key: cord-1007713-yeucs7d2
authors: Barh, D.; Tiwari, S.; Andrade, B. S.; Weener, M. E.; Goes-Neto, A.; Azevedo, V.; Ghosh, P.; Ganguly, N. K.
title: A novel multi-omics-based identification of symptoms, comorbid conditions, and possible long-term complications in COVID-19
date: 2020-12-09
journal: nan
DOI: 10.1101/2020.12.08.20245753
sha: 233e9c7563852449022a9a389cecce7cf2e2f7ef
doc_id: 1007713
cord_uid: yeucs7d2

Till date the comprehensive clinical pictures, comorbid conditions, and long-term complications of COVID-19 are not known. Recently using a multi-omics-based strategy, we have predicted the drugs for COVID-19 management with ~70% accuracy. Here, using a similar multi-omics-based bioinformatics approach and three-ways of analysis, we identified the symptoms, comorbid conditions, and short, mid and possible long-term complications of COVID-19 with ~90% precision. In our analysis (i) we identified 27 parent, 170 child, and 403 specific conditions associated with COVID-19. (ii) Among the specific conditions, 36 are viral and 53 short-term, 62 short to mid to long-term, 194 mid to long-term, and 57 are congenital conditions. (iii) At a cut off count of occurrence of 4, we found ~ 90% of the enriched conditions are associated with COVID-19. (iv) Except the dry cough and loss of taste, all other COVID-19 associated mild and severe symptoms are enriched. (v) Cardiovascular, pulmonary, metabolic, musculoskeletal, neuropsychiatric, kidney, liver, and immune system disorders are found as top comorbid conditions. (vi) Specific diseases such as myocardial infarction, hypertension, COPD, lung injury, diabetes, cirrhosis, mood disorders, dementia, macular degeneration, chronic kidney disease, lupus, arthritis etc. along with several other diseases are also enriched as top candidates. (vii) Interestingly, many cancers and congenital disorders associated with COVID-19 severity are also identified. (viii) Arthritis, dermatomyositis, glioma, diabetes, psychiatric disorder, cardiovascular diseases having bidirectional relationship with COVID-19 are also found as top ranked conditions. Based on the accuracy (~90%) of this analysis, long presence of SARS-CoV-2 RNA in human, and our previously proposed genetic remittance assumption, we hypothesize that all the identified comorbid conditions including the short-long-mid and mid-long non-communicable diseases (NCDs) could also be long-term consequences in COVID-19 survivors and warrants long-term observational studies.

Since the first report of SARS-CoV-2 infection between December 7, 2019 to December 12, 2019 from China [1] [2] [3] , as of November 10, 2020, the virus has infected 49,727,316 people with 1,248,373 deaths globally [4] . and (iv) these comorbid conditions could also be the long-term complications of COVID-19; in this analysis, we have used the same datasets (interactome, proteome, transcriptome, and bibliome) used in our previous report and a modified multi-omics approach [36] to predict the comorbid conditions, signs and symptoms, and the long-term complications in COVID-19.

Similar to our previous work [36] , we have used the same five omics data sets: interactome data (I) of Gordon et al., 2020 [37] , proteome data (P) of Bojkova et al., 2020 [38] , transcriptome profiles (T-1 and T-2) of Blanco-Melo et al., 2020 [39] and Xiong et al., 2020 [40] along with the same bibliome data (B). Only the upregulated genes or proteins were considered for analysis from the datasets used in this work. Individual omics data (I, P, T-1, T-2, B) and their three combinations were used. The combinations were P+T (P+T-1+T-2), P+T+I, and P+T+I+B.

Like our previous analysis, we have used the ToppFun and ToppGene modules of the ToppGene suite (https://toppgene.cchmc.org) with default parameters [41] for disease enrichment. In case of ToppGene module, the bibliome dataset (B) of 745 COVID-19 related genes were used as training set. The second enrichment tool used was Enrichr (https://amp.pharm.mssm.edu/Enrichr/) [42] . Six different databases integrated with the Enrichr [42] were selected to enrich the diseases or conditions. The GEO up, PheWeb, DisGeNET databases along with GWAS Catalog, OMIM Expanded, and Rare Diseases were used. The GWAS Catalogue, OMIM Expanded, and Rare Diseases based analysis were performed keeping in mind the "genetic predisposition" hypothesis (discussed later) to predict the possible genetic diseases associated with the gene sets used. Based on the P-value, Odds ratio, and combined score, the top 20 diseases from each analysis were then combined for a consolidated analysis.

Contrary to our previous analytic approach [36] , we have applied some additional considerations in this analysis. We have considered one of our previous hypotheses, i.e. "genetic remittance" [43] . According to this hypothesis, a virus or bacteria leaves a permanent signature inside host upon infection and that the host carries the signature for a long time. Therefore, pathways that are activated during the infection remains switched on for a considerable duration within the host and subsequently develop clinical symptoms in long term. The RNA of the SARS-CoV-2 remains active in the COVID-19 survivors for more than 75 days [20] and thus the virus can maintain the upregulation of these omics profile for long periods and as long-term consequences of it, the noncommunicable disease (NCD) pathways associated with these upregulated omics profile also remain active and subsequently will trigger the development of the clinical symptoms/phenotypes in long term.

In our gene-set-based disease enrichment, several unique terminologies for a disease or clinical symptom were enriched. Therefore, in the consolidated disease analysis, first we classified the enriched diseases or symptoms based on Disease Ontologies using Ontobee tool (http://www.ontobee.org) [44] . In this process, first we classified each disease or symptom under three relationships (parent -child -specific disease/symptom). For example, the "hypertensive disease" identified in gene-set-based disease enrichment is classified as cardiovascular system disease -vascular disease -hypertensive disease. Next, we grouped and counted each parent -child -specific disease/symptom based on parent, child, and specific disease/ symptom individually.

Further, based on the time or duration it takes to develop and present their clinical pictures in normal condition, each specific disease/ sign / symptom is further classified under short, short-mid, mid-long, short-mid-long, short-mid-long-genetic, mid-long-genetic, and congenital/genetic. For example, fever is classified under short and liver cirrhosis could be tagged with mid-long. Finally, based on the cumulative number of occurrence (the score), the diseases/conditions are ranked and the final results are considered based on this rank. A cut off 4 on the occurrence score was considered in most of the analysis to select the disease or symptoms. It should be noted that, a particular cumulative score for two or more different diseases are considered to have the same rank although they are listed one by one and diseases having same score have equal probability. The overall approach applied in our work is presented in Fig-1 . 

We generated 1210 classified parent -child -specific disease/symptom associations based on our top 20 enriched diseases for various omics datasets and their combinations using TopGene , Enricher , and Ontobee [44] . While we cleaned the data removing the duplicate of a specific disease or symptom and merged the similar diseases or symptoms to make the counting calculations, we obtained a dataset having 403 specific diseases or symptoms and used this dataset for further analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint

We identified 27 parent diseases or symptoms based on our consolidated analysis without classifying them based on the time duration needed to develop these diseases or symptoms. Infectious disease came at Rank-1, neoplasm (Rank-2), abnormal sign or symptom (Rank-3), cardiovascular system disease (Rank-4), immune system disorder (Rank-5), nervous system disease (Rank-6), musculoskeletal system disease (Rank-7), metabolic disorder (Rank-8), and mental disorder (Rank-9). At Rank-10 two diseases, namely, congenital anomalies and respiratory system disease are enriched. Eye disease is Ranked at 11, gastrointestinal system disease (Rank-12), urinary system disease (Rank-13), skin disease (Rank-14), liver disease (Rank-15), hematopoietic system disease (Rank-16), sepsis (Rank-17), Response to drug (Rank-18), behaviour process (Rank- 19) , and female reproductive system disease (Rank-19) constitute the top twenty disease classes (Fig-2A) . We found all most all the parent diseases as described by Clark et al. [15] . Our identified all the 27 parent diseases or symptoms are highly associated with COVID-19 which itself is a highly infectious disease [45] . Cancers [46] , cardiovascular diseases [47, 48] , autoimmune diseases [49, 50] , metabolic disorders [51, 52] , congenital heart disease [53, 54] , respiratory system disease [48] , gastrointestinal diseases [55] , kidney diseases [56, 57] , liver disease [58] , hematopoietic system . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint disease [59] , sepsis or septicaemia [60] are the reported key comorbid conditions in COVID-19 that are associated with an increased susceptibility, disease severity and mortality from COVID-19.

Considerable neurological [61, 62] , musculoskeletal [63, 64] , mental or psychological or behaviour process [30, 34] , reproductive system [65, 66] Eye diseases [67] , and skin disease [68, 69] manifestations are observed during the infection and may have long-term complications. A higher preterm labour in pregnant women infected with COVID-19 [70] is also reported. However, we did not find any literature supporting major congenital anomalies due to COVID-19. Therefore, the prediction of the parent disease groups is nearly 90% accurate in our analysis.

While we analysed for the important child diseases or conditions under each parent disease, we observed that, viral diseases constitute 75% of the diseases followed by bacterial infections under the parent infectious diseases. For neoplasm, liver, breast, gynaecologic, neurologic, and head and neck cancers are highly enriched. The key abnormal sign or symptoms are associated with blood followed by fever, pain, lung function and throat infection, fatigue, mental health, chest, and eye diseases. Under cardiovascular system disease, vascular diseases are the most frequent followed by myocardial disorders. The autoimmune diseases followed by immunodeficiency are the key diseases under the parent immune system disorder. Neurodegenerative disease, viral encephalitis, and other cerebral diseases are the top three conditions under nervous system disease category. The top three conditions under musculoskeletal system disease are bone inflammation disease, myopathy, and bone degenerative disease. Diabetes, lysosomal storage disease, metabolic syndrome X, and cholesterol level are top candidates under metabolic disorder. For mental disorder, mood disorder is most frequent followed by cognitive disorder, autism, and sleep disorder. Under respiratory system disease, asthma, COPD, pulmonary sarcoidosis, pneumonia, and lung injury are the top 5 conditions. Inflammatory bowel diseases and kidney disease are respectively top conditions under gastrointestinal system and urinary system diseases, respectively. Therefore, this child disease analysis is also nearly 90% accurate if we compared with the symptoms and comorbid conditions of COVID-19 described in various literatures. The details of this analysis are given in Fig-3 .

Apart from the above approach for child disease or symptoms analysis, we performed another enrichment analysis without considering the parent disease group (Fig-2B) . In this analysis, we directly enriched the top child conditions based on their number of occurrences from the 404 classified parent -child -specific disease/symptom associations. In this analysis too, the viral infection is ranked one. The common comorbid conditions such as autoimmune disease (Rank-2) [50] , vascular disease (Rank-4) [71] , kidney disease (Rank-5) [56, 57] , neurodegenerative disease (Rank-6) [72] , bone inflammation disease (Rank-7) [73] , myocardial disorder (Rank-7) [74] , mood disorder (Rank-7) [34] , breast cancer (Rank-10) [75] , liver disease (Rank-10) [58] , gynaecologic cancers (Rank-11) [76] , asthma (Rank-12) [77] , liver cancer (Rank-13) [78] , musculoskeletal abnormality (Rank-14) [ is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint 93], and ataxia (Rank-23) [94] etc. are among the top 25 child disease categories at a cut off score of 4 (Fig-2B) . Inflammatory bowel disease which may not be a comorbid condition in COVID-19 [95] is found enriched (Rank-9). Importantly, nervous system neoplasms (Rank-16), myopathy (Rank-16), hematopoietic system disease (Rank-16), head and neck cancer (Rank-18), and pulmonary sarcoidosis (Rank-22) also came as top child diseases.

Apart from these diseases, general symptoms of COVID-19 such as, blood related abnormalities (Rank-3), fever / severe fever with thrombocytopenia syndrome (Rank-19) [5] , pain (Rank-20) [18] , lung/ pulmonary function (Rank-22) [96, 97] , fatigue (Rank-24) [6] , sleep disorder (Rank-24) [98] , pneumonia [86] , conjunctivitis (Rank-24) [99] , skin diseases etc. are also enriched under top 25 child categories with occurrence cut off value of 4. We also found many other reported COVID-19 associated diseases/symptoms enriched below the cut off 4. For the details on the enriched child diseases/symptoms please see the Fig-2B .

Therefore, we achieved nearly 90% precision in identifying the diseases or symptoms associated with COVID-19 and hence the multi-omics based method we have developed and applied here is highly accurate and can be applied to other diseases too. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint

In this analysis, first we ranked the specific diseases and symptoms without considering the duration it takes to develop. Most commonly reported symptoms and comorbid conditions are found enriched in our analysis at a cut off specific disease occurrence score of 4. Interestingly, some diseases/ symptoms reported in isolated COVID-19 cases are also found beyond the cut off 4 (Fig-4) .

Top specific diseases without considering their duration to develop the clinical symptoms.

According to rank (with a cut off score 4), the enriched known or reported comorbid conditions or long-term complications are lupus erythematosus (Rank-1) [100] , depressive disorder / mental depression (Rank-2) [30, 101] , hepatitis C (Rank-3) [102] , breast cancer (Rank-4) [75] , arthritis (Rank-5) [103] , asthma (Rank-6) [10, 77] , liver cancer (Rank-6) [78] , tuberculosis (Rank-7) [104, 105] , diabetes (Rank-8) [82] , myocardial infarction (Rank-9) [35, 106] , macular degeneration (Rank-9) [80] , chronic kidney disease (Rank-9) [56, 57] , arteriosclerosis (Rank-10) [107] , ulcerative colitis (Rank-10) [108] , liver cirrhosis (Rank-11) [12, 109] , sepsis / septicaemia /septic shock (Rank-11) [60, 81] , other autoimmune diseases (Rank-12) [49, 50] , cerebrovascular accident / stroke (Rank-13) [110] , congenital anemia (Rank-13) [111] , COPD (Rank-13) [86] , multiple . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. myeloma (Rank-14) [112] , hypertensive disease (Rank-14) [9, 113] , dyslipidemia (Rank-15) [93] , metabolic syndrome X (Rank-15) [51, 114] , osteoporosis (Rank-16) [91] , prostate cancer (Rank-17) [115] , psoriasis (Rank-17) [116] , leukemia (Rank-18) [117, 118] , long QT syndrome (Rank-18) [119] , dementia (Rank-18) [120] , schizophrenia (Rank-18) [121] , intellectual disability (Rank-18) [122, 123] , diabetic kidney disease/ diabetic nephropathy (Rank-18) [124] etc.

In our analysis other clinical conditions such as ceroid lipofuscinosis neuronal (Rank-5), endometrial cancer (Rank-13), C1q deficiency (Rank-14), brain tumor (Rank-15), pulmonary sarcoidosis (Rank-15), congenital disorders of glycosylation (Rank-16), cervical and ovarian cancers (Rank-17), nasopharyngeal carcinoma (Rank-17), glomerulonephritis (Rank-17), thrombophilia (Rank-17), and melanoma (Rank-18) are also enriched. However, we could not get any report associating these conditions with COVID-19 (Fig-4) . As in our analysis most of the diseases are found correlated with COVID-19, we presume that these conditions could also be either comorbid or long-term consequences of COVID-19.

Further, in this analysis, we also found some diseases that are not so far reported to be associated with the increased risk or severity of COVID-19 such as HIV (Rank-14) [125] , IBD (Rank-15) [95] , and neuromyelitis optica (Rank-18) [126] . Interestingly, we also found atopy at Rank-18 which is found to have a protective role from severe complications of COVID-19 [127, 128] .

In this analysis, we also found several common symptoms (mild, severe, and long-term complications) of COVID-19 are enriched at a cut off value 4. These include influenza (Rank-5) [129] , dengue (Rank-7) [130] , fever / severe fever with thrombocytopenia syndrome (Rank-12) [5] , pain (Rank-13) [18] , dermatomyositis (Rank-14) [131] , embolism / thrombosis (Rank-15) [132] , dyspnea / dependence on respirator (ventilator) (Rank-16) [5] , conjunctivitis (Rank-17) [99] , pneumonia / pneumonitis (Rank-17) [86] , lchthyosis / keratosis (Rank-17) [133] , throat pain / strep throat / cold sores (Rank-18) [134] , fatigue/ transient alteration of awareness (Rank-18) [5] , abnormal chest sounds and nonspecific chest pain (Rank-18) [134] , anxiety disorder (Rank-18) [135] , infectious myocarditis (Rank-18) [136, 137] , aneurysm (Rank-18) [138] , and myositis (Rank-18) [139] , (Fig-4) . However, we could not find any report of COVID-19 association with cervical radiculitis (Rank-17), adjustment reaction (Rank-17), and dysmenorrhea pain (Rank-18).

Similar to the previous analysis, in this ranking we also found many diseases/symptoms reportedly associated with COVID-19 below the cut off 4. For example lactate dehydrogenase level (Rank 21) and D-dimer level (Rank 21) [16] etc. For the full list of the specific diseases/symptoms please see the (Fig-4) .

For better understanding of the COVID-19 associated specific clinical conditions based on our multi-omics profiles, we classified the 403 specific disease or symptoms based on the time or duration it takes to develop and if genetics is also involved. We grouped the diseases under six categories: short, short-mid, mid -long, short -mid -long, shortmid -long (genetic), mid -long (genetic), and congenital/ genetic. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint

Under this group, we classified the diseases/ signs/ symptoms under two groups: infectious and non-infectious or non-communicable diseases (NCDs). We found 35 infectious diseases are enriched and the top five diseases at a cut off count of occurrence of 4 are influenza (Rank-1), dengue (Rank-2), respiratory syncytial virus (RSV) infection (Rank-3), malaria (Rank-3), West Nile fever (Rank-4), marburg hemorrhagic fever (Rank-5) etc. (Fig-5A) . For the non-infectious disease/ NCDs or signs and symptoms group, we found 54 different short-term conditions. Among these, high light scatter reticulocyte percentage of red cells (Rank-1), sepsis or septicaemia (Rank-1), fever / severe fever with thrombocytopenia syndrome (Rank-2), pain (Rank-3), painful respiration or dyspnea or dependence on respirator (ventilator) (Rank-4), lipoprotein-associated phospholipase A2 activity and mass (Rank-5), conjunctivitis (Rank-5), pneumonia (Rank-5), thrombophilia (Rank-5), serum myeloperoxidase level (Rank-6), throat pain or strep throat (Rank-6), fatigue/ transient alteration of awareness (Rank-6), abnormal chest sounds and pain (Rank-6), anxiety and headache (Rank-6), viral encephalitis (Rank-6), C-reactive protein level (Rank-6), and septic shock (Rank-6) are the top conditions with the cut off occurrence score of 4. The details of these diseases or symptoms are presented in Fig-5A .

According to WHO, most common symptoms in COVID-19 are fever, dry cough and, tiredness. The less common symptoms include ache and pain, sore throat, diarrhoea, conjunctivitis, headache, loss of taste or smell, skin rash, and discolouration of toes or fingers. The serious symptoms that require medical interventions are breathing difficulty or shortness of breath, chest pain or pressure, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint and loss of speech or movement [140] . COVID-19 and influenza shares many common symptoms however, there are many differences too [141] . In our short-term infectious disease analysis, we observed that, influenza is the top candidate followed by dengue, respiratory syncytial virus (RSV) infection, and malaria (Fig-5A) . Literature also suggests that COVID-19 shares symptoms of dengue [130] and differential diagnosis includes all kinds of respiratory viral infections including respiratory syncytial virus (RSV) [142] . Similarly, malaria also shares many important symptoms of COVID-19 [143] . Therefore, the viral infections enriched in our analysis are highly accurate and all the viral diseases flagged in our analysis need to be considered with differential diagnosis for COVID-19.

While we considered the short-term specific non-infectious diseases/NCDs/ signs / symptoms, we found that most of the COVID-19 symptoms as described by WHO [140] such as fever / severe fever with thrombocytopenia syndrome (Rank-2) [144] , pain (Rank-3) [145] , painful respiration / dyspnea / dependence on respirator [Ventilator] (Rank-4) [5] , conjunctivitis (Rank-5) [99] , pneumonia (Rank-5) [86] , headache (Rank-6) [145, 146] , transient alteration of awareness (tiredness/ fatigue) (Rank-6) [5] , strep throat/ sore throat (Rank-6) [134] , abnormal chest sounds and nonspecific chest pain (Rank-6) [134] are found in our top ranked symptoms (Fig-5A) . However, dry cough, loss of taste or smell, and loss of speech or movement are not enriched as short-term symptoms. Interestingly, high light scatter reticulocyte percentage of red cells is found as the top candidate (Rank-1) sign in our analysis. Recently, high reticulocyte is reported to be significantly higher in critical patients and may be a prognostic predictor for poor outcomes [147] . Similarly, sepsis or septicemia is also enriched at Rank-1 in our analysis and sepsis is found to worsen the condition of critically ill COVID-19 patients [60] .

The cardiovascular diseases biomarker lipoprotein-associated phospholipase A2 (PLA2G7) is highly upregulated in severe COVID-19 pneumonia [148] . In our result, we found the lipoproteinassociated phospholipase A2 activity is ranked at 5. Thrombophilia, which also came at Rank-5, is highly prevalent in COVID-19 patients, however, is not associated with disease severity [149] . Myeloperoxidase could be a potential biomarker for detection of SARS-CoV-2 infection [150] . The serum myeloperoxidase level is found enriched at Rank-6 along with viral encephalitis, C-reactive protein, and septic shock (Fig-5A) . Encephalitis is frequent in older patients having age group >50 and mostly develops while under treatment in ICU [83] , level of C-reactive protein is positively associated with lung lesions and disease severity in COVID-19 [151] , and 70% of COVID-19 nonsurvivors develop septic shock [152] . Schistosomiases, matrix metalloproteinase level, plasma PCSK9 levels, lipoprotein level, epiglottitis, meningitis, and otitis media are found at Rank-7 (with the cut off occurrence score of 3) in our analysis. An early up-regulation of circulating MMP-9 is associated with respiratory failure in COVID-19 [153] , and lipoprotein level is associated with severity of COVID-19 [93] , while in September 2020 acute epiglottitis [154] and meningitis as initial symptoms of COVID-19 [155] are found in two separate COVID-19 patients. Similarly, otitis media is also observed in isolated cases [156] . Several conditions came at Rank-8 with a cut off occurrence score of 2. Among them, higher bilirubin level is observed in severe COVID-19 cases [157] , plasminogen activator inhibitor type 1 (PAI-1) is upregulated and extremely high levels of plasminogen activator (tPA) enhance spontaneous fibrinolysis and mortality [158] , and lower haemoglobin level is observed in severe COVID-19 cases [159] . Deregulation of parathyroid hormone level [160, 161] , elevated liver enzyme levels [162] , keratitis [163] , febrile seizures [164, 165] , cellulitis and sinusitis [166] are reported in isolated COVID-19 cases. Higher level of blood is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint lactate dehydrogenase and D-dimer (Rank-9, score-1) is associated with disease severity in COVID-19 [16] (Fig-5A) .

Therefore, ~90% of our predicted short-term diseases/symptoms/conditions associated with COVID-19 are correct at an occurrence cut off of 4 and several conditions associated with COVID-19 are also found enriched beyond the occurrence cut off of 4 indicating the high accuracy of the method we have developed. Further, majority of these identified diseases/symptoms/conditions are associated with COVID-19 severity and disease outcomes. Therefore, we predict that the signs and symptoms that we have identified, but not discussed or so far not reported in the literature may also be associated with COVID-19.

Under short to mid conditions, the top three conditions are hyperglycemia or dysglycemia (Rank-1), abnormal erythrocyte morphology (Rank-1), and chronic ulcer (Rank-1) (Fig-6A) . COVID-19 is reported to aggravate dysglycemia and in diabetic patients, it leads to hyperglycemia and poor patient outcomes [167] . COVID-19 patients with sepsis shows adverse effects on red blood cell morphology [168] , and re-bleeding from peptic ulcer is common in COVID-19 patients [169] . Fig-6 : A) Short to mid specific NCDs / conditions. B) Short to mid to long specific NCDs / conditions. C) Short to mid to long (genetic) specific NCDs / conditions. Under Short to Mid to Long conditions, the top five conditions found to be enriched are depressive disorders or depressed mood or mental depression at first rank (Rank-1) followed by recurrent mycobacterial infections (Rank-2), myocardial infarction (Rank-3), ulcerative colitis (Rank-4), and cerebrovascular accident or stroke (Rank-5). Embolism or thrombosis, cholesterol is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint level, and pulmonary sarcoidosis came at Rank-6. Cervical radiculitis and lchthyosis or keratosis are found to enrich at Rank -7. Dysmenorrhea pain and atopy are ranked at Rank-8 with an occurrence cut off of 4 followed by dural arteriovenous fistula (Rank-9) with an occurrence cut off of 3. Pericarditis, lung injury, lagophthalmos, cysticercosis, plantar warts, dystrophic epidermolysis bullosa, and cellulitis and abscess of fingers/toes are enriched at Rank-10 with a cut off occurrence score of 2 (Fig-6B) .

Current evidence suggests that COVID-19 shows various mental health problems including depression and mood and anxiety disorders [30, 101] . Nearly 28% COVID-19 patients are found to develop depressive mood disorders during their treatment [170] and acute COVID-19 patients may develop delirium in a significant proportion [171] . A recent report suggests that, a considerable percentage of COVID-19 patients develop mental disorders post recovery from the disease (14-90 days) and the patients having previous history of psychiatric disorders have higher incidence of COVID-19 [34] . Some reports suggest a higher mortality rate (11.6% to 14.3%) in patients with tuberculosis and COVID-19 co-infection [104, 105] . Myocardial infarction that came at Rank-3 is reported to be one of the most frequent cardiovascular syndromes in COVID-19 [35, 106] and in a meta-analysis ulcerative colitis (Rank-4) is found in 41.6% COVID-19 patients [108] and represents more severe symptoms than the patients with Crohn's disease [172] . In a single centre study, although stroke (Rank-5) is observed in 4.6% [173] and in a meta-analysis 1.1% COVID-19 cases; COVID-19 patients having stroke show severe symptoms, poorer prognosis, and 46.7% mortality rate [110] . Pulmonary embolism (Rank-6) and deep vein thrombosis are reported in 20%-40% and 0% to 69% cases in COVID-19, respectively [132] . A sharp decrease in total cholesterol level (Rank-6) and low-density lipoprotein is observed in COVID-19 patients [92] and hypolipidemia correlates with COVID-19 severity [93] . Skin disease Keratosis that came at Rank-7 with an occurrence cut off of 5 is observed as a symptom in COVID-19 [133] and a prehistory of actinic keratosis exhibit 10.8% COVID-19 cases [116] . Acute pericarditis (Rank-10) is reported as a primary symptom in COVID-19 in some cases [174] and lung injury (Rank-10) during COVID-19 and subsequent pulmonary fibrosis in COVID-19 survivors are a frequent finding [175] . Interestingly, atopy that came at Rank 8 with cumulative score of 4 is reported to show positive effect in COVID-19. SARS-CoV-2 infected patients having prehistory of atopy require less hospitalization and showed decreased mortality [127] (Fig-6B) . Similarly, menstruation has some protective effect from COVID-19 [176] . We could not find any literature showing correlation of COVID-19 with pulmonary sarcoidosis (Rank-6), cervical radiculitis (Rank-7), and dysmenorrhea pain severity (Rank-8). As in this analysis, we also found >90% precision at a cut off count of occurrence of 4, our other identified specific disease or symptoms could also be correlated with COVID-19 either in the form of a disease or comorbidity or long-term effect of COVID-19.

Since we have used OMIM Expanded and Rare Diseases databases in our Enricher-based [42] prediction, we got several genetic diseases as top candidates associated with COVID-19. These diseases are as follows: hereditary spherocytic/ haemolytic/ sickle cell anemia is the top disease (Rank-1) followed by erythropoietic protoporphyria (Rank-2), Cutis laxa, x-linked (Rank-2), Tay Sachs disease (Rank-2), spherocytosis (Rank-3), and dyskeratosis (Rank-4) (Fig-6C) . COVID-19 severity is associated with anemia [90] and patients with sickle cell anemia are at higher risk of developing severe COVID-19 [111] . However, we don't see any report on our other identified genetic diseases and their correlation with COVID-19. Nevertheless, based on the high confidence is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint of our analysis, we presume that the identified genetic conditions need careful observation on their genetic disease -COVID-19 interactions and outcomes in the long term.

While we classified the midlong term diseases or conditions into infectious, non-infectious, and genetics disease, four infectious diseases are enriched. These diseases are hepatitis C (Rank 1) followed by HIV (Rank 2), hepatitis B (Rank 3), and melioidosis (Rank 4) (Fig-7A) . Hepatitis is recently found to be a comorbid condition in COVID-19. In a systematic review it is reported that 14.1% and 21.4% of COVID-19 patients with hepatitis B and hepatitis C require ICU admission and hepatitis C confers 13% increased risk of fatality in COVID-19 patients [102] . However, people living with HIV (PLHIV) do not show poorer outcomes from COVID-19 [125] . We did not get any report on correlation between melioidosis and COVID-19.

The top 17 non-infectious diseases or NCD conditions enriched at a cut off occurrence score of 4 as per their rank are systematic lupus erythematosus (Rank-1), breast cancer (Rank-2), arthritis or rheumatoid arthritis (Rank-3), asthma (Rank-4), liver cancer (Rank-5), and diabetes (Rank-6). At Rank-7 macular degeneration, and chronic kidney disease are enriched with a cut off score of 13. Arteriosclerosis, liver cirrhosis, and other autoimmune diseases came at Rank-8, -9, and -10, respectively. Endometrial cancer, pain/ neuropathic pain, and COPD are enriched at Rank-11. At Rank-12, three diseases are enriched with a cut off score of 8. These diseases are multiple myeloma, hypertension/ hypertensive disease, and dermatomyositis. Glioma, metabolic syndrome X, and inflammatory bowel disease are Ranked at 13. At Rank-14 carotid atherosclerosis, osteoporosis, and lupus erythematosus (discoid) are found. Nine diseases are ranked at 15. They are cervical cancer, ovarian cancer, nasopharyngeal carcinoma, prostate cancer, other cardiomyopathy, psoriasis, adjustment reaction, and glomerulonephritis. At Rank-16, nineteen diseases are enriched with a cut off score of 4. These diseases are leukemia, colorectal cancer, melanoma, malignant germ cell tumor, aneurysm, infectious myocarditis, neuromyelitis optica, multiple sclerosis, Unverricht-Lundborg disease, pigmented villonodular synovitis, myositis, secondary hyperparathyroidism of renal origin, acquired amyloidosis, aphasia, dementia or Alzheimer's disease, schizophrenia, Crohn's disease, and diabetic kidney disease / diabetic nephropathy. Several other conditions are also enriched and the full list is given in Fig-7B .

Literature suggests that lupus (Rank-1) patients are more vulnerable to COVID-19 [100] and breast cancer (Rank-2) patients infected with COVID-19 show 13% mortality rate [75] . Arthritis that came at Rank-3 is reported to increase risk and severity of COVID-19 [103] . Although asthma came at Rank-4 and a comorbid condition, it may not increase the mortality rate [10, 77] . Hepatic injury is observed in 10-40% of patients with COVID-19 and therefore, in liver cancer (Rank-5) patients, COVID-19 aggravates the disease severity [78] . Diabetes that came at Rank-6 is having a bidirectional association with COVID-19. Diabetes increases the risk of severe COVID-19 or COVID-q9 associated mortality and patients with COVID-19 show early onset diabetes and severe metabolic complications associated with the disease [33, 82, 113] . Patients having a history of macular degeneration and or chronic kidney disease (Rank-7) are at increased risk of COVID-19 associated morbidity and mortality [80, 177, 178] . Reports suggest that arteriosclerosis or coronary artery calcification at Rank-8 is associated with worse prognosis [107] and liver cirrhosis (Rank-9) is associated with increased deaths in COVID-19 [12, 109] . Similarly, other autoimmune disease . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint (Rank-10) is also associated with increased risk of COVID-19 [50] . Neuropathic pain and COPD at Rank-11 are also found to associate with COVID-19. Reports suggest that nearly 2.3% of COVID-19 patients display neuropathic pain [179, 180] and COPD patients are at high risk of developing severe pneumonia and poor outcomes if infected with SARS-CoV-2 [86] .

Multiple myeloma and hypertension enriched at Rank-12 are also comorbid conditions. Multiple myeloma is associated with severe COVID-19 [112] and hypertension is found in 46% cases and is associated with severity and mortality of COVID 19 [9, 48, 113] . Similarly, other metabolic syndromes (Rank-13) are also associated with severity and death of COVID 19 [51, 114] . Individuals suffering from osteoporosis (Rank-14) [91] , cardiomyopathy (Rank-15) [15] , and psoriasis (Rank-15) are at high risk of developing severe COVID-19 [91] .

With a cut off occurrence score of 4 or (Rank-16), we found several conditions that are associated with COVID-19. Subarachnoid hemorrhage (SAH) is observed in COVID-9 patients and instability of aortic aneurysm is associated with SAH [138] . Myocarditis is one of the direct consequences (7% -23%) of SARS-CoV-2 infection and is associated with higher degree of morbidity and mortality from COVID-19 [136, 137] . Neurological changes caused by COVID-19 show similarities with multiple sclerosis [181] and myositis is a manifestation of SARS-CoV-2 infection [139] . Amyloid microclots are found in the native plasma of COVID-19 [182] and in diabetic patients, serum amyloid A (SAA) level may be associated with the severity of COVID-19 [183] . Aphasia is found in COVID-19 patients who have developed encephalopathy or ischemic stroke [184, 185] . Recent literature suggests that people suffering from dementia or Alzheimer's disease are at high risk of being infected and developing severe symptoms of COVID-19 [186, 187] . Similar to dementia, schizophrenia patients are also at higher risk of SARS-CoV-2 infection and poorer outcomes [121] . Although, patients with Crohn's disease exhibits less severe symptoms as compared to ulcerative colitis [108, 172] , patients with diabetic nephropathy shows >2 fold COVID-19 associated pneumonia and higher mortality as compared to other chronic kidney disease [124] . As mentioned earlier, two conditions IBD (Rank-13) and neuromyelitis optica (Rank-16) may not be associated with COVID-19 associated risk or severity [95, 126] . On the other hand, literature suggests that COVID-19 may trigger the development of dermatomyositis (Rank-12) [131] and Glioma (Rank-13) [188] . Similar to other analysis, we also found several COVID-19 associated conditions below the occurrence cut off value of 4. Interestingly, in this group at Rank-19, we found specific psychiatric disorders such as suicide tendency addiction. Recent report suggests that substance use disorders (SUD) or drug addicted people are at higher risk of being infected and develop severe COVID-19 [189] . Similarly, COVID-19 positive patient without a pre-history of any psychiatric condition is reported to show confusion, psychotic symptoms, and suicide attempt [190] . Therefore, in this analysis also we achieved ~90% accuracy in identifying comorbid or long-term consequences of COVID-19.

Importantly, we observed a lot of cancers enriched in our analysis such as breast cancer (Rank-2), liver cancer (Rank-5), endometrial cancer (Rank-11), cervical cancer, ovarian cancer, nasopharyngeal carcinoma, prostate cancer (Rank-15), leukemia, colorectal cancer, melanoma, malignant germ cell tumor (Rank-16), chondroma (Rank-17), sarcoma, lymphoma, larynx cancer (Rank-18), esophagal cancer, pharynx cancer, squamous cell carcinoma of mouth (Rank-19) among others (Fig-7B) . Considering our analysis that is showing high confidence in identifying the COVID-19 related conditions and complications, coupled with the facts that (i) some of these cancers such as breast cancer [75] , liver cancer [78] , gynaecologic cancers [76] , hematologic [79] , colon cancer [87] , prostate cancer [115] are already reported as comorbid conditions, (ii) glioma . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint may be developed due to COVID-19 [188] , and the fact of viral carcinogenesis process [191, 192] ; we hypothesize that the cancers we have identified in our analysis could be the long-term consequence of COVID-19.

The genetic diseases that are identified for mid to long term based analysis are ceroid lipofuscinosis neuronal (Rank-1), C1q deficiency (Rank-2), long QT syndrome (Rank-3) Papillon Lefevre syndrome (Rank-3), Polyglandular syndrome (Rank-5), familial idiopathic basal ganglia calcification (Rank-5), and spinocerebellar ataxia (Rank-5) (Fig-7C) . We could not find any literature correlating COVID-19 with these genetic conditions. Since our analysis is giving high accuracy in identifying COVID-19 associated conditions, a careful and long observation is required to understand if there is any association of SARS-CoV-2 infection with these genetic conditions.

Mid to long specific infectious diseases. B) Mid to long specific NCDs / conditions. C) Mid to long (genetic) specific NCDs / conditions.

Interestingly in our analysis, we found 57 congenital or genetic diseases that could be related to COVID-19. The top three diseases are congenital hemolytic anemia (Rank-1), congenital disorders of glycosylation (Rank-2), and occipital horn syndrome (Rank-3). At Rank-4 with an occurrence cut off score of 4, we found seven diseases and they are gangliosidosis GM1 type 3, Sandhoff disease, beta-galactosidase-1 deficiency, syndrome associated intellectual disability, cleft palate, congenital coagulation defects, and genital organ defects. With an occurrence cut off score of 3, ceroid storage disease and aspartylglucosaminuria are enriched at Rank-5. Adrenoleukodystrophy, paget disease of bone, asperger syndrome, autism spectrum disorder, microcephaly, arthrogryposis, congenital limbs . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint defect, cystic fibrosis, rhizomelic chondrodysplasia punctate, fetal hemoglobin quantitative trait locus, and familial erythrocytosis are found at Rank-6 with an occurrence cut off score of 2. The complete list of this group of diseases is given in Fig-8 ).

Among these identified diseases, some congenital diseases have been reported to show positive or negative correlation with COVID-19. However, majority of the congenital diseases identified here have no information so far on their association with COVID-19. Patients with hemolytic anemia (Rank-1), specifically sickle cell anemia are at higher risk of developing severe COVID-19 [111] . Down syndrome (Rank-4) that represents intellectual disability exhibits 4-fold increased risk of severity and 10-fold increased risk of mortality from COVID-19 [193] and autism spectrum disorder (Rank-6) may also be a risk factor [88, 89] . On the other hand, congenital coagulation defects (Rank-4) or congenital bleeding disorders are associated with more favourable outcomes of COVID-19 [194] and fetal hemoglobin (Rank-6) may play a protective role against COVID-19 as the neonates, infants, and children show low prevalence of SARS-CoV-2 infection [195, 196] . Cystic fibrosis (Rank-6) patients may be at risk but are probably not vulnerable to COVID-19 due to their current treatment of cystic fibrosis [197, 198] and according to Paget's Association, Paget's disease (Rank-6) is not a risk factor for COVID-19 [199] . As our analysis is providing some important congenital disease and COVID-19 associations, the effect of COVID-19 on our other identified congenital conditions require careful and long-term investigation to find if there is any correlation. 

WHO predicted that COVID-19 could cause long-term health complications such as cardiac muscle damage and heart failure, damage of lung tissue and lung failure, anosmia, pulmonary embolism, heart attack, stroke, cognitive impairment, anxiety, depression, post-traumatic stress disorder, sleep disorder, pain in muscles and joint, fatigue [31] . A recent report suggest that nearly 70% young and low-risk COVID-19 survivors develop one or more organs impairment within four months after initial symptoms of SARS-CoV-2 infection. Impairment of heart is observed in 32% cases, lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and spleen (6%). Further, single organ damage is observed in 66% cases while multi-organ injury is found in 25% subjects [32] . It is also reported recently that one in five COVID-19 survivors develops mental illness for the first time such as . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.08.20245753 doi: medRxiv preprint anxiety, depression, and insomnia within 90 days from the first COVID-19 symptoms shown and COVID-19 patients having pre-existing psychiatric disorder are at risk of COVID-19 severity [34] . The individuals recovering from COVID-19 are also developing substance use disorder [22] , confusion, psychotic symptoms, and suicide tendency [30, 190] . Apart from these, COVID-19 is found to trigger arthritis [200] , dermatomyositis [131] , glioma [188] , and early onset of diabetes and severe metabolic complications [33] . Considering the facts that (i) all these NCDs and mental health conditions are found enriched at top ranks in our analysis along with several conditions, (ii) high confidence of our analysis (~90%), (iii) most of our identified conditions are associated with severity of COVID-19, (iv) the bidirectional relationship between diabetes and COVID-19 [33] , psychiatric disorder and COVID-19 [34] , COVID-19 and cardiovascular system diseases [35] , (v) presence of SARS-CoV-2 viral RNA in patients body for long time after recovery [20] , and (vi) our "genetic remittance" assumption [43] ; we hypothesize that in long-term, COVID survivors may develop various conditions we have identified in this analysis. However, as COVID-19 is a new disease, long-term observational studies are required on COVID-19 survivors to assess the longterm consequences of the SARS-CoV-2 infection.

In this analysis, using multi-omics (proteome, transcriptome, interactome, and bibliome) data of SARS-CoV-2 infection and a unique bioinformatics strategy, we have identified mild and severe symptoms, associated comorbid conditions, short and long term complications of COVID-19. Based on available literature, our predictions are found to have ~90% precision in identifying the COVID-19 associated mild and severe symptoms, comorbid conditions, and long-haul complications. This indicates that the method we have developed is highly accurate and can be applied to other diseases and pandemics too. In this analysis, we have identified the disease/conditions using the omics profiles upregulated due to SARS-CoV-2 infection. Since the viral RNA remains active for several months within the COVID-19 survivors, these upregulated omics profile remains switched on for a long time and hence the corresponding NCD pathways may lead to the development of the respective NCD as a long-term consequence of SARS-CoV-2 infection. The limited literature on long-term consequences of COVID-19 so far available also supports our hypothesis. However, long-term observational studies are required to further support our findings.

DB: conceived and designed the experiment, data collection and analysis, result interpretation, and wrote the paper; ST and BSA preformed re-analysis; PG: data interpretation and edited the article, MEW, AGN, VA, NKG: provided technical inputs. All authors have read and approved the article.

Authors declare no competing interest. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 9, 2020. ;

A Novel Coronavirus from Patients with Pneumonia in China

A new coronavirus associated with human respiratory disease in China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Determine the most common clinical symptoms in COVID-19 patients: a systematic review and meta-analysis

Critical complications of COVID-19: A descriptive meta-analysis study

Longitudinal symptom dynamics of COVID-19 infection in primary care

Comorbidities and severity of coronavirus disease 2019 patients

Prevalence of underlying diseases in died cases of COVID-19: A systematic review and meta-analysis

Does Asthma Increase the Mortality of Patients with COVID-19?: A Systematic Review and Meta-Analysis

A meta-analysis of the impact of COVID-19 on liver dysfunction

High rates of 30-day mortality in patients with cirrhosis and COVID-19

Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions

SARS-CoV-2) and polycystic ovarian disease: Is there a higher risk for these women?

Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study

Predictors of COVID-19 severity: a systematic review and metaanalysis

COVID-19 Patients: A Systematic Review and Meta-Analysis of Laboratory Findings, Comorbidities, and Clinical Outcomes Comparing Medical Staff versus the General Population

Persistent Symptoms in Patients After Acute COVID-19

Extrapulmonary manifestations of COVID-19

Long-Term SARS-CoV-2 Infection Associated with Viral Dissemination in Different Body Fluids Including Bile in Two Patients with Acute Cholecystitis

Assessment and characterisation of post-COVID-19 manifestations

Long-term Health Consequences of COVID-19

Long-term COVID-19 symptoms in a large unselected population. medrxiv 2020. 24. van den Borst B

Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution

Post COVID 19 acute acalculous cholecystitis raising the possibility of underlying dysregulated immune response, a case report

Ocular surface impairment after COVID-19: a cohort study

Sudden irreversible hearing loss post COVID-19

Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report

Epidemiology of mental health problems in COVID-19: a review

Multiorgan impairment in low-risk individuals with long COVID

New-Onset Diabetes in Covid-19

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives

Multi-omics-based identification of SARS-CoV-2 infection biology and candidate drugs against COVID-19

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Proteomics of SARS-CoV-2-infected host cells reveals therapy targets

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients

ToppGene Suite for gene list enrichment analysis and candidate gene prioritization

Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

Linking common non-coding RNAs of human lung cancer and M

Ontobee: A Linked Data Server and Browser for Ontology Terms

Proceedings of the 2nd International Conference on Biomedical Ontologies (ICBO)

Comprehensive review of coronavirus disease 2019 (COVID-19)

The risk and prognosis of COVID-19 infection in cancer patients: A systematic review and meta-analysis

Impact of cerebrovascular and cardiovascular diseases on mortality and severity of COVID-19-systematic review, meta-analysis, and meta-regression

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and metaanalysis

COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series

Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis

Metabolic syndrome and COVID-19: An update on the associated comorbidities and proposed therapies

A metabolic handbook for the COVID-19 pandemic

Adult congenital heart disease and the COVID-19 pandemic

COVID-19) Pandemic Implications in Pediatric and Adult Congenital Heart Disease

COVID-19 and Gastrointestinal Disease. Implications for the Gastroenterologist

Renal complications in COVID-19: a systematic review and meta-analysis

The kidney and COVID-19 patients -Important considerations

Moheb I: COVID 19 and liver: An A-Z literature review. Dig Liver Dis

Is COVID-19 a New Hematologic Disease? Stem Cell Rev

Sepsis and Coronavirus Disease 2019: Common Features and Anti-Inflammatory Therapeutic Approaches

COVID-19: A Global Threat to the Nervous System

Neurological associations of COVID-19

Musculoskeletal symptoms in SARS-CoV-2 (COVID-19) patients

Musculoskeletal Consequences of COVID-19

Potential risks of SARS-CoV-2 infection on reproductive health

SARS-CoV-2 and the next generations: which impact on reproductive tissues?

COVID-19 and ocular implications: an update

A Review of the Dermatological Manifestations of Coronavirus Disease 2019 (COVID-19)

COVID-19 and Skin Manifestations: An Overview of Case Reports/Case Series and Meta-Analysis of Prevalence Studies

Clinical features and outcomes of pregnant women with COVID-19: a systematic review and meta-analysis

COVID-19 -A vascular disease

COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable?

Managing rheumatoid arthritis during COVID-19

COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors

Comprehensive review of implications of COVID-19 on clinical outcomes of cancer patients and management of solid tumors during the pandemic

COVID-19 outcomes of patients with gynecologic cancer in

A global respiratory perspective on the COVID-19 pandemic: commentary and action proposals

Impacts of COVID-19 on Liver Cancers: During and after the Pandemic

When hematologic malignancies meet COVID-19 in the United States: Infections, death and disparities

Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Septic shock presentation in adolescents with COVID-19

Diabetes mellitus increases the risk of hospital mortality in patients with Covid-19: Systematic review with meta-analysis

Encephalopathy in patients with COVID-19: A review

Clinical outcomes and features of COVID-19 in patients with primary immunodeficiencies in New York City

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

Sin DD: COVID-19 and COPD

The Risk and Prevalence of COVID-19 Infection in Colorectal Cancer Patients: a Systematic Review and Meta-analysis

Psychosocial and Behavioral Impact of COVID-19 in Autism Spectrum Disorder: An Online Parent Survey

Could autism spectrum disorders be a risk factor for COVID-19?

Anemia is associated with severe coronavirus disease 2019 (COVID-19) infection

Osteoporosis in the age of COVID-19

Cholesterol in Relation to COVID-19: Should We Care about It?

Hypolipidemia is associated with the severity of COVID-19

Ataxia as a presenting manifestation of COVID -19: Report of a single case

COVID-19 in patients with inflammatory bowel disease: A systematic review of clinical data

Abnormal pulmonary function in COVID-19 patients at time of hospital discharge

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery

A systematic review of COVID-19 and obstructive sleep apnoea

Conjunctivitis in COVID-19 patients: frequency and clinical presentation

COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics. Front Immunol 2020

Psychiatric face of COVID-19

COVID-19 among patients with hepatitis B or hepatitis C: A systematic review

Impact of COVID-19 pandemic on rheumatoid arthritis from a Multi-Centre patientreported questionnaire survey: influence of gender, rural-urban gap and north-south gradient

Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases

Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts

A current review of COVID-19 for the cardiovascular specialist

Coronary Artery Calcification and Complications in Patients With COVID-19

Systematic Review on Inflammatory Bowel Disease Patients With Coronavirus Disease 2019: It Is Time to Take Stock

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study

Stroke and Novel Coronavirus Infection in Humans: A Systematic Review and Meta-Analysis

Sickle cell trait and the potential risk of severe coronavirus disease 2019-A mini-review

Multiple myeloma and COVID-19

Brazilian Diabetes Society Study G: Severity and mortality of COVID 19 in patients with diabetes, hypertension and cardiovascular disease: a meta-analysis

Metabolic Syndrome and COVID-19 Mortality Among Adult Black Patients in New Orleans. Diabetes Care

Impact of COVID-19 on Prostate Cancer Management: Guidelines for Urologists

Dermatological diseases presented before COVID-19: Are patients with psoriasis and superficial fungal infections more vulnerable to the COVID-19?

Outcomes of COVID-19 in patients with CLL: a multicenter international experience

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes

Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa

Schizophrenia and COVID-19: risks and recommendations

COVID-19 deaths in people with intellectual disability in the UK and Ireland: descriptive study

Intellectual and developmental disability and COVID-19 case-fatality trends: TriNetX analysis

The impact of COVID-19 in diabetic kidney disease and chronic kidney disease: A population-based study

Coronavirus disease 2019 (COVID-19) outcomes in HIV/AIDS patients: a systematic review

Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders

Atopy is predictive of a decreased need for hospitalization for coronavirus disease 2019

Atopic status protects from severe complications of COVID-19

Comparison of Clinical Features of COVID-19 vs Seasonal Influenza A and B in US Children

Coronavirus Disease of 2019: a Mimicker of Dengue Infection?

Dermatomyositis during COVID-19 Pandemic (A Case Series): Is there a Cause Effect Relationship?

A Review of Venous Thromboembolism Phenomena in COVID-19 Patients

Skin findings in the COVID-19 pandemic in the Region of Murcia

Features of Mild-to-Moderate COVID-19 Patients With Dysphonia

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

COVID-19 and Myocarditis: What Do We Know So Far?

Systematic review of COVID-19 related myocarditis: Insights on management and outcome

Letter to editor: Severe brain haemorrhage and concomitant COVID-19 Infection: A neurovascular complication of COVID-19

Myositis as a manifestation of SARS-CoV-2. Ann Rheum Dis 2020. 140. WHO: COVID-19 affects different people in different ways. Most infected people will develop mild to moderate illness and recover without hospitalization

Clinical features of COVID-19 and influenza: a comparative study on

A Review of Coronavirus Disease-2019 (COVID-19)

COVID-19 and malaria: A symptom screening challenge for malaria endemic countries

SARS-CoV-2 induced thrombocytopenia as an important biomarker significantly correlated with abnormal coagulation function, increased intravascular blood clot risk and mortality in COVID-19 patients

COVID-19 Pandemic and Neurological Disease: A Critical Review of the Existing Literature

Headache in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Narrative Review

Red cell distribution width (RDW): a prognostic indicator of severe COVID-19

Abnormal Upregulation of Cardiovascular Disease Biomarker PLA2G7 Induced by Proinflammatory Macrophages in COVID-19 patients

High Prevalence of Acquired Thrombophilia Without Prognosis Value in Patients With Coronavirus Disease

Blood Myeloperoxidase-DNA, a biomarker of early response to SARS-CoV-2 infection? Allergy

C-reactive protein levels in the early stage of COVID-19

Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with (COVID-19)

Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure

COVID-19 infection presenting with acute epiglottitis

Meningitis as an Initial Presentation of COVID-19: A Case Report. Front Public Health

New type of corona virus induced acute otitis media in adult

Bilirubin levels in patients with mild and severe Covid-19: A pooled analysis

Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

Anemia and iron metabolism in COVID-19: a systematic review and metaanalysis

A Novel Case of Hypoparathyroidism Secondary to SARS-CoV-2 Infection

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease

Liver Enzyme Elevation in Coronavirus Disease 2019: A Multicenter, Retrospective, Cross-Sectional Study

The ocular surface, coronaviruses and COVID-19

COVID-19) Associated With Febrile Status Epilepticus in a Child

Seizures associated with coronavirus infections

Orbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-19

COVID-19 and diabetes mellitus: An unholy interaction of two pandemics

Red blood cell morphology in patients with COVID-19-related anaemia

Peptic Ulcer Disease as a Common Cause of Bleeding in Patients with Coronavirus Disease

COVID-19 and mental health: A review of the existing literature

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research

Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study

Acute pericarditis as a primary presentation of COVID-19

Pulmonary Fibrosis in COVID-19 Survivors: Predictive Factors and Risk Reduction Strategies

A Multi-hospital Study in Wuhan, China: Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection

CKD is a key risk factor for COVID-19 mortality

COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup

Neurological Aspects of SARS-CoV-2 Infection: Mechanisms and Manifestations

A COVID-19 patient with intense burning pain

Long-Term Respiratory and Neurological Sequelae of COVID-19

Prevalence of amyloid blood clots in COVID-19 plasma

Serum amyloid A protein has been undervalued as a biomarker of COVID-19

Encephalopathy in COVID-19 Presenting With Acute Aphasia Mimicking Stroke

COVID-19 presenting with agraphia and conduction aphasia in a patient with left-hemisphere ischemic stroke

Preexisting Comorbidities Predicting COVID-19 and Mortality in the UK Biobank Community Cohort

Anticipating and Mitigating the Impact of the COVID-19 Pandemic on Alzheimer's Disease and Related Dementias

Can COVID-19 induce glioma tumorogenesis through binding cell receptors? Med Hypotheses

COVID-19 risk and outcomes in patients with substance use disorders: analyses from electronic health records in the United States

Severe psychiatric disturbance and attempted suicide in a patient with COVID-19 and no psychiatric history

Human viruses and cancer

Molecular mechanisms of viral oncogenesis in humans

COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study Of 8 Million Adults

Do congenital bleeding disorders have a protective effect against COVID-19? A prospective study

COVID-19 in Newborns and Infants-Low Risk of Severe Disease: Silver Lining or Dark Cloud?

A hypothesis about the role of fetal hemoglobin in COVID-19

Impact of COVID-19 on people with cystic fibrosis

COVID-19 meets Cystic Fibrosis: for better or worse?

COVID-19 and The Paget's Association

EP01 Post COVID-19 reactive arthritis