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Id Subject Object Predicate Lexical cue
T1 0-55 Sentence denotes A Southeast Asian Perspective on the COVID-19 Pandemic:
T2 56-116 Sentence denotes Hemoglobin E (HbE)-Trait Confers Resistance Against COVID-19
T3 118-126 Sentence denotes Abstract
T4 127-252 Sentence denotes As of November 25, 2020, over 60 million people have been infected worldwide by COVID-19, causing almost 1.43 million deaths.
T5 253-384 Sentence denotes Puzzling low incidence numbers and milder, non-fatal disease have been observed in Thailand and its Southeast (SE) Asian neighbors.
T6 385-616 Sentence denotes Elusive genetic mechanisms might be operative, as a multitude of genetic factors are widely shared between the SE Asian populations, such as the more than 60 different thalassemia syndromes (principally dominated by the HbE trait).
T7 617-771 Sentence denotes In this study, we have plotted COVID-19 infection and death rates in SE Asian (SEA) countries against heterozygote HbE and thalassemia carrier prevalence.
T8 772-915 Sentence denotes COVID-19 infection and death incidence numbers appear inversely correlated with the prevalence of HbE and thalassemia heterozygote populations.
T9 916-1210 Sentence denotes We posit that the evolutionary protective effect of the HbE and other thalassemic variants against malaria and the dengue virus may extend its advantage to resistance to COVID-19 infection, as HbE heterozygote population prevalence appears to be positively correlated with immunity to COVID-19.
T10 1211-1377 Sentence denotes Host immune system modulations induce antiviral interferon responses and alter structural protein integrity, thereby inhibiting cellular access and viral replication.
T11 1378-1438 Sentence denotes These changes are possibly engendered by HbE carrier miRNAs.
T12 1439-1574 Sentence denotes Proving this hypothesis is important, as it may shed light on the mechanism of viral resistance and lead to novel antiviral treatments.
T13 1575-1664 Sentence denotes This development can thus guide decision-making and action to prevent COVID-19 infection.
T14 1666-1676 Sentence denotes Background
T15 1677-1810 Sentence denotes The coronavirus pandemic (COVID-19) has to date infected over 60 million people worldwide, causing more than 1.43 million deaths [1].
T16 1811-1979 Sentence denotes The latest COVID-19 statistics for the Kingdom of Thailand as of November 25, 2020, were 3942 confirmed cases and 60 deaths in a total population of 66.6 million [2,3].
T17 1980-2158 Sentence denotes These numbers translate to 56.25 cases and 0.86 deaths per million inhabitants, respectively, both being puzzlingly low among countries with reliable statistical information [4].
T18 2159-2298 Sentence denotes The whole of the Mekong River basin and other Southeast (SE) Asian (SEA) neighbors seems to share Thailand’s low infection and death rates.
T19 2299-2427 Sentence denotes Myanmar, Laos, Cambodia, and China’s Yunnan province all report similarly minimal infection rates (Table 1, Figures 1, 2) [4,5].
T20 2428-2540 Sentence denotes Many attribute this low incidence to Thai social and cultural practices promoting an inherent social distancing.
T21 2541-2641 Sentence denotes When greeting one another, Thais do not shake hands or hug, but use the “wai”, a prayer-like motion.
T22 2642-2789 Sentence denotes An outdoor lifestyle combined with mask wearing practices due to pre-existing environmental pollution was already in place before the pandemic [5].
T23 2790-3117 Sentence denotes Thailand’s efficient, robust, and responsive grassroots-level universal health care system, directed by able scientists, has greatly impacted preventive and treatment measures [6] even with a rising prevalence of pre-existing comorbidities like obesity, diabetes, and hypertension in the whole of the Mekong river region [7,8].
T24 3118-3266 Sentence denotes Others might argue that Thailand’s low testing frequency (19 tests per 1000 people) might underestimate the magnitude of the COVID-19 situation [3].
T25 3267-3497 Sentence denotes Here, we need to bear in mind that while all returning residents are tested and quarantined, community testing only occurs when tracing contacts or for symptomatic cases seeking treatment (virtually non-existent in the community).
T26 3498-3652 Sentence denotes Another way of looking at the extent of testing relative to the scale of the outbreak is to ask: how many tests does a country do to find 1 COVID-19 case?
T27 3653-3841 Sentence denotes The WHO has suggested around 10–30 tests per confirmed case as a general benchmark of adequate testing, and the Thai average as of November 5, 2020 was 649.7 tests per 1 positive case [9].
T28 3842-3922 Sentence denotes With her porous land border crossings, Thailand allows for population movements.
T29 3923-4001 Sentence denotes Furthermore, COVID-19 infection rates have increased in its western neighbors.
T30 4002-4078 Sentence denotes Yet Thailand has not seen any increase in the number of local COVID19 cases.
T31 4079-4226 Sentence denotes After several months without local infections, single-digit indigenous re-emergences have died out spontaneously both in Thailand and Vietnam [10].
T32 4227-4325 Sentence denotes Elusive locally-shared, genetic determinants may provide an explanation to the above observations.
T33 4327-4387 Sentence denotes Epidemiology of HbE and Thalassemia Traits in Southeast Asia
T34 4388-4549 Sentence denotes SE Asia is the third most populous region in the world [11], encompassing 10 countries with more than 650 million people inhabiting an area over 4.5 million km2.
T35 4550-4657 Sentence denotes SE Asia is a genetic cauldron of different ethnicities descending from diverse and complex origins [11,12].
T36 4658-4872 Sentence denotes Shaped by local malarial environmental pressures, SE Asia’s common genetic denominator is thalassemia, presenting with over 60 different allelic variants, but mainly dominated by 4 major thalassemic syndromes [13].
T37 4873-5041 Sentence denotes The α-thalassemias, with a gene prevalence approaching 40% in northern Thailand and Laos, are considerably less common in Malaysia and the Philippines (around 5%) [13].
T38 5042-5142 Sentence denotes The β-thalassemias showing local variations in genetic prevalence account for up to 9% of all cases.
T39 5143-5229 Sentence denotes Thirdly, Hb Constant Spring [CS] is also seen, with gene frequencies of up to 8% [13].
T40 5230-5308 Sentence denotes HbE, the thalassemic symbol of SE Asia, is increasingly encountered worldwide.
T41 5309-5473 Sentence denotes HbE gene prevalence may reach up to 70% locally in northeastern Thailand and and up to 62% at the triple border region between Thailand, Cambodia, and Laos [13–15].
T42 5474-5678 Sentence denotes Apart from SE Asia, thalassemia genes (including HbE) are also present with diminishing gene frequency in Yunnan, Nepal, Northeastern India, Pakistan, Sri Lanka, Bangladesh, Hong Kong, and Taiwan [13–24].
T43 5680-5739 Sentence denotes Epidemiological Evidence of HbE Protection Against COVID-19
T44 5740-6000 Sentence denotes Intriguing epidemiological observations suggest, and biological evidence supports, an inverse correlation between increasing HbE/thalassemia trait prevalence rates and decreased susceptibility to, and fatality from, COVID-19 infections (Table 1, Figures 1, 2).
T45 6001-6243 Sentence denotes Local COVID-19 infections within Thailand vary 6-fold between the northeast (2.84% of total cases) versus the south (19%), in tandem with regional variations in HbE gene frequency (70% in the northeast compared to 12% in the south) [3,13,25].
T46 6244-6420 Sentence denotes Similarly, Malaysia, which borders southern Thailand, has an HbE trait frequency of only 3.8% [26] but reports substantially higher COVID19 infections compared to Thailand [4].
T47 6421-6661 Sentence denotes Interestingly, in Cambodia and Laos (where zero COVID-19 deaths are reported) (Table 1), thalassemia mutation rates are similar to Thailand [13]; for Cambodia, the thalassemia prevalence is 62.7% (HbE being the most prevalent, at 56%) [27].
T48 6662-6818 Sentence denotes In Myanmar (HbE carrier rates vary between 1.9 and 42% depending on ethnic group and geography), low infection and death rates are also seen (Table 1) [28].
T49 6819-7027 Sentence denotes Vietnam and the neighboring Chinese province of Yunnan both report low COVID-19 infection rates, with locally high prevalence of HbE trait in line with other mainland SE Asian nations (Table 1) [15–24,29–31].
T50 7028-7191 Sentence denotes In Vietnam, the Mon-Khmer-speaking ethnic groups are genetically closer to the Thai-Lao-Cambodian border populations and report HbE gene prevalence up to 36% [29].
T51 7192-7385 Sentence denotes Singapore, where the prevalence of β-thalassemia trait is 0.9% and HbE trait is 0.55% [32], was severely hit by COVID-19 compared to neighboring Thailand, but the death rates were very low [4].
T52 7386-7570 Sentence denotes The high number of cases in Singapore seems to stem from clusters in male migrant workers living in close proximity in crowded living quarters, promoting higher infectious spread [33].
T53 7571-7815 Sentence denotes These migrant workers are from various ethnic groups (e.g., Bengali and Tamil) with higher HbE/thalassemia trait prevalence but also higher glucose-6-phosphate dehydrogenase (G6PD) deficiency rates, compared to resident Singaporeans [32,34,35].
T54 7816-7956 Sentence denotes G6PD-deficient patients have been shown to be highly susceptible to enteroviruses, human dengue virus, and human coronavirus 229E infection.
T55 7957-8031 Sentence denotes They also tend to develop severe pneumonia after microbial infection [36].
T56 8032-8260 Sentence denotes Consequently, close proximity overrides the protective effects of HbE and/or selectively potentiates the risk to infect the ones without the hypothetically protective trait, especially from patients carrying a higher viral load.
T57 8261-8395 Sentence denotes Thailand’s and Singapore’s effective 14-day quarantine policy of all arrivals have now virtually eradicated local COVID-19 cases [37].
T58 8396-8602 Sentence denotes In the remainder of SE Asia and South Asian territories, the trend continues with increasing COVID-19 infection and death rates where HbE/thalassemia trait prevalence is low (Table 1, Figures 1, 2) [14–23].
T59 8603-8761 Sentence denotes In Brazil, a country severely hit by COVID-19, despite heavy early Italian migrations, less than 2% of Brazilian blood donors exhibit hemoglobinopathies [38].
T60 8762-8859 Sentence denotes Similarly, Spain, also severely affected by COVID-19, has a thalassemia trait of only 0.92% [39].
T61 8860-9049 Sentence denotes Despite its higher thalassemia trait prevalence, Italy was severely hit by COVID-19, initially in Lombardy, with a traditionally low carrier rate compared to islands and coastal areas [40].
T62 9050-9301 Sentence denotes Greece [40] and Cyprus [41], with an effective lock-down, a distancing strategy, and a higher, homogenous carrier rate, seem to be experiencing lower COVID-19 rates compared to their European peers, even during the second wave (Table 1, Figures 1, 2).
T63 9303-9335 Sentence denotes How is the HbE Trait Protective?
T64 9336-9586 Sentence denotes The hypothesis we posit is that thalassemia traits in general, and particularly HbE, are protective against COVID-19 infection in similar ways to the numerous thalassemia traits conferring protection against malaria [30,42] and the dengue virus [43].
T65 9587-9741 Sentence denotes Herd immunity development traditionally requires that 60% of the population becomes homogeneously infected by or vaccinated against an infectious disease.
T66 9742-9999 Sentence denotes However, recent mathematical models introducing age and activity heterogeneities into population models predict that herd immunity can be achieved at 43% [44], a level substantially lower than the observed prevalence of HbE in some areas of SE Asia [13–15].
T67 10000-10149 Sentence denotes In fact, in countries where the HbE trait is above 43%, the numbers of both COVID-19 infections and deaths have been minimal (Table 1, Figures 1, 2).
T68 10150-10277 Sentence denotes The genetic and molecular mechanisms of this hypothesized protection are as yet elusive, but biological evidence is suggestive.
T69 10278-10404 Sentence denotes Hemoglobinopathy-induced red blood cell structural modifications hinder invasion, growth, and migration of plasmodium [42,45].
T70 10405-10548 Sentence denotes Recent studies in thalassemias have pointed to the involvement of microRNAs (miRNAs) in malarial pathogenesis and anti-plasmodial defense [45].
T71 10549-10812 Sentence denotes MicroRNAs (miRNAs) are 18–25 nucleotide long, small, non-coding RNA molecules whose production is strictly regulated and abundant in all human cells [46]. miRNAs can downregulate gene expression in translational repression and target around 60% of all genes [46].
T72 10813-10937 Sentence denotes They exhibit decisive regulatory functions associated with a variety of disease processes, including microbial defense [46].
T73 10938-11167 Sentence denotes In dengue virus infection, which is perennially endemic in SE Asia, red blood cell precursors in Thai carriers of thalassemia and HbE trait were significantly less susceptible to the dengue virus compared to normal controls [43].
T74 11168-11281 Sentence denotes This was the first report documenting an antiviral effect of the HbE trait akin to its anti-malarial effect [43].
T75 11282-11580 Sentence denotes A large number of miRNAs have also been implicated in dengue virus defense via structural protein integrity alterations inhibiting access of viral replication machinery to the cytoskeletal apparatus (miR-223) [47], but also through modulations of the host immune interferon response (miR-155) [48].
T76 11581-11722 Sentence denotes Remarkably, increased levels of the latter molecule have been reported in β-thalassemia/HbE patients and linked to BACH1 downregulation [49].
T77 11723-11933 Sentence denotes The same miRNA molecule was also reported to inhibit dengue virus replication by inducing antiviral interferon responses through the same BACH1 pathway downregulation and heme oxygenase-1-(HO-1) induction [48].
T78 11934-12174 Sentence denotes Rare putative loss-of-function variants of X-chromosomal toll-like receptor 7 (TLR7) causing immunological defects in type I and II interferon production have been very recently identified in 4 young male patients with severe COVID-19 [50].
T79 12175-12364 Sentence denotes Type I and II interferon (IFN) responses have been implicated in the initiation of an early immune response to clear the SARS-CoV-2 coronavirus and prevent the development of COVID-19 [50].
T80 12365-12546 Sentence denotes Moreover, the addition of interferon beta-1b to other antivirals in the clinical setting was also more effective in treating COVID-19 patients and rendering them noninfectious [51].
T81 12547-12730 Sentence denotes HO-1 pathway derangements have been implicated in severe COVID-19 infection [52] and in causing exhaustion of hematopoietic stem cells, possibly leading to immune system failure [53].
T82 12731-12840 Sentence denotes Similar structural and molecular mechanisms might be operative in immune effector cells of HbE heterozygotes.
T83 12841-13021 Sentence denotes The hypothesized conferred protection against COVID-19 could also derive from local SE Asian HLA-class allotypes, possibly in linkage disequilibrium with the thalassemia mutations.
T84 13022-13192 Sentence denotes Protection from and resistance to severe malaria has been described in association with HLA antigens in the African continent [54,55] and the ABO blood group system [56].
T85 13193-13476 Sentence denotes However, no HLA associations with COVID-19 infection have been noted in a recent report [57] but an association with the ABO blood group system was confirmed, with bearers of the blood group A phenotype showing an increased risk for COVID-19 infection compared to blood group O [58].
T86 13477-13635 Sentence denotes The O phenotype appears protective to malaria [56] and its worldwide distribution seems to have been shaped by the parasite’s selective genetic pressure [56].
T87 13636-13849 Sentence denotes The frequency of the O blood group in Thailand is 40.5% [59] and its relatively high prevalence along with the high HbE heterozygote frequency could further potentiate the hypothesized antiviral protective effect.
T88 13850-13989 Sentence denotes A similarly intriguing hypothesis querying whether Italian β-thalassemia subjects are immunized against COVID-19 has been put forward [60].
T89 13990-14190 Sentence denotes We believe that the diluted carrier population sizes available in southern European countries are not of the magnitude presently observed in SE Asia and could lead to erroneous interpretation [60,61].
T90 14192-14245 Sentence denotes Limitations and Proving the HbE Protection Hypothesis
T91 14246-14388 Sentence denotes We are not claiming causality at this stage but are hypothesizing an interesting association that needs to be tested with regard to causality.
T92 14389-14656 Sentence denotes Simple hemoglobin electrophoresis of the approximately 4000 infected Thai COVID-19 cohort patients as a case control study will reveal whether the prevalence of thalassemia traits in general (and HbE in particular) differs between infected and uninfected populations.
T93 14657-14724 Sentence denotes Advanced molecular analyses can be performed on the affected cases.
T94 14725-14891 Sentence denotes G6PD and ABO blood group analyses could also be performed to elucidate whether the COVID-19-infected cohort has a higher representation of these genetic determinants.
T95 14892-15175 Sentence denotes Furthermore, miRNA analyses and genetic polymorphism and molecular studies of the BACH1/HO-1 pathway and interferons would elucidate the mechanism of resistance and eventually lead to novel treatment modalities via miRNA decoys or miRNA mimetics or interferon administration [46,51].
T96 15177-15188 Sentence denotes Conclusions
T97 15189-15537 Sentence denotes We theorize that another “Amazing Thailand” attribute [62], an evolutionary HbE variant arising in Thailand through natural selection possibly around 2000 years ago in a malaria-endemic region, might hypothetically be providing its carriers survival advantages with resistance to malaria, dengue virus, and possibly also to COVID-19 infection [63].
T98 15538-15703 Sentence denotes Host immune system modulations induce antiviral interferon responses as well as alter structural protein integrity and inhibit cellular access and viral replication.
T99 15704-15776 Sentence denotes These changes are possibly engendered by HbE/thalassemia carrier miRNAs.
T100 15777-15916 Sentence denotes Proving the hypothesis is of importance, as it may shed light on the mechanisms of viral resistance and lead to novel antiviral treatments.
T101 15917-16003 Sentence denotes These developments can guide decision-making and action to prevent COVID-19 infection.
T102 16005-16021 Sentence denotes Acknowledgements
T103 16022-16051 Sentence denotes We are thankful to James T.A.
T104 16052-16137 Sentence denotes Marshall and Professor Bengt Hallengren for their invaluable input on the manuscript.
T105 16138-16159 Sentence denotes Conflicts of interest
T106 16160-16165 Sentence denotes None.
T107 16166-16184 Sentence denotes Source of support:
T108 16185-16205 Sentence denotes Departmental sources
T109 16207-16330 Sentence denotes Figure 1 HbE and any thalassemia carrier prevalence (%) versus COVID-19 cases per million (M) people on November 25, 2020.
T110 16331-16465 Sentence denotes Figure 2 HbE and any thalassemia carrier prevalence (%) versus COVID-19 confirmed deaths per million (M) people on November 25, 2020.
T111 16466-16627 Sentence denotes Table 1 HbE and any Thalassemia carrier prevalence are given and opposed against COVID-19 infections and deaths per one million (M) population [1,3,4,13,15–32].
T112 16628-16762 Sentence denotes Prevalence/Country HbE carrier (%) Any thalassemia carrier (%) HERD immunity limit (%) COVID-19 deaths per M COVID-19 cases per M
T113 16763-16798 Sentence denotes Thailand 53 52.6 43 0.86 55.76
T114 16799-16825 Sentence denotes Laos 53 52.6 43 0 3.3
T115 16826-16858 Sentence denotes Cambodia 62 62.7 43 0 18.18
T116 16859-16895 Sentence denotes Myanmar 42 44.1 43 30.8 1376.26
T117 16896-16933 Sentence denotes Indonesia 33 56 43 57.03 1757.74
T118 16934-16985 Sentence denotes Yunnan Province (China) 39.1 21.7 43 0.43 4.09
T119 16986-17019 Sentence denotes Vietnam 35.6 30 43 0.36 13.4
T120 17020-17053 Sentence denotes India 30 21 43 95.77 6524.88
T121 17054-17097 Sentence denotes Bangladesh 8.68 11.89 43 38.28 2678.73
T122 17098-17138 Sentence denotes Malaysia 3.8 16.25 43 10.07 1596.74
T123 17139-17177 Sentence denotes Sri Lanka 0.5 15.8 43 3.41 879.88
T124 17178-17212 Sentence denotes Hong Kong 2 10 43 1.84 269.44
T125 17213-17252 Sentence denotes Philippines 2 8.2 43 72.99 3772.82
T126 17253-17289 Sentence denotes Pakistan 0.4 9 43 34.23 1668.98
T127 17290-17325 Sentence denotes Taiwan 0.027 8.4 43 0.29 25.57
T128 17326-17366 Sentence denotes Singapore 0.64 3.85 43 4.79 9937.71
T129 17367-17402 Sentence denotes Brazil 1.81 43 790.65 28785.87
T130 17403-17437 Sentence denotes Spain 0.92 43 933.98 34110.80
T131 17438-17472 Sentence denotes France 3.2 43 769.64 32996.77
T132 17473-17505 Sentence denotes Italy 12 43 848.57 24065.13
T133 17506-17538 Sentence denotes Greece 15 43 129.23 9127.55
T134 17539-17571 Sentence denotes Cyprus 35 43 52.52 10502.35