key: cord-0899488-hqoqb8j4
authors: Samadizadeh, Saeed; Masoudi, Maha; Rastegar, Mostafa; Salimi, Vahid; Shahbaz, Mahsa Bataghva; Tahamtan, Alireza
title: COVID-19: why does disease severity vary among individuals?
date: 2021-03-05
journal: Respir Med
DOI: 10.1016/j.rmed.2021.106356
sha: e7dfdc09df4513ce895c4b7f61c11de6bccb4483
doc_id: 899488
cord_uid: hqoqb8j4

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the current pandemic, coronavirus disease 2019 (COVID-19). While all people are susceptible to the SARS-CoV-2 infection, the nature and severity of the disease vary significantly among individuals and populations. Importantly, reported disease burdens and case fatality rates differ considerably from country to country. There are, however, still uncertainties about the severity of the disease among individuals or the reason behind a more severe disease in some cases. There is a strong possibility that the severity of this disease depends on a complicated interaction between the host, virus, and environment, which leads to different clinical outcomes. The objective of this article is to point out the essential influential factors related to the host, virus, and environment affecting the clinical outcome of COVID-19.

suggests that children suffer from less severe COVID-19, which could be because of their 142 lower intensity of viral exposure and lower expression of ACE2 and TMPRSS2 receptors in 143 their upper and lower airways (32, 47) . A still-developing immune system with relatively 144 lower levels of inflammation-driving cytokines, absence of high-risk factors, and more programs, the number of involved people, and the pattern of death due to COVID 19 were 155 relatively low (53). Two mechanisms have been considered to explain this non-specific 156 effect: trained immunity and heterologous immunity (52). The "trained immunity" of such confounding (56). As another live attenuated vaccine, the Measles-Mumps-Rubella (MMR) 168 can help prevent worsen outcomes of COVID-19 because of its capability to induce "trained" 169 non-specific innate immune cells like the BCG vaccine (57). The common features between 170 MMR viruses and SARS-CoV-2 such as transmission and their primary replication in the 171 upper respiratory tract and cross-protective innate immunity offered by MMR vaccines, led to 172 reconsidering MMR vaccination for immuno-prophylaxis against . The 173 ability of past vaccinations to generate immunity against non-self antigens provides a 174 preferred condition for the immune system to increase the specific immunity against SARS- and mutating at a rate as expected for other RNA viruses; the estimated average evolutionary 214 rate for SARS-CoV-2 is 1.20 × 10 -3 nucleotide substitutions per site per year, with mutations arising during every replication cycle (71). The result of virus replication is the production of 216 different mutants, and natural selection is decisive about which one will be predominant.

Notably, a study has recently claimed that there are two types (S and L) of the virus, where L 218 type is suggested to be more aggressive and spread more quickly (72). Another study also 219 mentioned three central variants named A, B, and C, of which A is the ancestral types 220 according to the bat outgroup coronavirus (73) . However, there is a little data on whether the 221 severity of COVID-19 is dependent on viral determinants such as genetic variation, viral 222 load, and coinfection. (105), and ACE2 expression increases due to exposure to 312 air pollution (106) .

Diet might also be another independent risk factor in the development of severe infection. It 315 is crucial to consume healthy, fresh, and nutritive foods and avoid diets including saturated 316 fats, sugars, and refined carbohydrates, contributing to obesity and type 2 diabetes (107) .

Although these products are not proven to be precisely concerning COVID-19, consumption 318 of the above-mentioned products leads to chronic inflammation and impairs host defense 319 against viruses due to the activation of the innate immune system and the impairment of to invigorate the immune system and avoid undesirable outcomes of infections (110) .

Vitamin D deficiency is a general health issue in many regions. Its deficiency links to the 327 development and progression of several comorbidities and susceptibility to infectious 328 diseases. Vitamin D plays a vital role in modulating innate and adaptive immune responses 329 (111, 112) . It is reported that vitamin D insufficiency is highly prevalent in severe COVID-19 330 patients (96) . There is also a relationship between vitamin D consumption and reduced risk of 331 COVID-19 and influenza infection (113) . Importantly, vitamin D consumption could be 332 beneficial in COVID-19 due to its enhancing effects on regulatory T cell (Treg) levels (114, 

Vitamin C is one of the most important sources of antioxidants (116) . Since the cytokine 335 storm increases oxidative stress in patients suffering from COVID-19, vitamin C may be 336 useful to reduce ARDS associated with COVID-19 (117) . Notably, it is reported that high-337 dose of oral vitamin C has antiviral effects with no significant side effects (118, 119) . (98) . Therefore, iron consumption could be beneficial by decreasing chronic 345 cough hyper-responsiveness and allergic inflammation in the lungs (121, 122) . Also, there is 346 data that Zinc consumption could limit the cytokine storm in COVID-19 due to anti-347 inflammatory activity (123) . 349 Socioeconomically, poor nutritional status is generally influenced by poverty and could be 350 enumerated as a significant risk factor for the disease severity. In a study, people from Asia 351 and black-colored skin people were shown to have a higher risk of death from COVID-19, 352 partially attributed to deprivation as a significant problem (124) . Besides, Hispanics and 353 indigenous communities of Latin America may have been facing the pandemic more 354 vulnerably due to the deprivation and social disparities (125, 126) . Also, the health care 355 system's inefficiency in low-and middle-income countries dramatically increases the impact 356 of COVID-19 (126) . Notably, there is evidence of more virus transmission in crowded areas 357 (127) . For example, many cases of COVID-19 in the U.S. have occurred among older adults living in nursing homes or Long-term homecare facilities (128) . Occupational risks for 359 getting a severe disease are also notable. Essential workers in healthcare, social care, sanitary 360 services, and transportation simply cannot work from home due to their job's characteristics.

Therefore, these groups are more likely to be exposed to the virus, potentially putting them in 362 the high-risk group (129) . 

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