 2020 2020 313607428 10 2019 13 1 2020 21 1 2020 Copyright © 2020 Christophe Angelo 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.Idiopathic hyperammonemia is a rare but potentially fatal complication occurring in patients with acute leukemia or bone marrow transplantation. The role of some specific anticancer drugs may be discussed, but the etiology of hyperammonemia is often multifactorial. We report the case of a 40-year-old woman who developed fatal idiopathic hyperammonemia two weeks after induction chemotherapy with idarubicin-aracytine for acute myeloid leukemia. Despite intensive care management and extrarenal epuration, the patient was declared brain dead two days after hyperammonemia onset.\n==== Body\n1. Introduction\nIdiopathic hyperammonemia (IHA) has been described for the first time in the 1980's after induction chemotherapy for acute leukemia [1]. It has also been occasionally reported in patients receiving bone marrow transplantation or suffering from multiple myeloma [2–4]. This complication occurs often with some delay after the start of chemotherapy, in the absence of underlying liver disease. Among the medications possibly associated with IHA, cytarabine has been frequently cited [1, 5]. As in the here reported observation, the role of other precipitating factors may also be debated. The possible involvement of parenteral nutrition or intestinal microbial proliferation is discussed.\n\n2. Case Presentation\nA 40-year-old woman without previous medical history was admitted to the Haematology Department for progressive fatigue and grade 2-3 dyspnoea which appeared one month before. The physical examination found a patient in a good general condition, but with extreme pallor. Laboratory investigations revealed hemoglobin 5.8 g/dl, white blood cell count 6040/mm³ with 36% blasts, and platelet count 58,000/mm³. Liver function tests were normal. The diagnosis of acute myeloid leukemia (AML) with inv(16)(p13.1q22), CBF-MYH11 (FISH analysis) was obtained. The induction chemotherapy included idarubicin 12 mg/m2 (days 1–3) and aracytine 200 mg/m2 (days 1–7). The diagnosis of acute myeloid leukemia (AML) with inv(16)(p13.1q22), CBF-MYH11 (FISH analysis) was obtained. On day 6, after the initiation of chemotherapy, the patient developed neutropenic fever and empiric treatment with piperacillin/tazobactam was started. She developed cytarabine-induced skin lesions and diffuse pancolitis with ascites. This was confirmed by the findings of the contrast-enhanced abdomen computed tomography (CT) that showed a major oedematous involvement of the caecal mucosa (22 mm) and of the right colonic mucosa; there was also a diffuse distension (3 cm diameter) of the small intestine with a thickening of the last loops (Figure 1). Due to this abdominal complication, parenteral nutrition (Aminomix Novum 3, Fresenius, 1500 ml/day, corresponding to 12 gN) was begun on day 10. The patient was transferred to the intensive care unit (ICU) on day 13 for tachycardia, hypotension, and respiratory distress. The abdomen was distended with absence of bowel sounds. The patient was conscious and oriented, and neurological testing was normal. Chest-X-ray examination did not reveal pneumonia. Arterial blood gas analysis showed pH 7.30, pCO2 32 mmHg, and bicarbonate 20 mmol/l. Serological testing for HBV and HCV antibodies was negative; CMV IgG were >500 U/l. Antimicrobial therapy was switched for ceftazidime and vancomycin after the identification of Enterococcus faecium in bronchoalveolar lavage and blood culture. Hemodynamics remained stable, without need of vasopressors, and repeated blood culture was sterile. Stool culture revealed Gram-positive flora, but no Clostridium difficile nor other pathogens, with the limitation that stool culture was not repeated. On day 16, there was an unexpected impairment of consciousness leading to intubation for coma progression. The plasma ammonia level was 688 μmol/l, with the other relevant laboratory investigations displayed in Table 1. Abdomen ultrasound examination excluded the presence of a portal-systemic shunt. The brain computed tomography did not demonstrate cerebral edema. The electroencephalogram confirmed severe slowing of electrical activity (delta waves, 4 Hz), but without triphasic waves. Analysis of serum amino acids revealed high levels of glutamine, low levels of citrulline, and normal levels of ornithine. There was an extremely high glutamine concentration (7976 μmol/l) into the cerebrospinal fluid (CSF). Parenteral nutrition was interrupted, without any possibility of enteral feeding. Continuous venovenous hemofiltration (CVVH) was started and completed by intermittent hemodialysis, without significant efficacy on ammonia clearance. The patient received also intravenous carnitine supplementation (100 mg/kg/d), lactulose intrarectally, and two doses of rifaximin 550 mg via the nasogastric tube. Coma persisted, with a Glasgow Coma Scale score at 3/15 and delta-wave coma but no seizure activity at repeat EEG. Other causes of encephalopathy were excluded (uremic or sepsis-associated encephalopathy, infectious encephalitis, etc.). According to clinical and electrophysiological criteria, the patient was declared brain dead on day 18 after the start of chemotherapy. At postmortem examination, the liver architecture appeared relatively well preserved with about 10–20% of the hepatocytes presenting ballooning and nuclear loss in the pericentrolobular area. There was no evidence of intestinal necrosis.\n\n3. Discussion\nThis patient developed fatal hyperammonemic encephalopathy less than 3 weeks after the start of induction chemotherapy based on the combination cytarabine-idarubicin to treat a recently diagnosed AML. This delay is consistent with a previous case who developed a similar clinical course on day 21 after having received high-dose cytarabine and mitoxantrone for AML and with other literature cases, even if a shorter delay (a few hours) was occasionally observed [6, 7]. The true incidence of IHA in patients receiving chemotherapy for acute leukemia is not known, as ammonia levels are usually not measured in asymptomatic patients, but reached 2.4% in the largest literature series [8]. Most of these cases occurred in the absence of severe hepatic dysfunction and other causes of hyperammonemia could also be ruled out. Therefore, this hyperammonemia is often classified as idiopathic [1, 2]. We can however assume that most of the systemic ammonia pool is originally generated in the gastrointestinal tract and this was likely the case in the present observation. The clinical presentation is usually characterized by rapidly progressive signs of central nervous system dysfunction including coma and seizures [9]. The prognosis is usually extremely poor, with a mortality rate around 80% [1, 2]. At postmortem examination, brain swelling and herniation are commonly observed. Our observation confirmed the presence of high glutamine levels in the CSF; as a metabolite of ammonia, the intracellular accumulation of glutamine may be responsible for an osmotic effect with astrocyte swelling [1]. The liver is usually free from preexisting disease. Ultrastructural liver changes differ from those observed in Reyes syndrome and usually reveal congestion, fatty infiltration, and cholestasis.\n\nThe origin of hyperammonemia is likely multifactorial. Cytarabine itself contributes very slightly to ammonia formation through a metabolic process of deamination [4]. Among other chemotherapy agents, 5-fluorouracil (5-FU) has also been associated in some cases with hyperammonemia [6]. However, ammonia is a product of 5-FU metabolism, and the clinical course of hyperammonemia is usually transient and benign. L-asparaginase is also often related to IHA with a mechanism that is also not fully understood [10]. There is insufficient evidence to prove that a congenital metabolic disorder is responsible for hyperammonemia. For the patients explored by plasma amino acid determinations, no specific profile could be identified. In our case, a urea cycle defect was unlikely based on slightly low plasma levels of citrulline, but normal plasma levels of ornithine and arginine, absence of argininosuccinate, and normal urinary levels of orotic acid [11]. Our patient had also no evidence of a preexisting congenital liver disease (Wilson's disease, for example). The role of some additional precipitating factors may also be discussed. Among them, sepsis, dehydration, and nitrogen load by parenteral nutrition are commonly found and were present in our patient [1, 9, 12]. The ammonia production could also have been increased by the ileus-related microbial proliferation [13]. Reports of hyperammonemia due to urease-producing bacteria such as Klebsiella spp., Proteus spp., Corynebacterium spp., and Staphylococcus spp. are commonly found, while Enterococcus faecium is not frequently cited [14].\n\nSeveral strategies have been proposed to control hyperammonemia (Table 2) [15]. Some pharmacological agents (sodium benzoate and sodium phenylacetate) have been proposed to promote the elimination of ammonia, with variable outcomes [16]. In addition to ammonia-trapping agents, hemodialysis should be initiated early to promote ammonia elimination [17]. It has been suggested to continue hemodialysis until the blood ammonia concentration has dropped below 200 μmol/l for a period of at least 24 hours. Continuous venovenous hemofiltration (CVVH) is a possible alternative to hemodialysis. Even if it appears less effective than hemodialysis, CVVH is a continuous method that could be maintain for a longer period and could clear newly produced nitrogen [18]. However, these techniques may be limited by ammonia overproduction. The molecular adsorbent recirculating system (MARS) is an epuration technique based upon albumin dialysis. It could promote the elimination of bilirubin, bile acid, ammonia, and cytokines. It has been used with some efficacy in a case of L-asparaginase-related hyperammonemia [19]. Adequate nutritional support is essential to avoid protein catabolism or excessive protein intake by parenteral nutrition. Any medication impairing intestinal motility should be avoided. Finally, the long-term oral administration of a strain (SF68) of Enterococcus faecium was able to reduce the production of ammonia and the severity of encephalopathy in a single study of patients with cirrhosis and a normal dietary nitrogen intake [20]. Other strains (Lactobacillus, Bifidobacterium, etc.) have been tested using the same probiotic approach [15].\n\nConsent\nInformed consent was obtained from the relatives.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nAuthors' Contributions\nChristophe Angelo and Edwige Boulet wrote the paper. Marie-Françoise Vincent performed the specialized laboratory investigations. Mina Komuta performed the postmortem analysis. Philippe Hantson and Nicole Straetmans supervised the patient's management and revised the paper.\n\nFigure 1 Contrast-enhanced abdomen computed tomography with oedematous thickening of the caecal and colonic mucosa.\n\nTable 1 Laboratory data before and after hyperammonemic coma.\n\n \tNormal range\tDay 1 (start of chemotherapy)\tDay 7 (end of chemotherapy)\tDay 13 (ICU admission)\tDay 16 (coma onset)\tDay 17\tDay 18 (death)\t\nMaximal daily temperature (°C)\t \t36.6\t38.4\t38.8\t37.3\t37.2\t35.8\t\nCRP (mg/l)\t<5\t2.6\t236.4\t463.8\t313.6\t292.1\t340.5\t\nAmmonia (μmol/l)\t<64\tn.d.\tn.d.\tn.d.\t688\t1989\t992\t\nTotal bilirubin (mg/dl)\t<1.2\t0.5\t0.8\t5.8\t6.5\t5.7\t6.4\t\nAlkaline phosphatase (IU/l)\t35–105\t40\t28\t21\t35\t37\t42\t\nGamma-glutamyl transpeptidase (IU/l)\t<40\t16\t46\t28\t32\t36\t41\t\nAspartate aminotransferase (IU/l)\t15–35\t12\t12\t45\t28\t37\t42\t\nAlanine aminotransferase (IU/l)\t7–35\t12\t9\t31\t22\t21\t23\t\nInternational normalized ratio\t0.80–1.20\t1.15\t1.53\t1.64\t1.39\t1.42\t1.46\t\nArterial lactate (mmol/l)\t0.5–2.2\tn.d.\tn.d.\t2.8\t2.1\t2.9\t2.7\t\nTriglycerides (mg/dl)\t<150\tn.d.\tn.d.\tn.d.\tn.d.\t513\t390\t\nn.d., not done.\n\nTable 2 Common therapeutic options for hyperammonemia.\n\nIntervention\tMechanism\t\nLactulose\tAcceleration of intestinal transit time\t\nIntestinal antibiotics (digestive decontamination)\tReduction of intestinal microbial proliferation\t\nAdministration of probiotics\tChanges in intestinal microbiota\t\nSodium benzoate/phenylacetate\tConjugation with glycine to form hippuric acid and promote urea excretion\t\nCarnitine\tRegulation of fatty acids metabolism\t\nReduction in protein intake, avoidance of catabolism\tDecreased activity of urea cycle and ammonia production\t\nEpuration techniques (HD, CVVH, MARS)\tIncreased ammonia elimination\n==== Refs\n1 Watson A. J. Karp J. E. Gordon Walker W. Chambers T. Risch V. R. Brusilow S. W. Transient idiopathic hyperammonaemia in adults The Lancet 1985 326 8467 1271 1274 10.1016/s0140-6736(85)91554-5 2-s2.0-0022380694 \n2 Davies S. M. Szabo E. Wagner J. E. Ramsay N. K. Weisdorf D. J. Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation Bone Marrow Transplantation 1996 17 6 1119 1125 8807124 \n3 Kwan L. Wang C. Levitt L. Hyperammonemic encephalopathy in multiple myeloma New England Journal of Medicine 2002 346 21 1674 1675 10.1056/nejm200205233462119 2-s2.0-0037162105 \n4 Fine P. Adler K. Gerstenfeld D. Idiopathic hyperammonemia after high-dose chemotherapy The American Journal of Medicine 1989 86 5 p. 629 10.1016/0002-9343(89)90406-3 \n5 Chen Y.-H. Chiou T.-J. Hsu Y.-N. Liu C.-Y. Idiopathic hyperammonemia after chemotherapy with vinorelbine, topotecan, and cisplatin in a patient with acute lymphocytic leukemia Hematology/Oncology and Stem Cell Therapy 2010 3 4 199 202 10.5144/1658-3876.2010.199 2-s2.0-79952023078 21150241 \n6 Metzeler K. H. Boeck S. Christ B. Idiopathic hyperammonemia (IHA) after dose-dense induction chemotherapy for acute myeloid leukemia: case report and review of the literature Leukemia Research 2009 33 7 e69 e72 10.1016/j.leukres.2009.01.008 2-s2.0-67349120011 19230970 \n7 Liaw C. C. Wang H. M. Wang C. H. Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection Anticancer Drugs 1999 10 3 275 281 10.1097/00001813-199903000-00004 2-s2.0-0032796813 10327032 \n8 Mitchell R. B. Wagner J. E. Karp J. E. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases The American Journal of Medicine 1988 85 5 662 667 10.1016/s0002-9343(88)80239-0 2-s2.0-0024203002 3189370 \n9 Nott L. Price T. J. Pittman K. Patterson K. Fletcher J. Hyperammonemia encephalopathy: an important cause of neurological deterioration following chemotherapy Leukemia & Lymphoma 2007 48 9 1702 1711 10.1080/10428190701509822 2-s2.0-34548596943 17786705 \n10 Leonard J. V. Kay J. D. S. Acute encephalopathy and hyperammonaemia complicating treatment of acute lymphoblastic leukaemia with asparaginase The Lancet 1986 327 8473 162 163 10.1016/s0140-6736(86)92304-4 2-s2.0-0022644970 \n11 Laemmle A. Hahn D. Hu L. Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation Molecular Genetics and Metabolism 2015 114 3 438 444 10.1016/j.ymgme.2015.01.002 2-s2.0-84924190234 25639153 \n12 Kobayashi S. Ito M. Sano H. Idiopathic hyperammonemia that developed during initial treatment with steroid in a patient with newly diagnosed leukemia Journal of Pediatric Hematology/Oncology 2015 37 6 e361 e363 10.1097/mph.0000000000000255 2-s2.0-84938748872 25222063 \n13 Jones E. A. Craigie A. Tavill A. S. Franglen G. Rosenoer V. M. Protein metabolism in the intestinal stagnant loop syndrome Gut 1968 9 4 466 469 10.1136/gut.9.4.466 2-s2.0-0014319395 5677282 \n14 Otsuji K. Simizu S. Endo T. A case of infectious enterocolitis with hyperammonemia Journal of UOEH 2017 39 4 271 276 10.7888/juoeh.39.271 2-s2.0-85038123837 29249740 \n15 Matoori S. Leroux J.-C. Recent advances in the treatment of hyperammonemia Advanced Drug Delivery Reviews 2015 90 55 68 10.1016/j.addr.2015.04.009 2-s2.0-84939563610 25895618 \n16 del Rosario M. Werlin S. L. Lauer S. J. Hyperammonemic encephalopathy after chemotherapy Journal of Clinical Gastroenterology 1997 25 4 682 684 10.1097/00004836-199712000-00026 2-s2.0-0031460362 9451687 \n17 Berry G. T. Bridges N. D. Nathanson K. L. Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation Archives of Neurology 1999 56 4 481 484 10.1001/archneur.56.4.481 2-s2.0-0032918755 10199339 \n18 Wong K. Y. Wong S. N. Lam S. Y. Tam S. Tsoi N. S. Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration Pediatric Nephrology 1998 12 7 589 591 10.1007/s004670050511 2-s2.0-0031681271 9761361 \n19 Beziat G. Tavitian S. Picard M. Faguer S. Recher C. Huguet F. Multiple severe toxicities of L-asparaginase and their innovative management during induction therapy of acute lymphoblastic leukemia in an adult patient Case Reports in Hematology 2019 2019 6 9086570 10.1155/2019/9086570 \n20 Loguerci C. Abbiati R. Rinaldi M. Romano A. Blanco C. D. V. Coltorti M. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy Journal of Hepatology 1995 23 1 39 46 10.1016/0168-8278(95)80309-2 2-s2.0-0029066628 8530808\n\n",
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"title": "Fatal Idiopathic Hyperammonemia after Induction Chemotherapy for Acute Myeloid Leukemia.",
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"abstract": "BACKGROUND\nData regarding the prevalence of metallo-β-lactamases (MBLs) among Pseudomonas aeruginosa isolates in cystic fibrosis patients are scarce. Furthermore, there is limited knowledge on the effect of MBL production on patient outcomes. Here we describe a fatal respiratory infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient and the results of the subsequent epidemiological investigation.\n\n\nMETHODS\nP. aeruginosa isolates collected in the index patient and among patients temporally or spatially linked with the index patient were analyzed in terms of antibiotic susceptibility profile and MBL production. Whole-genome sequencing and phylogenetic reconstruction were also performed for all P. aeruginosa isolates producing VIM-type MBLs. A VIM-producing P. aeruginosa strain was identified in a lung biopsy of a lung transplant recipient with cystic fibrosis. The strain was VIM-1-producer and belonged to the ST308. Despite aggressive treatment, the transplant patient succumbed to the pulmonary infection due to the ST308 strain. A VIM-producing P. aeruginosa strain was also collected from the respiratory samples of a different cystic fibrosis patient attending the same cystic fibrosis center. This isolate harbored the blaVIM-2 gene and belonged to the clone ST175. This patient did not experience an adverse outcome.\n\n\nCONCLUSIONS\nThis is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient. The circulation of P. aeruginosa isolates harboring MBLs pose a substantial risk to the cystic fibrosis population due to the limited therapeutic options available and their spreading potential.",
"affiliations": "Division of Infectious Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy. ela.carugati@gmail.com.;Romeo and Enrica Invernizzi Pediatric Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.;Division of Infectious Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Cystic Fibrosis Microbiology Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Romeo and Enrica Invernizzi Pediatric CRC, Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.;Cystic Fibrosis Microbiology Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Romeo and Enrica Invernizzi Pediatric Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.;Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Romeo and Enrica Invernizzi Pediatric Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via Festa del Perdono 7, 20122, Milan, Italy.;Direzione Medica di Presidio, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Laboratory of Microbiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Division of Infectious Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Romeo and Enrica Invernizzi Pediatric CRC, Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.;Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.;Division of Infectious Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.",
"authors": "Carugati|M|M|https://orcid.org/0000-0002-3187-5905;Piazza|A|A|;Peri|A M|AM|;Cariani|L|L|;Brilli|M|M|;Girelli|D|D|;Di Carlo|D|D|;Gramegna|A|A|;Pappalettera|M|M|;Comandatore|F|F|;Grasselli|G|G|;Cantù|A P|AP|;Arghittu|M|M|;Gori|A|A|;Bandi|C|C|;Blasi|F|F|;Bandera|A|A|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; C417264:VIM-1 metallo-beta-lactamase; D001618:beta-Lactamases",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-020-05338-3",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5338\n10.1186/s12879-020-05338-3\nCase Report\nFatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature\nhttps://orcid.org/0000-0002-3187-5905Carugati M. ela.carugati@gmail.com 12 Piazza A. 3 Peri A. M. 1 Cariani L. 4 Brilli M. 5 Girelli D. 4 Di Carlo D. 3 Gramegna A. 67 Pappalettera M. 6 Comandatore F. 3 Grasselli G. 78 Cantù A. P. 9 Arghittu M. 10 Gori A. 1711 Bandi C. 5 Blasi F. 67 Bandera A. 17 IFALT working group 1 grid.414818.00000 0004 1757 8749Division of Infectious Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n2 grid.26009.3d0000 0004 1936 7961Division of Infectious Diseases and International Health, Duke University, 181 Hanes House, 300 Trent Drive, Durham, 27710 USA \n3 grid.4708.b0000 0004 1757 2822Romeo and Enrica Invernizzi Pediatric Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy \n4 grid.414818.00000 0004 1757 8749Cystic Fibrosis Microbiology Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n5 grid.4708.b0000 0004 1757 2822Romeo and Enrica Invernizzi Pediatric CRC, Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy \n6 grid.414818.00000 0004 1757 8749Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n7 grid.4708.b0000 0004 1757 2822Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via Festa del Perdono 7, 20122 Milan, Italy \n8 grid.414818.00000 0004 1757 8749Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n9 grid.414818.00000 0004 1757 8749Direzione Medica di Presidio, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n10 grid.414818.00000 0004 1757 8749Laboratory of Microbiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy \n11 grid.4708.b0000 0004 1757 2822Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy \n26 8 2020 \n26 8 2020 \n2020 \n20 63521 5 2020 11 8 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\nData regarding the prevalence of metallo-β-lactamases (MBLs) among Pseudomonas aeruginosa isolates in cystic fibrosis patients are scarce. Furthermore, there is limited knowledge on the effect of MBL production on patient outcomes. Here we describe a fatal respiratory infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient and the results of the subsequent epidemiological investigation.\n\nCase presentation\nP. aeruginosa isolates collected in the index patient and among patients temporally or spatially linked with the index patient were analyzed in terms of antibiotic susceptibility profile and MBL production. Whole-genome sequencing and phylogenetic reconstruction were also performed for all P. aeruginosa isolates producing VIM-type MBLs. A VIM-producing P. aeruginosa strain was identified in a lung biopsy of a lung transplant recipient with cystic fibrosis. The strain was VIM-1-producer and belonged to the ST308. Despite aggressive treatment, the transplant patient succumbed to the pulmonary infection due to the ST308 strain. A VIM-producing P. aeruginosa strain was also collected from the respiratory samples of a different cystic fibrosis patient attending the same cystic fibrosis center. This isolate harbored the blaVIM-2 gene and belonged to the clone ST175. This patient did not experience an adverse outcome.\n\nConclusions\nThis is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient. The circulation of P. aeruginosa isolates harboring MBLs pose a substantial risk to the cystic fibrosis population due to the limited therapeutic options available and their spreading potential.\n\nKeywords\nCystic fibrosisLung transplantPseudomonas aeruginosaMetallo-β-lactamasesCase reporthttp://dx.doi.org/10.13039/501100003407Ministero dell’Istruzione, dell’Università e della RicercaARS01_00530issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPseudomonas aeruginosa is a non-glucose fermenter Gram-negative rod, frequently encountered in the respiratory tract of cystic fibrosis patients. P. aeruginosa is characterized by a low natural antimicrobial susceptibility and by an outstanding ability for selecting and spreading antimicrobial resistance in vivo [1, 2].\n\nIn 2018 the European Centre for Disease Prevention and Control (ECDC) reported that 19.2% of the P. aeruginosa invasive isolates tested were resistant to two or more antimicrobial groups [3]. Higher rates of multi-drug resistance were found in the cystic fibrosis population; when P. aeruginosa isolates collected from cystic fibrosis patients in Northern Europe over the period 2006–2012 were analysed, multi-drug resistance was detected in 61.4% of the isolates [4]. Carbapenem resistance was reported by ECDC in 17.2% of the strains tested, with large inter-country variations (0.0% in Iceland, 15.8% in Italy, and 55.1% in Romania) [3].\n\nCarbapenem resistance in P. aeruginosa is mediated by several mechanisms including: i) intrinsic P. aeruginosa resistance, such as the expression of inducible AmpC cephalosporinase, which is associated with a reduced susceptibility to imipenem [5]; ii) acquired resistance through chromosomal gene mutations, such as the mutational inactivation or downregulation of the OprD porin, which drives imipenem resistance and decreases meropenem susceptibility. In addition, the overexpression of efflux pumps of P. aeruginosa plays a major role in mutation-driven resistance [6]; iii) horizontally acquired resistance, such as genes encoding carbapenemases. These genes are typically located in class 1 integrons inserted into transposable elements. Among carbapenemases, metallo-β-lactamases (MBLs) are the most prevalent in P. aeruginosa. While at least nine different types of acquired MBLs have been described, the VIM-type is among the most important for geographic dissemination [7]. Furthermore, the VIM-type has broader substrate specificities and a higher affinity for carbapenems compared to other MBLs [8].\n\nCarbapenemase production, and specifically MBL production, is rarely documented in patients with cystic fibrosis. Mustafa and collaborators did not detect any carbapenemase production when analyzing P. aeruginosa isolates collected from cystic fibrosis patients in Northern Europe [4]. Furthermore, the impact of P. aeruginosa antimicrobial resistance on the outcome of lung transplant in cystic fibrosis patients is still controversial [9]. To the best of our knowledge, four cases of MBLs detection in cystic fibrosis patients have been reported in the literature. Of these, only two reported outcome information and none were characterized by an adverse outcome [10–13]. Here we describe a fatal infection due to VIM-1- producing P. aeruginosa in a cystic fibrosis patient following lung transplantation. We also detail the epidemiological investigation performed in our medical center after the isolation of P. aeruginosa producing VIM-type MBLs.\n\nCase presentation\nMethods\nP. aeruginosa isolates collected in the index patient and among patients linked with the index patient were analyzed. The analysis involved the following steps: i) identification of bacterial isolates and susceptibility profile; ii) detection of carbapenemase activity; iii) whole genome sequencing (WGS) and phylogenetic analysis. Details can be found in the Supplementary Materials.\n\nCase description\nA 29 year-old female with end-stage cystic fibrosis lung disease (FEV1 21%, lung allocation score 47.6) underwent bilateral orthotopic lung transplant in 2018. Pre-transplant respiratory cultures were positive for extensively-drug resistant mucoid and non-mucoid P. aeruginosa with reduced susceptibility to carbapenems. She was exposed to carbapenems approximately 12 months prior to transplant. On day 7 after transplant the patient developed a right pleural empyema, requiring a thoracic drainage and broad-spectrum antimicrobial therapy (amikacin and ceftazidime). Respiratory cultures collected on the same day grew extensively-drug resistant mucoid P. aeruginosa (isolate SK76). SK76 showed a reduced susceptibility to meropenem but results were negative for carbapenemase production (Table 1). On day 34, due to worsening clinical conditions and progression of the infection in the right pleural cavity, the patient was transferred to the intensive care unit (ICU) and a right pneumonectomy was performed. Lung biopsy cultures collected on day 34 grew extensively-drug resistant P. aeruginosa, resistant to carbapenems (isolate SK77). Resistance to carbapenems was mediated by the production of blaVIM-1 carbapenemase (Fig. 1). Despite aggressive antimicrobial treatment (levofloxacin, high-dose colistin and high-dose extended-infusion meropenem) and invasive life-support measures (venous-venous extracorporeal membrane oxygenation and continuous renal replacement therapy), the patient died on day 56.\nTable 1 Antimicrobial susceptibility profiles of the P. aeruginosa isolates SK76, SK77, and SK78\n\n\tSK76\tSK77\tSK78\t\nMIC (mcg / ml)\tMIC (mcg / ml)\tMIC (mcg / ml)\t\nAmikacin\t16\tI\t> 16\tR\t16\tI\t\nGentamicin\t> 4\tR\t> 4\tR\t> 4\tR\t\nTobramycin\t> 4\tR\t> 4\tR\t> 4\tR\t\nCiprofloxacin\t> 1\tR\t0.5\tS\t> 1\tR\t\nLevofloxacin\t> 2\tR\t1\tS\t> 2\tR\t\nColistin\t< 2\tS\t< 2\tS\t< 2\tS\t\nPiperacillin/tazobactam\t< 8\tS\t> 16\tR\t> 16\tR\t\nPiperacillin\t< 8\tS\t> 16\tR\t> 16\tR\t\nCefepime\t> 8\tR\t> 8\tR\t> 8\tR\t\nCeftazidime\t4\tS\t> 32\tR\t> 32\tR\t\nCeftazidime/avibactam\t< 2\tS\t> 8\tR\t> 8\tR\t\nCeftolozane/tazobactam\t< 1\tS\t> 4\tR\t> 4\tR\t\nImipenem\t> 8\tR\t> 8\tR\t> 8\tR\t\nMeropenem\t8\tI\t32\tR\t8\tI\t\nFosfomycin\t> 128\tR\t16\tS\t16\tS\t\nAztreonam\t< 1\tS\t> 256\tR\t> 256\tR\t\nVIM-type carbapenemase\tneg\tpos\tpos\t\nFig. 1 Heatmap of the resistance gene presence/absence of the Pseudomonas aeruginosa isolates SK76, SK77, and SK78. The antimicrobial gene family is shown on the first column on the left\n\n\n\nWhole genome sequencing (WGS) analysis showed that isolates SK76 and SK77 belonged to two different and unrelated Sequence Types (STs): ST253 and ST308, respectively (Fig. 2). Furthermore, SK76 and SK77 harbored a different resistance genes content. SK76 was characterized by the following resistance determinants: aadA7, aac(6′)-Ib7, blaPDC-9, blaOXA-488, blaOXA-20, sul1, and gyrA. On the contrary, the following resistance genes were detected in SK77: blaVIM-1, aadA7, blaPDC-7, blaPER-1, blaOXA-488, and sul1 (Fig. 1).\nFig. 2 Maximum likelihood phylogenetic tree including the three Pseudomonas aeruginosa isolates of the study (SK76, SK77 and SK78) and background strains retrieved from the PATRIC database\n\n\n\nThe detection of VIM-type MBLs among a cystic fibrosis patient prompted an epidemiological investigation in our medical center. All the respiratory cultures of patients attending the adult and pediatric cystic fibrosis center in 2018 were screened for the presence of MBLs. Similarly, all the patients admitted to the intensive care unit at the same time the index patient was admitted were screened for the presence of MBLs-producing isolates. A blaVIM-2 P. aeruginosa isolate was detected in the respiratory cultures of a male patient admitted to our adult cystic fibrosis center in 2018 for fever and worsening respiratory function (isolate SK78). The past medical history of this patient was characterized by: i) chronic colonization with methicillin-susceptible Staphylococcus aureus, mucoid and non-mucoid P. aeruginosa; ii) three respiratory exacerbations requiring treatment with carbapenems in the 12 months prior to the isolation of SK78; iii) end-stage lung disease (FEV1 27%). After the isolation of SK78, the patient was treated with high-dose extended-infusion meropenem and amikacin, without any reported adverse effects. Antimicrobial treatment led to fever remission and global clinical improvement. Twelve months after the isolation of SK78, the patient was still alive with a stable, although severe, pulmonary function (FEV1 27%). Isolate SK78 was characterized by a reduced susceptibility to meropenem and by the following additional resistance genes: aac(6′)-Ib7, blaOXA-50, and gyrA (Table 1 and Fig. 1). SK78 belonged to the epidemic high-risk clone ST175 (Fig. 2). No other MBLs-producing isolates were identified by our epidemiological investigation.\n\nDiscussion and conclusions\nTo the best of our knowledge, this is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a cystic fibrosis lung transplant recipient. Among the four cases of MBLs-producing P. aeruginosa infections in cystic fibrosis patients already available in the literature, only two reported outcome data and only one involved a transplant recipient [10–13].\n\nOur description highlights several substantial issues. First, the broad spectrum of resistance of P. aeruginosa isolates producing MBLs and the limited therapeutic options available for their treatment. Second, the virulence of P. aeruginosa isolates producing MBLs and their impact on the patient outcomes. Third, the spreading potential of P. aeruginosa isolates producing MBLs. Fourth, the need for stringent and efficient antimicrobial stewardship and infection control policies in cystic fibrosis centers.\n\nBroad spectrum of resistance of P. aeruginosa isolates producing MBLs and limited therapeutic options available for their treatment\nThe broad spectrum of resistance of P. aeruginosa isolates producing MBLs restricts therapeutic options to few molecules, such as colistin, fosfomycin, aztreonam, and cefiderocol [7]. Of these, cefiderocol is not yet clinically available. Furthermore, some of these molecules (e.g. colistin) are characterized by a narrow therapeutic window, which contributes to the occurrence of drug-related adverse events. It is also worth noting that the production of MBLs is typically associated with additional resistance mechanisms, as shown by strain SK77 and SK78. For this reason, combination therapies are needed to contain infections due to MBL-producing isolates. There is still no consensus on the most appropriate antibiotic combinations to be used in the setting of these difficult-to-treat infections [14].\n\nVirulence of P. aeruginosa isolates producing MBLs and their impact on the patient outcomes\nThe evaluation of the virulence of P. aeruginosa isolates producing MBLs in comparison to the virulence of sensitive P. aeruginosa strains is a hot topic [15, 16]. Acquisition of resistance is thought to be linked with fitness costs that decrease the virulence of multi-drug resistant P. aeruginosa strains [17–20]. However, several studies reported the presence of resistance mutations not associated with fitness costs and the development of compensatory or suppressor mutations in multi-drug resistant strains. Compensatory and suppressor mutations allow multi-drug resistant strains to regain their initial fitness, so that, in the end they preserve their original virulence [19, 21, 22]. Persoon and collaborators reviewed the charts of 198 patients admitted at the Erasmus Medical Center in Rotterdam (Netherlands) in the period 2008–2016 and who had a culture positive for P. aeruginosa producing blaVIM enzymes. P. aeruginosa producing blaVIM enzymes isolates were strongly associated with the death of 32 patients, leading to a 16.2% attributable mortality [23]. While the infection with strain SK77 likely contributed to the death of our female patient, the infection with strain SK78 did not substantially alter the clinical course of our male patient. Whether the adverse outcome of our female patient was mainly due to the pathogenicity of the VIM-producing isolate or to the severe pre-existing comorbidities of the host is difficult to be ascertained.\n\nSpreading potential of P. aeruginosa isolates producing MBLs\nMBLs are generally located on transposable genetic elements, which largely increases the spreading potential of these strains. Furthermore, ST308 is a recently reported emerging high-risk clone, while ST175 is among the three major international high-risk extensively-drug resistant clones and is widely distributed in several European countries [24]. Although isolates SK77 (ST308) and SK78 (ST175) did not cause an outbreak in our medical center, their spreading potential cannot be ignored. In this setting, appropriate epidemiological investigations and stringent infection control procedures are mandatory.\n\nNeed for stringent and efficient antimicrobial stewardship and infection control policies in cystic fibrosis centers\nThe selective antimicrobial pressure promoted by broad-spectrum agents favors the emergence of resistant strains. Specifically, previous studies have shown an association between the use of piperacillin/tazobactam, quinolones, and cephalosporins and the emergence of VIM-positive P. aeruginosa isolates [25]. Furthermore, cystic fibrosis patients harboring MBLs in their respiratory tract may serve as hospital sources of carbapenemases. The acquisition of extensively-drug resistant P. aeruginosa isolates, especially clonal isolates, is known to be associated with increased pulmonary exacerbation rate, exaggerated lung function decline, and progression to end-stage lung disease [26]. For these reasons, segregation of patients harboring MBLs and environmental decontamination of areas where these patients transitioned may be need in order to avoid the dissemination of VIM-positive P. aeruginosa isolates in cystic fibrosis centers [13].\n\nDespite the relevance of the data presented, this study has several limitations. We did not confirm the location of the blaVIM genes in class 1 integrons in the bacterial chromosome of the P. aeruginosa isolates evaluated. Genes encoding carbapenemases are generally found in class 1 integrons along with determinants of aminoglycoside resistance. These integrons are often inserted into transposable elements, which contributes to the spreading potential of these strains. Furthermore, we did not perform virulence studies. Our epidemiological investigation was restricted to the year 2018: the circulation of P. aeruginosa strains harboring MBLs in our medical center before 2018 was not assessed. Finally, our epidemiological investigation was limited to patients: potential environmental sources of P. aeruginosa isolates producing MBLs were not evaluated and the sources of the isolates SK77 and SK78 were not identified.\n\nIn summary, we described the first fatal infection due to P. aeruginosa producing VIM-type MBLs in a cystic fibrosis lung transplant recipient. P. aeruginosa producing VIM-type MBLs represents a matter of concern because of the limited therapeutic options available and its dissemination potential, especially in the setting of fragile hosts, such as cystic fibrosis patients.\n\nSupplementary information\n\nAdditional file 1.\n\n\n \n\nAbbreviations\nECDCEuropean Centers for Disease Prevention and Control\n\nFEV1Forced expiratory volume in the first second\n\nICUIntensive care unit\n\nMBLSMetallo-β-lactamases\n\nSTsSequence types\n\nWGSWhole genome sequencing\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12879-020-05338-3.\n\nWe acknowledge the scientific contribution and support of the IFALT working group. Internal Medicine Department, Division of Infectious Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano (Milano, Italy): Laura Alagna, Marina Allegrini, Alessandra Bandera, Matteo Bolis, Manuela Carugati, Valentina Ferroni, Andrea Gori, Teresa Itri, Davide Mangioni, Debora Mondatore, Valeria Pastore, Federica Portunato. Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano (Milano, Italy): Stefano Aliberti, Francesco Blasi, Letizia Corinna Morlacchi, Martina Oriano, Valeria Rossetti, Paolo Tarsia, Leonardo Terranova. Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano (Milano, Italy): Rosaria Carrinola, Francesco Damarco, Paolo Mendogni, Mario Nosotti. Alessandro Palleschi, Ilaria Righi, Lorenzo Rosso, Davide Tosi. Pathology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano (Milano, Italy): Stefano Bogetto Ferrero. Department of Department of Pathophysiology and Transplantation, Università degli Studi di Milano (Milano, Italy): Mario Clerici, Claudio Fenizia, Daria Trabattoni. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (Milano, Italy): Claudia Alteri, Carlo Federico Perno. Department of Clinical and Experimental Medicine, Università degli Studi di Sassari (Sassari, Italy): Giovanni Sotgiu. Genprobio srl: Marco Ventura, Claudio Pessina. Prossima Isola srl: Daniele Idini.\n\nAuthors’ contributions\nConceptualization: M.C., A.M.P., C.B., F.B., A.G2., A.B. Methodology: M.C., A.M.P., L.C., A.P, A.B. Lab analysis: L.C, D.G., M.A., A.P., M.B., F.C., D.C.D. Writing, original draft preparation: M.C., A.P., L.C, A.G1. Writing, review and editing: A.G1., M.P., G.G., A.P.C., IFALT working group. Supervision: C.B., F.B., A.G2., A.B. The author(s) read and approved the final manuscript.\n\nFunding\nThis research was funded by the Italian ‘Ministero dell’Istruzione, dell’Università e della Ricerca’, grant number ARS01_00530. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nEthics approval and consent to participate\nThe submission of this case report for publication was notified to the local IRB (Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy) and the need for ethics approval was waived. The patient attending our adult cystic fibrosis center and in whom blaVIM-2 was detected signed written informed consent for participation in this case report.\n\nConsent for publication\nThe patient attending our adult cystic fibrosis center and in whom blaVIM-2 was detected signed written informed consent for publication in this study of his personal clinical details.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Poole K Pseudomonas aeruginosa: resistance to the max Front Microbiol 2011 2 65 10.3389/fmicb.2011.00065 21747788 \n2. Breidenstein EBM de la Fuente C Hancock R Pseudomonas aeruginosa: all roads lead to resistance Trends Microbiol 2011 19 419 426 10.1016/j.tim.2011.04.005 21664819 \n3. European Centre for Disease Prevention and Control Surveillance of antimicrobial resistance in Europe 2018 2019 Stockholm ECDC \n4. 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Pollini S Fiscarelli E Mugnaioli C Di Pilato V Ricciotti G Neri AS Pseudomonas aeruginosa infection in cystic fibrosis caused by an epidemic metallo-β-lactamase-producing clone with a heterogeneous carbapenem resistance phenotype Clin Microbiol Infect 2011 17 1272 1275 10.1111/j.1469-0691.2011.03466.x 21375657 \n13. Pollini S Mugnaioli C Dolce D Campana S Neri AS Taccetti G Chronic infection sustained by a Pseudomonas aeruginosa high-risk clone producing the VIM-1 metallo-β-lactamase in a cystic fibrosis patient after lung transplantation J Cyst Fibros 2018 17 470 474 10.1016/j.jcf.2018.01.007 29444761 \n14. Petrosillo N Ioannidou E Falagas ME Colistin monotherapy vs. combination therapy: evidence from microbiological, animal and clinical studies Clin Microbiol Infect 2008 14 816 827 10.1111/j.1469-0691.2008.02061.x 18844682 \n15. Juan C Pena J Oliver A Host and pathogen biomarkers for severe Pseudomonas aeruginosa infections J Infect Dis 2017 215 S44 S51 10.1093/infdis/jiw299 28375513 \n16. Gomez-Zorrilla S Juan C Cabot G Camoez M Tubau F Oliver A Impact of multidrug resistance on the pathogenicity of Pseudomonas aeruginosa: in vitro and in vivo studies Int J Antimicrob Agents 2016 47 368 374 10.1016/j.ijantimicag.2016.02.010 27079153 \n17. Andersson DI The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 2006 9 461 465 10.1016/j.mib.2006.07.002 16890008 \n18. Andersson DI Hughes D Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 2010 8 260 271 10.1038/nrmicro2319 20208551 \n19. Olivares Pacheco J Alvarez-Ortega C Alcalde Rico M Martinez JL Metabolic compensation of fitness costs is a general outcome for antibiotic-resistant Pseudomonas aeruginosa mutants overexpressing efflux pumps mBio 2017 8 e00500 e00517 10.1128/mBio.00500-17 28743808 \n20. Sun Z Jiao X Peng Q Jiang F Huang Y Zhang J Antibiotic resistance in Pseudomonas aeruginosa is associated with decreased fitness Cell Physiol Biochem 2013 31 347 354 10.1159/000343372 23485684 \n21. Skurnik D Roux D Cattoir V Danilchanka O Lu X Yoder-Himes DR Enhanced in vivo fitness of carbapenem-resistant oprD mutants of Pseudomonas aeruginosa revealed through high-throughput sequencing Proc Natl Acad Sci U S A 2013 110 20747 20752 10.1073/pnas.1221552110 24248354 \n22. Suarez C Pena C Gavald L Tubau F Manzur A Dominguez MA Influence of carbapenem resistance on mortality and the dynamics of mortality in Pseudomonas aeruginosa bloodstream infection Int J Infect Dis 2010 14 e73 e78 10.1016/j.ijid.2009.11.019 \n23. Persoon MC Voor AF van Meer MPA Bokhoven KC Gommers D Vos MC Mortality related to Verona Integron encoded Metallo-β-lactamase-positive Pseudomonas aeruginosa: assessment by a novel clinical tool Antimicrob Resist Infect Control 2019 8 107 10.1186/s13756-019-0556-9 31244998 \n24. Abdouchakour F Aujoulat F Licznar-Fajardo P Marchandin H Toubiana M Parer S Intraclonal variations of resistance and phenotype in Pseudomonas aeruginosa epidemic high-risk clone ST308: a key to success within a hospital? Inter J Med Microbiol 2018 308 279 289 10.1016/j.ijmm.2017.11.008 \n25. Voor AF Severin JA Hagenaars MBH de Goeij I Gommers D Vos MC VIM-positive Pseudomonas aeruginosa in a large tertiary care hospital: matched case control studies and a network analysis Antimicrob Resist Infect Control 2018 7 32 10.1186/s13756-018-0325-1 29492262 \n26. Parkins MD Somayaji R Waters VJ Epidemiology, biology, and impact of clonal Pseudomonas aeruginosa infections in cystic fibrosis Clin Microbiol Rev 2018 31 e00019 10.1128/CMR.00019-18 30158299\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "20(1)",
"journal": "BMC infectious diseases",
"keywords": "Case report; Cystic fibrosis; Lung transplant; Metallo-β-lactamases; Pseudomonas aeruginosa",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003550:Cystic Fibrosis; D024901:Drug Resistance, Multiple, Bacterial; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D008826:Microbial Sensitivity Tests; D010802:Phylogeny; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D012141:Respiratory Tract Infections; D066027:Transplant Recipients; D001618:beta-Lactamases",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "635",
"pmc": null,
"pmid": "32847524",
"pubdate": "2020-08-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23485684;20223693;20208551;28375513;29276044;18844682;27572406;18276121;29444761;16890008;31462403;8373273;12562689;31341563;31244998;21664819;29492262;21747788;17682106;24248354;28743808;21375657;21530894;30158299;27079153",
"title": "Fatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature.",
"title_normalized": "fatal respiratory infection due to st308 vim 1 producing pseudomonas aeruginosa in a lung transplant recipient case report and review of the literature"
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"abstract": "Diagnosis of hemophagocytic syndrome remains a challenge in particular during pregnancy. Concomitant presence of clinical and biological signs, for example, fever, pancytopenia, hyperferritinemia, and hypertriglyceridemia, should alert clinicians to suspect HPS and proceed to prompt treatments.",
"affiliations": "Obstetrics and Gynecology Service Brest Medical University Hospital Brest France.;Inserm CIC 1412 Brest Medical University Hospital Brest France.;Department of Internal Medicine Brest Medical University Hospital Brest France.;Obstetrics and Gynecology Service Brest Medical University Hospital Brest France.;Obstetrics and Gynecology Service Brest Medical University Hospital Brest France.;Department of Internal Medicine Brest Medical University Hospital Brest France.;Obstetrics and Gynecology Service Brest Medical University Hospital Brest France.",
"authors": "Rousselin|Aline|A|;Alavi|Zarrin|Z|;Le Moigne|Emmanuelle|E|;Renard|Sarah|S|;Tremouilhac|Christophe|C|;Delluc|Aurélien|A|;Merviel|Philippe|P|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1172CCR31172Case ReportCase ReportsHemophagocytic syndrome in pregnancy: case report, diagnosis, treatment, and prognosis A. Rousselin et al.Rousselin Aline elinarousselin31@gmail.comaline.rousselin@chu-brest.fr \n1\nAlavi Zarrin \n2\nLe Moigne Emmanuelle \n3\nRenard Sarah \n1\nTremouilhac Christophe \n1\nDelluc Aurélien \n3\nMerviel Philippe \n1\n\n1 \nObstetrics and Gynecology Service\nBrest Medical University Hospital\nBrest\nFrance\n\n2 \nInserm CIC 1412\nBrest Medical University Hospital\nBrest\nFrance\n\n3 \nDepartment of Internal Medicine\nBrest Medical University Hospital\nBrest\nFrance\n* Correspondence\n\nAline Rousselin, Obstetrics and Gynecology service, Centre Hospitalier Régional Universitaire de Brest, 29200 Brest, France. Tel: +33 (0) 619258745; Fax: +33 2 29 02 00 17; E‐mails: elinarousselin31@gmail.com and aline.rousselin@chu-brest.fr\n12 9 2017 11 2017 5 11 10.1002/ccr3.2017.5.issue-111756 1764 17 3 2017 28 6 2017 07 8 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nDiagnosis of hemophagocytic syndrome remains a challenge in particular during pregnancy. Concomitant presence of clinical and biological signs, for example, fever, pancytopenia, hyperferritinemia, and hypertriglyceridemia, should alert clinicians to suspect HPS and proceed to prompt treatments.\n\nCase reportdiagnosishemophagocytic syndromeoocyte donationpregnancy source-schema-version-number2.0component-idccr31172cover-dateNovember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:08.11.2017\n\nClinical Case Reports \n2017 ; 5 (11 ): 1756 –1764\n==== Body\nIntroduction\nMacrophage activating syndrome is also called hemophagocytic syndrome (HPS). It may be primary as in familial hemophagocytic lymphohistiocytosis (HLH), Chediak–Higashi, Griscelli, and Purtilo syndromes, or secondary as in case of malignancies hemato‐oncology, oncologic diseases, infectious diseases, or autoimmune disease. HPS is rare but underdiagnosed and can be life‐threatening if undiagnosed. Its incidence is estimated between 0.8% and 4% cases per year including pediatric and adult HPS 1.\n\nHemophagocytic syndrome is known since the 1950s, and further described by Risdall et al. 2. The pathophysiology consists of activation of T lymphocytes and natural killer cells (HLH), either secondary to an opportunistic infection, or primary due to a deficiency of immunomodulatory mechanisms.\n\nThis HLH immune activation leads to a high production of pro‐inflammatory cytokines. These cytokines activate the monocyte–macrophage system and enhance the HLH in a positive feedback 3, 4, 5, 6, 7.\n\nThese macrophages are responsible for hemophagocytosis expressed clinically by various symptoms such as fever, lymphadenopathy, hepatosplenomegaly. Clinical presentation of these signs strongly suggests HPS.\n\nHemophagocytic syndrome occurrence in pregnancy is rare and there are only a few reported cases in the literature 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. Here, we describe a case of HPS during the third trimester (30 weeks of gestational age (GA)) of pregnancy: its diagnosis, treatment, and fetal and maternal outcomes. This case is further compared with the literature to set forth a proposal for advancement of best clinical practices in HPS during pregnancy.\n\nMethods\nWe present here the case of a primigravida 44‐year‐old woman who presented at 30 weeks GA + 4 days to the emergency room for fever of 39.4°C associated with a cough since 15 days. This patient had a history of primary infertility salpingectomy for hydrosalpinx. Raynaud syndrome with positive antinuclear antibodies (e.g., antiribonucleoproteins) and moderate peripheral thrombocytopenia have been diagnosed since 2 years. Antiphospholipid antibodies were negative. The pregnancy was achieved by in vitro fertilization with oocyte donation. Despite abnormal (i.e., dark circles on the legs and arms) skin pigmentation early in pregnancy, the diagnosis of lupus (i.e., before pregnancy onset, she has been followed up for thrombocytopenia and suspicion of autoimmune disease) or Sharp syndrome (mixed connective tissue disease) could not be confirmed. Nevertheless, given the suspicion of autoimmune disease, aspirin 75 mg/day was started.\n\nAt the emergency room, the patient presented with fever of 39.4°C, blood pressure at 99/62 mmHg, heart rate at 121/min, and oxygen saturation at 98% on room air. There was no history of infection or recent travel. The chest radiography showed some pulmonary infiltrates. Other clinical examinations were normal except for the presence of submandibular adenopathy. Blood biology workup showed moderate pancytopenia and inflammatory syndrome (Table 1). The fetal heart rate recording showed tachycardia (i.e., due to the high fever, 170 beats per min). As a result, the patient was hospitalized in gynecology–obstetrics unit (Fig. 1). Intravenous antibiotic (amoxicillin 1 g tid) was started and the baseline laboratory workups (urinary and blood bacteriological analyses) were negative.\n\nTable 1 Laboratory trends from baseline to Day 9\n\n\tD0\tD2\tD3\tD4\tD9\t\nTemperature (°C)\t39.4\t38.2\t–\t36.1\t37\t\nHemoglobin (g/dL)\t8.4\t8.6\t9.3\t7.9\t9\t\nPlatelets (Giga/L)\t130\t107\t103\t85\t74\t\nLeukocytes (Giga/L)\t3.4\t2\t2.1\t–\t3.1\t\nLymphocytes (Giga/L)\t–\t0.37\t0.58\t–\t0.73\t\nPolynuclear neutrophils (Giga/L)\t–\t1.42\t1.3\t0.6\t2.11\t\nC‐reactive Protein (mg/L)\t64\t90.6\t121\t160\t47\t\nALAT (UI/L)\t–\t–\t–\t51\t–\t\nASAT (UI/L)\t–\t–\t–\t106\t–\t\nHaptoglobin (g/L)\t–\t–\t–\t<0.1\t–\t\nLDH (UI/L)\t–\t–\t–\t1520\t–\t\nFibrinogen (g/L)\t4.45\t4.45\t4.89\t4.89\t–\t\nCephalin clotting time\t–\t–\t–\t1.34\t–\t\nKaolin clotting time\t–\t–\t–\t1.16\t–\t\nTriglyceridemia (mg/dL)\t–\t–\t–\t2.85\t–\t\nFerritinemia (μg/L)\t–\t–\t–\t1373\t498\t\nPotassium (mmol/L)\t–\t–\t–\t3.4\t–\t\nProteinuria (g/L)\t–\t–\t–\t0.45\t–\t\nJohn Wiley & Sons, LtdFigure 1 The investigative approaches and initial treatments.\n\nWithin a few hours of antimicrobial therapy, there was an improvement of pulmonary symptoms, yet a deterioration of pancytopenia.\n\nUpon patient's arrival to the internal medicine unit, a bi‐antimicrobial therapy with azithromycin and amoxicillin was started. After 48 h of treatment, new biological deteriorations were observed (Table 1): moderate hepatic cytolysis, cholestasis, hemolysis, low potassium, hypertriglyceridemia, hyperferritinemia, inflammatory syndrome, elevated proteinuria (with normal blood pressure), and deterioration of pancytopenia.\n\nAdditional laboratory workup in search for antinuclear antibodies showed very slight amount (one positive antinuclear antibodies reading out of 320). All infectious explorations were negative (blood culture, cytobacteriological examination of urine, parvovirus B 19 serology, and PCR, searching for pneumococcus, legionella, mycoplasma pneumoniae, and chlamydiae, EBV, HCV, TPHA, and VDRL, and HIV serology, and tuberculosis). The patient had immunity against CMV, rubella, and toxoplasmosis.\n\nDeterioration of liver function warranted an abdominal ultrasound which showed isolated and moderate hepatomegaly.\n\nHemophagocytic syndrome was suspected given the clinicobiological characteristics associating fever, hepatomegaly, pancytopenia, hyperferritinemia, and hypertriglyceridemia. This diagnosis was promptly confirmed by myelogram (Fig. 2).\n\nFigure 2 Attached macrophages forming a giant cell with multiple nuclei. Phagocytosis of red blood cells and platelets.\n\nThe myelogram did not show abnormal cells such as Sternberg, or osteoblasts, or osteoclasts. Given the HPS confirmation, parenteral glucocorticosteroids (GC) were started (methylprednisolone at 1 mg/kg). Maturation of fetal lungs was achieved. At the same time, antibiotic spectrum was again enlarged and amoxicillin was replaced with cefotaxime. The clinical and biological evolution became promptly satisfactory. Thromboprophylaxis was started.\n\nIn obstetric terms, fetal ultrasound monitoring showed intrauterine growth restriction below the 3rd percentile (i.e., fetal weight: 1548 g at 32 GA + 3 days), with normal fetal and maternal vascular ultrasound. At 38 GA + 4 days, because of the low weight for intrauterine growth restriction (i.e. 2258 g ± 15%), gestational diabetes, and detected oligohydramnios, it was decided to induce labor. The patient gave birth at 38 GA + 6 days, to a girl weighing 2380 g (1st percentile) and in good health.\n\nDuring the postpartum, oral GC prednisolone was continued for 4 weeks at the dosage of 60 mg per day. A decrease in dosage was scheduled at 3 months postpartum. No HPS relapse occurred after discontinuation of GC and no new autoimmune disease symptoms were found during follow‐up. The newborn's 8‐month clinical examination showed a normal growth without any sign of neurological damage.\n\nResults\nTables 2 and 3 display the review of HPS peri‐pregnancy data from the literature and our work.\n\nTable 2 Displays the results of the comparison between our case and the related literature (first part)\n\nAuthors/[biblio]\tGestational age (weeks)\tMaternal age (years)\tKnown risk factors\tPrepartum complications\tClinical signs\tLaboratory work up\tHPS etiology\tStudy year\t\nGill et al. 11\n\t18\t30\tNo\tNon\tFever, hepatomegaly\tPancytopenia, cytolysis\tUnclear\t1994\t\nMihara et al. 10\n\t16\t32\tNo\tNon\tFever\tPancytopenia, hyperferritinemia, markedly elevated LDH\tEBV\t1999\t\nNakabayashi et al. 13\n\t21\tND\tNo\tPreeclampsia, DIVC, IUGR\tFever\tThrombopenia, leukopenia, cytolysis\tUnclear\t1999\t\nChmait et al. 9\n\t29\t24\tNo\tDIVC\tAdenopathy, fever\tPancytopenia, cytolysis\tEBV (postmortem diagnosis)\t2000\t\nYamagushi et al. 17\n\t2nd trimester\tND\tNo\tNo\tFever, skin lesions\tPancytopenia, hypertriglycemia, hyperferritinemia, cytolysis\tHSV\t2005\t\nPérard et al. 12\n\t22\t28\tLupus\tPreeclampsia\tFever\tPancytopenia, hypertriglycemia, hyperferritinemia\tLupus\t2007\t\nHahaoka et al. 27\n\t23\t33\tNo\tLymphoma diagnosed\tFever, hepatosplenomegaly\tPancytopenia\tB‐cell Lymphoma\t2007\t\nTeng et al. 8\n\t23\t28\tNo\tTransfusion for anemia compensation and dyspnea improvement\tFever, hepatosplenomegaly\tAnemia, thrombopenia, hypertriglycemia\tAutoimmune hemolytic anemia\t2009\t\nShukla et al. 28\n\t23\t10\tNo\tNo\tFever, hepatosplenomegaly\tPancytopenia, hypertriglycemia, hyperferritinemia\tUnclear\t2011\t\nArewa et al. 16\n\t21\t31\tNo\tNo\tFever, jaundice, abdominal pain\tPancytopenia\tHIV\t2011\t\nHannebicque Montaigne et al. 5\n\t29\t21\tMixed connectivitis (lupus, cryoglobulinemia, Gougerot–Sjogren)\tICU transfer at 22 GA due to vascular failure, bilateral PE, at 25 GA\tFever\tPancytopenia, hyperferritinemia, hypertriglycemia\tLupus\t2012\t\nDunn et al. 14\n\t19\t41\tStill disease\tNo\tFever, skin lesions\tCytolysis, anemia, leukopenia, hypertriglycemia, hyperferritinemia\tStill Disease\t2012\t\nMayama et al. 19\n\t21\t28\tNo\tNo\tFever\tPancytopenia hyperferritinemia\tParvovirus B 19\t2014\t\nTumian et al. 15\n\t38\t35\tNo\tNo\tJaundice\tAnemia, thrombopenia, hypertriglycemia, cytolysis\tCMV (postmortem diagnosis)\t2015\t\nSamra et al. 18\n\t16\t36\tNo\tNo\tFever, hepatosplenomegaly\tPancytopenia, hyperferritinemia\tUnclear\t2015\t\nCurrent\t30\t44\tRaynaud syndrome\tAutoimmune\tFever, hepatomegaly\tPancytopenia, hyperferritinemia et hypertriglycemia, cytolysis\tHistory of autoimmune disease\t2015\t\nND, Not documented; IUGR, intrauterine growth retardation; DIVC, disseminated intravascular coagulation; PE, pulmonary embolism; GA, gestational age; CMV, cytomegalovirus; HSV, herpes simplex virus; HIV, human immunodeficiency virus; ICU, intensive care unit; EBV, Epstein–Barr virus.\n\nJohn Wiley & Sons, LtdTable 3 Displays the results of the comparison between our case and the related literature (second part)\n\nAuthors/[biblio]\tPrepartum treatments\tMortality risk factors\tC‐section yes/no\tNeonatal gestational age (weeks)\tNeonatal outcome\tMaternal outcome\tStudy year\t\nGill et al. 11\n\tIg IV\tAnemia + thrombopenia\tNo\tFull‐term\tAlive\tAlive\t1994\t\nMihara et al. 10\n\tGlucocorticoides, Ig IV, aciclovir, gabexate\tDIVC, age >30\tNo\t35\tAlive\tAlive\t1999\t\nNakabayashi et al. 13\n\tIgIV\tPreeclampsia, DIVC\tYes\t29\tAlive (respiratory distress)\tAlive\t1999\t\nChmait et al. 9\n\tIg IV, Aciclovir\tDIVC\tYes\t30\tAlive\t\nDead\n\nmulti‐organ failure\n\t2000\t\nYamagushi et al. 17\n\tGlucocorticoides, cyclosporine, aciclovir\tHyperferritinemia\tYes (breech presentation)\t37\tAlive\tAlive\t2005\t\nPérard et al. 12\n\tGlucocorticoides, IgIV\tAnemia + thrombopenia + hyperferritinemia\tNo\t30\tAlive\tAlive (postpartum cerebral hemorrhage)\t2007\t\nHahaoka et al. 27\n\tChemotherapy R‐CHOP, Cell transplantation\tAge >30, anemia + thrombopenia\tYes\t28 (fetal distress)\tAlive\tAlive\t2007\t\nTeng et al. 8\n\tGlucocorticoides (treatment failure, improvement after birth)\tAnemia + thrombopenia\tYes\t29\tDead (respiratory distress)\tAlive\t2009\t\nShukla et al. 28\n\tGlucocorticoides, abortion\tAnemia + thrombopenia, hyperferritinemia\tNo\t10\tSpontaneous miscarriage\tAlive\t2011\t\nArewa et al. 16\n\tAntimalaria, HAART\tAge >30, anemia + thrombopenia\tNo\tFull‐term\tAlive\tAlive\t2011\t\nHannebicque Montaigne et al. 5\n\tIg IV, glucocorticoides\tAnemia + thrombopenia + hyperferritinemia\tNo\t38\tAlive (neuro postnatal follow‐up, MRI visible cerebral anoxia (asphyxial stigmata)\tAlive\t2012\t\nDunn et al. 14\n\tGlucocorticoides\tAge >30\tYes (IUGR + twin pregnancy)\t30\tAlive\tAlive\t2012\t\nMayama et al. 19\n\tGlucocorticoides\tHyperferritinemia\tNo\t38\tAlive\tAlive\t2014\t\nTumian et al. 15\n\t\nPostpartum onset: glucocorticoides\n\nIgIV, cyclosporine\n\tAge >30, DIVC, retard diagnostic\tYes (fetal distress)\t38\tAlive\tDead multi‐organ failure\t2015\t\nSamra et al. 18\n\tGlucocorticoides\tAge >30, hyperferritinemia\tNo\tFull‐term\tAlive\tAlive\t2015\t\nCurrent\t\nAntibiotherapies\n\nglucocorticoides\n\tAge >30, hyperferritinemia\tNo\t38\tAlive\tAlive\t2015\t\nIUGR, intrauterine growth retardation; DIVC, disseminated intravascular coagulation; Ig IV, immunoglobulin intravenous; HAART, highly active antiretroviral therapy.\n\nJohn Wiley & Sons, LtdHPS diagnosis: clinical and biological symptoms\nHemophagocytic syndrome diagnosis was carried out taking into account several specific clinical signs, such as fever >38.5°C, splenomegaly, hepatomegaly, lymphadenopathy, pulmonary infiltrates, erythema, purpura, and neurological evidence. Biological abnormalities were pancytopenia, cholestasis and cytolysis, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased LDH 4, 7, 20, 21. According to the literature, fever is the most prevalent clinical sign conveying patient to seek medical help, that is, the fever is often associated with pancytopenia and cytolysis 10 (Tables 2 and 3).\n\nHPS diagnostic tools\nGold standard diagnostic tool is myelogram which allows identification of hemophagocytosis. Our patient's myelogram showed rich, infiltrated, and benign histiocyte–macrophages. In the absence of histological evidence, a repeated myelogram should be performed 22.\n\nOf note, hemophagocytosis is common in cases of polytransfusion or hematologic diseases and is not regarded as a pathognomonic criterion of HPS 23.\n\nHPS etiology\nEtiological evaluation led to ruling out anyneoplasia 6, 7 (solid malignant tumors, hematologic malignancy). Upon patient questioning, no deterioration of general state was reported. Clinical examination did not reveal any mass or poly lymphadenopathy syndrome. In addition, the myelogram and blood workup did not reveal neoplastic malignant cells. Given the patient's medical history, HPS secondary to autoimmune disease seemed highly likely after excluding any infectious disease. Immune deficiency‐related HPS is very common 4, 6, 15, 16, 17, 18, 19 (45%). The most prevalent pathogens responsible for immune deficiency‐related HPS were reported to be herpesviridae, in particular, CMV, EBV, and HSV. Other less prevalent pathogens were mycobacteria and parasites. Advanced stages of HPS are reported to be secondary to HIV infection 16, 24. In immune deficiency‐related HPS, there is a challenge distinguishing the symptoms induced by pathogens from those secondary to immunosuppression. Indeed, most cases of secondary HPS have been reported in chronic immunosuppression, that is, patients with renal failure, HIV, hematologic or autoimmune disease. Immune deficiency‐related HPS was ruled out given the negative infectious workup.\n\nHPS treatments\nAccording to the literature, autoimmune related HPS can be treated by the following therapies: GC, intravenous immunoglobulins, methotrexate, and biotherapies 11, 25, 26. The use of GC in our patient allowed reduction in disease progression and complications. Disease progression and its related complications were reduced after GC therapy.\n\nHPS prognosis\nHemophagocytic syndrome prognosis was positive with satisfactory outcomes for the mother and the fetus. In case of autoimmune disease, the literature has reported only a few cases of positive pregnancy outcomes 10, 13, 16. Fatal pregnancy outcomes have been reported across several reports 8, 9, 15.\n\nDiscussion\nHPS diagnosis\nHemophagocytic syndrome diagnosis is challenging given its rare but serious characteristics often requiring intensive care. The median age for HPS occurrence is 48 yo [35–62 yo] 20 with male predominance 7, 20. There have only been a few reported cases of HPS during pregnancy with sometimes fatal fetal and maternal outcomes 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. According to the literature, the mean age for HPS onset during pregnancy is 31 yo and diagnosis is carried out at the second trimester (around 22 GA) 8, 12, 13, 16, 17, 19, 27, 28.\n\nHPS etiology\nAccording to the literature, autoimmune disease‐related HPS prevalence is around 7.2% 6, 12. Systemic diseases such as lupus (a prevalence of 2.4%, Wong et al. 29) or Still's disease are the most prevalent cases of secondary HPS 6, 7, 29, 30. In prepartum, our patient presented with moderate peripheral autoimmune thrombocytopenia accompanied by antiribonucleoprotein antibodies and Raynaud's syndrome. In the absence of other events, no specific treatment was started. Nevertheless, the association of the above symptoms with the hormonal changes induced by pregnancy raised the question of vascular‐placental risk. Thus, acetyl salicylate DL‐lysine was prescribed during the entire pregnancy.\n\nFardet et al. 31 developed a diagnostic score for the adult HPS. It consists of several items: autoimmune disease, maximum temperature, hepatomegaly, splenomegaly, levels of hemoglobin, platelets and leukocytes levels, hyperferritinemia, hypertriglyceridemia, levels of fibrinogen and transaminase, hemophagocytosis found on the bone marrow. This score is a diagnostic aid for gynecologist–obstetrician facing an uncommon but serious pathology often underdiagnosed. It is accessible on http://saintantoine.aphp.fr/score/. According to this score, there was a 96.7% probability that our patient had HPS.\n\nHPS and pregnancy‐induced risk factors\nPregnancy is a time when the immune system is strongly stimulated and the placenta plays the role of immunological barrier between the fetus and the mother 28. However, this mechanism fails in pregnancy pathologies such as preeclampsia. Given the variable immunological disturbances during pregnancy, it becomes a favorable context to trigger HPS in the presence of additional risk factors such as systemic disease or infection 20. To date, there is no literature on oocyte donation and recipient mother's immune conflict. Nevertheless, we did set forth such likely correlation, that is, the recipient's immunological reaction seemed to be triggered against the presence of unknown genetic matter. Several studies have highlighted an increased rate of pregnancy‐induced hypertension and preeclampsia in patients who underwent in vitro fertilization by oocyte donation versus oocytes of the recipient (OR = 3.3; 95% CI [1.2–8.9]) 32, 33, 34. We believe that this higher pregnancy‐induced hypertension and preeclampsia can be explained by the recipient's immunological reaction triggered against the presence of unknown genetic matter, that is, allogeneic graft. Triggered immunological mechanism of the mother impairs placental implantation and increases maternal systemic resistance leading to preeclampsia and further complications of autoimmune reaction 35. During pregnancy, in the presence of numerous biological signs similar to those of HPS, clinicians should first preclude a differential diagnosis of preeclampsia. Preeclampsia was excluded in our patient case.\n\nHPS prognosis\nMortality rate linked to the primary or secondary HPS is very high. In HPS, prognosis is poor in 49% of cases and patients with HIV or malignant hemopathy are at higher risk of mortality 6, 7. The literature has put forward the mean premature GA of 30 weeks 7, 11, requiring most likely a C‐section for fetal and maternal salvage in cases of preeclampsia or cerebral hemorrhage 9, 12, 13, 14, 15, 17. Kaito et al. identified the following risk factors of mortality: maternal age >30 years, intravascular disseminated coagulation, anemia associated with thrombocytopenia, cholestasis, elevated ferritin, and β2 microglobulinemia 36.\n\nHPS treatment\nTo date, there is no consensus on the best management of either primary or secondary HPS. The overall aim of treatment is to resolve all hydroelectric disorders, transfuse in case of cytopenia, and manage organ failures 37. In addition, it is necessary to treat the cause of HPS: antimicrobial treatment, chemotherapy, or immunomodulators. GC have played a major role in treatment of HPS between 1994 and 2004 and this regardless of the underlying etiology 18.\n\nEven though immunoglobulins are being regarded as the first‐line treatments for HPS, GC have been used as the first‐line treatments in most reported cases 8, 11, 16, 19. Immunoglobulins and cyclosporine have been mostly used for HPS treatment in GC‐resistant cases 18.\n\nConclusion\nHemophagocytic syndrome is not well known during pregnancy, yet can be fatal. Mother's and fetus's prognoses are poor and require vital emergency care. HPS diagnosis is a challenge due to variable clinical presentation and nonspecificity of the clinical and biological findings. Mortality, prognosis, and disease progression may be influenced by delay in diagnosis, treatment onset, and HPS etiology. This case and its comparison to the literature showed the absence of consensual diagnosis and management of HPS. Making the right diagnosis in a timely manner during pregnancy seems to be the most significant barrier to treatment and would offer the best prognosis for the patient. Multidisciplinary team work is mandatory to reach prompt diagnosis for such uncommon yet fatal disorder during pregnancy. Clinicians should be alerted when there is an association of clinical and biological signs such as fever, pancytopenia, hyperferritinemia, and hypertriglycemia to suspect HPS and proceed with prompt treatments. To reach consensus on diagnostic criteria for HPS, diagnostic scoring tools, for example, Fardet et al. 31 scoring, as well as novel therapies such as immune modulators combined with biotherapies should be taken into account in further observational studies.\n\nAuthorship\nAR, PM, and ZA: contributed to the study design and methodology. AR, PM, ZA, AD, and ELM: contributed to the data interpretation and wrote the manuscript. AR, ELM, AD, CT, and SR: provided patient care and follow‐up, collected patient data, laboratory workup, and interpreted the data. AR and PM: performed the review of literature.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nCréput , C. \n, \nL. \nGalicier \n, \nE. \nOksenhendler \n, and \nE. \nAzoulay \n. 2005 \nSyndrome d'activation lymphohistiocytaire : revue de la littérature, implications en réanimation . Réanimation \n14 :604 –613 .\n2 \n\nRisdall , R. J. \n, \nR. W. \nMcKenna \n, \nM. E. \nNesbit \n, \nW. \nKrivit \n, \nH. H. \nBalfour \n, \nR. L. \nSimmons \n, et al. 1979 \nVirus‐associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis . Cancer \n44 :993 –1002 .225008 \n3 \n\nEmmenegger , U. \n, \nD. J. \nSchaer \n, \nC. \nLarroche \n, and \nK. A. \nNeftel \n. 2005 \nHaemophagocytic syndromes in adults: current concepts and challenges ahead . Swiss Med. 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"issn_linking": "2050-0904",
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"journal": "Clinical case reports",
"keywords": "Case report; diagnosis; hemophagocytic syndrome; oocyte donation; pregnancy",
"medline_ta": "Clin Case Rep",
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"pubdate": "2017-11",
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"title": "Hemophagocytic syndrome in pregnancy: case report, diagnosis, treatment, and prognosis.",
"title_normalized": "hemophagocytic syndrome in pregnancy case report diagnosis treatment and prognosis"
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"abstract": "Super-refractory status epilepticus is a rare medical and neurological emergency due to the high mortality and morbidity associated with this condition. Furthermore, there is very little data regarding its incidence, etiology, and management in the pregnant population with super-refractory status epilepticus. The treatment of super-refractory status epilepticus during pregnancy is specifically a major challenge as there are limited available therapeutic options due to the well-established teratogenicity of most antiepileptic drugs and the unknown safety profile of some of the anesthetics commonly used for seizure control. We report a case of successfully treated super-refractory status epilepticus in a 29-year-old, 26 weeks pregnant female who after an emergent delivery and prolonged exposure to multiple antiepileptic drugs recovered full neurological function.",
"affiliations": "Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.;Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.",
"authors": "Carrasco|Cinthya|C|;Schwalk|Audra|A|;Hwang|Byungkwan|B|;Iwuji|Kenneth|K|https://orcid.org/0000-0001-5489-233X;Islam|Ebtesam|E|",
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"doi": "10.1177/2050313X211000455",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211000455\n10.1177_2050313X211000455\nCase Report\nSuper-refractory status epilepticus in a 29-year-old pregnant female\nCarrasco Cinthya\nSchwalk Audra\nHwang Byungkwan\nhttps://orcid.org/0000-0001-5489-233X\nIwuji Kenneth\nIslam Ebtesam\nDepartment of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA\nKenneth Iwuji, Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street Stop 9902, Lubbock, TX 79430-9902, USA. Email: kenneth.iwuji@ttuhsc.edu\n23 3 2021\n2021\n9 2050313X21100045510 2 2021\n11 2 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nSuper-refractory status epilepticus is a rare medical and neurological emergency due to the high mortality and morbidity associated with this condition. Furthermore, there is very little data regarding its incidence, etiology, and management in the pregnant population with super-refractory status epilepticus. The treatment of super-refractory status epilepticus during pregnancy is specifically a major challenge as there are limited available therapeutic options due to the well-established teratogenicity of most antiepileptic drugs and the unknown safety profile of some of the anesthetics commonly used for seizure control. We report a case of successfully treated super-refractory status epilepticus in a 29-year-old, 26 weeks pregnant female who after an emergent delivery and prolonged exposure to multiple antiepileptic drugs recovered full neurological function.\n\nEpilepsy\nstatus epilepsy\npregnancy\nsupra-refractory status epilepsy\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nSuper-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that persists at least 24 h, despite the administration of intravenous anesthetic drugs (IVADs), including those cases where SE recurs after the reduction or withdrawal of anesthesia.1 SRSE is seen in about 12% to 26% of SE cases in the general population.2 The exact prevalence among pregnant patients remains unclear. Pregnancy is associated with variety of endocrine, physiological, and psychological changes, which might contribute to lowering the seizure threshold. SRSE carries high maternal mortality rate with increased rate of fetal complications.3 In a Turkish population–based study, pulmonary embolism, cerebrovascular event, and cerebral vein thrombosis were attributed as the cause of death in maternal deaths that are accompanied by epilepsy.4\n\nMedications used for the treatment of SRSE include benzodiazepines (BZDs), antiepileptic drugs (AEDs), and IVADs, often used simultaneously. There are no guidelines providing specific recommendations for the treatment of SRSE. Furthermore, the management of pregnant patients is even more challenging due to the teratogenicity of most first- and second-line AEDs and the lack of available literature studies regarding the safety of prolonged use of IVADs in this population.\n\nCase report\n\nA 29-year-old, 26 weeks pregnant patient presented with a past medical history of hypertension, traumatic brain injury (TBI), synthetic marijuana abuse, and generalized seizure disorder (diagnosed after TBI in 2014 and has not been compliant with taking her AEDs). She developed seizure activity while driving, leading to a motor vehicle accident. On arrival to the emergency department, she continued to experience generalized tonic-clonic seizures. Repeat doses of intravenous (IV) lorazepam were required to physically suppress the convulsions. IV magnesium was given as it was unknown at this point whether eclampsia was playing a role in her condition. Emergency medical services (EMS) reported that the patient had large amounts of synthetic marijuana in her possession at the scene.\n\nOn physical examination, she was somnolent with a Glasgow Coma Scale score of 6.5 Vital signs were stable. She was noted to have a gestational uterus and a concave right cranial defect secondary to her prior TBI. She was intubated for airway protection due to declining neurological status and was taken to the medical intensive care unit.\n\nInitial electroencephalography (EEG) showed periodic lateralized discharges in the right hemisphere. Head imaging were negative for acute findings. Laboratory results showed an elevated white blood count of 23.6 × 103/µL and a high random urine protein/creatinine ratio of 0.6. Cerebrospinal fluid analysis, blood and urine cultures, and liver function tests, among others, all of which were unremarkable.\n\nShe was started on IV levetiracetam and midazolam, but her seizure activity persisted. Midazolam was discontinued. Propofol 55 mcg/kg/min, fosphenytoin 100 mg IV three times per day, lacosamide 400 mg IV twice per day, ketamine 2 mg/kg/h, and pentobarbital 2 mg/kg/h were added to the regimen, given the persistent abnormal EEG findings. An EEG burst suppression pattern (seizure control) was finally achieved for the first time after 25 h of pharmacologic therapy at maximal doses. Propofol was eventually discontinued.\n\nWeaning of pentobarbital was attempted after several days of non-epileptic EEG pattern, but bilateral cerebral hemisphere seizure activity quickly recurred, forcing continued use of pentobarbital at maximum doses. However, no improvement in the EEG tracing was obtained after increasing this medication and EEG seizure activity continued. Furthermore, fetal distress was noted on hospital day 6 requiring an emergent bedside cesarean section. After delivery, valproic acid and pyridoxine were added, and burst suppression pattern was again achieved on hospital day 10. The patient’s neurological status slowly improved, allowing for liberation from mechanical ventilation. Finally, after 14 days of hospitalization, a normal EEG pattern was obtained, and the patient was transferred out of the intensive care unit. The patient’s baby had a prolonged hospitalization, but was eventually discharged home.\n\nDiscussion\n\nThe incidence of SE ranges from approximately 5 to 40 per 100,000 with a recent meta-analysis reporting an annual incidence of 12.6 per 100,000.2 SRSE is uncommon in any patient population, and even more so in the pregnant population. It is considered a medical emergency, as sustained seizure activity is associated with a risk of permanent brain damage, and significant morbidity and mortality. The mortality rate of SE in the general population ranges from 20% to 40%.6 In addition, SRSE in pregnant patients can compromise placental flow, causing fetal hypoxia, potentially leading to severe neurodevelopmental delays.3 Hence, it is imperative to promptly identify and treat the etiology of SRSE in order to suppress seizure activity as early as possible.\n\nSE in pregnancy is caused by many things including TBI, strokes, cavernous angiomas, pyridoxine deficiency, eclampsia, noncompliance with AEDs, viral encephalitis, systemic lupus erythematosus, reversible cerebral vasoconstriction syndrome, subarachnoid hemorrhage, NMDA (N-methyl-D-aspartate) receptor antibody-mediated autoimmune encephalitis, and hormonal changes associated with pregnancy.7 Eclampsia was considered as a contributor to SRSE in our patient, but after a thorough investigation by the obstetricians, this diagnosis was ruled out. This patient’s SRSE was likely due to the combination of risk factors making her seizures so refractory to treatment.\n\nWhen deciding on a treatment for SE in pregnancy, the control of seizure activity must be balanced against the potential risks of the AEDs for the developing fetus.8 Regarding SE in general, BZDs continue to be the initial drug of choice for suppression of seizure activity. However, when they are unsuccessful at controlling seizure activity, AEDs should be added to the treatment regimen.2 The choice of which AEDs to use was very difficult for this patient, given the safety profile for each medication in gravid patients. Levetiracetam was added first, but fosphenytoin, lacosamide, and valproic acid were eventually added secondary to the worsening clinical condition.\n\nIf the seizure activity continues for at least 24 h, despite the addition of IVADs, the diagnosis of SRSE is confirmed, as in this patient.1 Unfortunately, IVADs are the last available pharmacological option for the treatment of SE and there is no general consensus regarding which specific drug should be used, especially in the pregnant population.\n\nThere are several proposed therapies for the management of SRSE in the general population, all of which include the use of three classes of medications: BZDs, AEDs, and IVADs. However, these recommendations are primarily based on clinical reports and have not been studied in pregnant patients. Furthermore, most of these medications have known teratogenic effects. Early identification and treatment of patients with epilepsy may help to decrease unfavorable outcome. This case illustrates the successful treatment of SRSE in a pregnant patient, without significant long-term adverse effects for the patient or her child.\n\nConclusion\n\nThe management of SRSE is extremely challenging, especially for pregnant patients, as evidence-based protocols for treatment are currently unavailable. The current pharmacological options are limited, and most of them have teratogenic effects, but if SRSE is left untreated, it may become life-threatening not only for the mother but also for their offspring. Further studies are needed in order to determine the safest therapies for this patient population.\n\nAuthor contribution: All authors contributed equally.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article. The patient had capacity at the time consent was obtained.\n\nORCID iD: Kenneth Iwuji https://orcid.org/0000-0001-5489-233X\n==== Refs\nReferences\n\n1 Shorvon S Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011; 134 (10 ): 2802–2818.21914716\n2 Marawar R Basha M Mahulikar A , et al . Updates in refractory status epilepticus. Crit Care Res Pract 2018; 2018 : 9768949.29854452\n3 Goodwin JF Lawson CW. Status epilepticus complicating pregnancy. Br Med J 1947; 2 (4521 ): 332.20257575\n4 Yucel A Tanacan A Atalay F , et al . Maternal deaths with epilepsy: a population-based study in Turkey. Eur J Obstet Gynecol Reprod Biol 2020; 258 : 33–37.33401066\n5 Teasdale G Maas A Lecky F , et al . The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol 2014; 13 (8 ): 844–854.25030516\n6 Logroscino G Hesdorffer DC Cascino G , et al . Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia 2001; 42 (8 ): 1031–1035.11554890\n7 Rajiv KR Radhakrishnan A. Status epilepticus in pregnancy: etiology, management, and clinical outcomes. Epilepsy Behav 2017; 76 : 114–119.28899640\n8 Etemad L Moshiri M Moallem SA. Epilepsy drugs and effects on fetal development: potential mechanisms. J Res Med Sci 2012; 17 (9 ): 876–881.23826017\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "9()",
"journal": "SAGE open medical case reports",
"keywords": "Epilepsy; pregnancy; status epilepsy; supra-refractory status epilepsy",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X211000455",
"pmc": null,
"pmid": "33854779",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21914716;28899640;20257575;29854452;33401066;23826017;11554890;25030516",
"title": "Super-refractory status epilepticus in a 29-year-old pregnant female.",
"title_normalized": "super refractory status epilepticus in a 29 year old pregnant female"
} | [
{
"companynumb": "US-UCBSA-2021017560",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDAZOLAM"
},
"drugadditional": null,
"d... |
{
"abstract": "Secondary esophageal cancers from prior thoracic radiation therapy are rare but challenging cases to deliver standard combined modality therapy as part of a curative approach. In patients with prior exposure to cardiopulmonary-toxic chemotherapy or radiotherapy, management requires meticulous multidisciplinary evaluation given the morbidity associated with surgery in the previously irradiated thorax and re-irradiation of the spinal cord, heart, and lungs. Oftentimes, suboptimal treatment regimens, either with compromised radiation coverage, attenuated chemotherapy doses, or exclusion of surgery, are required to avoid significant toxicity. The physical properties inherent to protons allow for optimal coverage of tumor while achieving remarkably low dose to surrounding normal tissue compared to standard photon treatment. Proton therapy has been studied across various disease sites and may facilitate treatment intensification for radiation-associated esophageal tumors. While no comparative studies have evaluated the efficacy and safety of protons versus photons for esophageal cancer, three cases of radiation-associated esophageal cancer presented in this series are exemplary to highlight the benefit of protons in this unique clinical circumstance. The technical considerations in planning, including passively scattered versus pencil-beam scanning technique, as well as the clinical course and tolerance to treatment, are discussed, which may guide consideration of this advanced treatment modality in this disease site.",
"affiliations": "Department of Radiation Oncology, Emory University, Atlanta, GA, USA.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.;Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.;Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Patel|Sagar A|SA|;Edgington|Samantha K|SK|;Adams|Judith|J|;Morse|Christopher|C|;Ryan|David P|DP|;Hong|Theodore S|TS|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2018.09.06",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "10(1)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Protons; esophageal cancer; re-irradiation",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "155-160",
"pmc": null,
"pmid": "30788171",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": "12200357;15800321;17372278;17401004;19667275;20634481;22646630;23102695;24556041;24635657;25815477;27629865",
"title": "Novel use of proton beam therapy for neoadjuvant treatment of radiation-associated squamous cell carcinoma of the esophagus.",
"title_normalized": "novel use of proton beam therapy for neoadjuvant treatment of radiation associated squamous cell carcinoma of the esophagus"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-01034",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"... |
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