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      The effect of COVID-19 pandemic restrictions on neovascular AMD patients treated with treat-and-extend protocol

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          Abstract

          Purpose

          To investigate the adherence rate of neovascular age-related macular degeneration (nAMD) patients in treat-and-extend (TAE) protocol to their anti-vascular endothelial growth factor (anti-VEGF) intravitreal injection (IVI) appointments and to evaluate the functional and anatomical outcomes of the patients who attended and did not attend their IVI appointments during the coronavirus disease 2019 (COVID-19) restriction period (RP).

          Methods

          The patients with nAMD having IVI appointments between March 16 and June 1, 2020 (RP in Turkey) were included in this retrospective study. For adherence analysis, the patients who attended (Group 1, n = 44) and who did not attend (Group 2, n = 60) their IVI appointment visits during the RP ( V RP) were evaluated according to their last visit before the RP ( V 0). For outcome analysis, the patients who attend V RP and have follow-up (Group 1a, 46 eyes) and who did not attend V RP but later attended for follow-up (Group 2a, 33 eyes) were evaluated for functional (best-corrected visual acuity, BCVA [logMAR]) and anatomical (optical coherence tomography [OCT] disease activity) outcomes at the first visit after RP ( V 1) and last visit within six months after RP ( V 2). Patients received a complete ophthalmologic evaluation with anti-VEGF (Aflibercept) IVI administration at all visits.

          Results

          The adherence rate of the patients to V RP was 42.3% (44/104). The patients in Group 1 were significantly younger (mean ± SD years, 71.0 ± 8.1 vs. 74.7 ± 8.0, p = 0.024), had better median [IQR] BCVA at their first presentation (0.30 [0.54] vs. 0.61 [1.08], p = 0.023) and V 0 (0.40 [0.48] vs. 0.52 [0.70], p = 0.031), and had less hypertension (36.4% vs. 58.3%, p = 0.044) than Group 2. The mean ± SD delay of planned IVI at V RP in Group 2a was 13.9 ± 6.2 weeks. Disease activity in OCT was significantly higher in Group 2a than Group 1a at V 1 (60.6% vs. 32.6%, p = 0.025). In Group 2a, the median (IQR) BCVA was significantly worse at V 1 (0.70 [0.58]) and V 2 (0.70 [0.59]) than V 0 (0.52 [0.40], p = 0.047 and p = 0.035, respectively).

          Conclusions

          More than half of the scheduled nAMD patients in TAE protocol missed their IVI visits during the RP, which resulted in a delay of their treatments. The delay of IVI treatment in those patients resulted in an increase in OCT disease activity and a decrease in BCVA.

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          Most cited references33

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

            The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues 1 were cerebrovascular diseases (22%) and diabetes (22%). Another study 2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, 3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study. Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. 4 The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). 4 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. 5 ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. If this hypothesis were to be confirmed, it could lead to a conflict regarding treatment because ACE2 reduces inflammation and has been suggested as a potential new therapy for inflammatory lung diseases, cancer, diabetes, and hypertension. A further aspect that should be investigated is the genetic predisposition for an increased risk of SARS-CoV-2 infection, which might be due to ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in Asian populations. Summarising this information, the sensitivity of an individual might result from a combination of both therapy and ACE2 polymorphism. We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs. Based on a PubMed search on Feb 28, 2020, we did not find any evidence to suggest that antihypertensive calcium channel blockers increased ACE2 expression or activity, therefore these could be a suitable alternative treatment in these patients. © 2020 Juan Gaertner/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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              Ranibizumab for neovascular age-related macular degeneration.

              Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration. In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab. Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Contributors
                m.orkunsevik@gmail.com
                Journal
                Int Ophthalmol
                Int Ophthalmol
                International Ophthalmology
                Springer Netherlands (Dordrecht )
                0165-5701
                1573-2630
                17 April 2021
                : 1-11
                Affiliations
                GRID grid.16477.33, ISNI 0000 0001 0668 8422, Department of Ophthalmology, , Marmara University School of Medicine, ; Fevzi Çakmak Mah, Muhsin Yazıcıoğlu Cd, No: 10, Marmara Üniversitesi Pendik Eğitim ve Araştırma Hastanesi, Kat: 3, Oftalmoloji Servisi, Pendik, 34899 Istanbul, Turkey
                Author information
                http://orcid.org/0000-0001-7130-4798
                http://orcid.org/0000-0001-5426-1992
                http://orcid.org/0000-0002-5526-691X
                http://orcid.org/0000-0001-6264-5304
                http://orcid.org/0000-0003-2907-2852
                Article
                1854
                10.1007/s10792-021-01854-6
                8052549
                33864577
                7245991a-e64c-41de-b710-4681e14aa937
                © The Author(s), under exclusive licence to Springer Nature B.V. 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 31 January 2021
                : 8 April 2021
                Categories
                Original Paper

                Ophthalmology & Optometry
                coronavirus disease-2019,covid-19,neovascular age-related macular degeneration,namd,treat-and-extend protocol

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