Covid-19 Infection and its Adverse Effects on Multiorgan

Shehnaz Sultana¹, Samuel Abraham Joshi Davala², Venkateshwari Ananthapur¹, Penagaluru  Pardhanandana Reddy^3,4*

¹Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Telangana, India

²Virinchi Hospitals, Telangana, India

³Bhagwan Mahavir Medical Research Centre, AC Guards, Telangana, India

⁴MAA Research Foundation, Telangana, India

^*Corresponding author: Penagaluru  Pardhanandana Reddy, Research Director, Bhagwan Mahavir Medical Research Centre and MAA Research Foundation, Hyderabad, Telangana, India

Received: 28 January 2022; Accepted: 04 February 2022; Published: 18 February 2022

1. Introduction

Covid-19 has been emerged as a global pandemic ca-

used by SARS-CoV-2. Though respiratory involve-ment, ranging from mild upper respiratory symptoms to acute respiratory distress syndrome (ARDS) is the hallmark of SARS-CoV-2 infection [1], it also imparts multiorgan involvement. The precise patho-physiology of SARS-CoV-2 infection is still subtle due to the emergence of new variants. Nevertheless, a reliable remark is the presence of a proinflammatory surge, the so-called cytokine storm, which is assumed to be central to the pathogenesis of the acute lung injury-acute respiratory distress syndrome spectrum that amplifies the immune response of alveolar tissue [2]. The speed of disease progression is extensively influenced by the presence of comorbidities and of extrapulmonary organ injuries. Although considera-ble emphasis has been on the pulmonary complica-tions, it is important to be aware of the other complications and its effect on multiorgan which can be a substantial contributor to the mortality related to Covid-19 infection. The present review emphasizes the updated literature on Covid-19 infection and its effect on multiorgan, which includes myocarditis, acute kidney damage, delirium, gastrointestinal symptoms (see Sec. 2), and post recovery complica-tion mucormycosis (see Sec. 3).

2. Multiorgan Manifestations

2.1 Myocarditis

Covid-19 has an extensive range of cardiovascular complications, which include acute-onset heart fail-ure, arrhythmias, acute coronary syndrome, myocar-ditis, and cardiac arrest [3, 4]. The foremost case of Covid-19 complicated with fulminant myocarditis was reported by Jia et al [5]. Myocarditis shows a variety of clinical presentations, such as fatigue, chest pain, palpitations to life-threatening presentations like cardiogenic shock or sudden cardiac death associated with ventricular arrhythmias [6]. The exact mechanism of cardiac injury in Covid-19 patients remains poorly understood. However, there are several possible hypotheses on the pathogenesis of Covid-19 and myocarditis such as (i) direct damage to cardiomyocytes by circulating virus through binding to ACE2 receptors [7] (ii) severe cytokine release syndrome by dysregulated response by types 1 and 2 helper T cells which lead to severe systematic inflammatory response resulting in cardiomyocytes hypoxia and apoptosis (iii) overactivation of the auto-immune system with possible interferon mediated hyperactivation of innate and adaptive immune systems.

Cardiac injury has shown uneven rates of mortality reaching up to 51% in Covid-19 patients [3]. There are few reports showing pathological evidence that Covid-19 directly invades the heart [8]. Viral particles with the morphology and size of corona-viruses were detected in interstitial macrophages, but there was no evidence of SARS-CoV-2 genomic material in the myocardium [9]. Pathological post-mortem biopsies of Covid-19 patients showed only a few interstitial mononuclear inflammatory infiltrates, but no significant damage in the heart tissue [4]. Numerous observational studies have reported cardiac injury among hospitalized Covid-19 patients [3, 10, 11]. Selman et al (2020) described the first case of Covid-19 related fatal fulminant myocarditis in an infant. The presence of the viral genome in myocardial tissue together with local inflammation is remarkable. Negative inflammatory indicators sugg-est the existence of direct damage by the virus [12]. A retrospective study described a new paediatric condition connecting myocarditis, infection with SARS-CoV- 2 and multisystem inflammatory syndrome mimicking an incomplete Kawasaki disease [13]. A 10-year-old male positive for Covid-19 infection was suspected for Kawasaki disease, and later found to have myocarditis [14].

A meta-summary of SARS-CoV-2 induced myoca-rditis cases included 31 studies on 51 patients among them 12 cases were confirmed myocarditis while 39 had possible myocarditis. The average age was 55 years and 69% of them were males. Fever, shortness of breath, cough and chest pain were the common presenting symptoms. Electrocardiogram report showed non-specific ST segment and T-wave changes and ventricular tachycardia. Most of the patients had elevated cardiac and inflammatory biomarkers levels. Left ventricular dysfunction and hypokinesis were common among the patients. In 10 patients cardiac magnetic resonance (CMR) estab-lished the diagnosis with features of cardiac oedema and cardiac injury. Few patients required mechanical ventilation and extracorporeal membrane oxygena-tion, 30% of the patients recovered but 27% died [15]. Marc et al (2021) summed up the results of 277 cardiac autopsy reports from 22 studies, that demonstrated the modest frequencies of Covid-19 related cardiac histopathologies. Non-myocarditis inflammatory infiltrate and single cell ischemia are the often-reported cardiac findings occurring in 12.6% and 13.7% of the cases respectively. In 4.7% of the patients acute myocardial infarctions were reported, while in 7.2% of the cases myocarditis was reported [16].

There is current discussion on whether cardiac complications of Covid-19 result from myocardial viral infection or are secondary to systemic inflame-mation and thrombosis. Adam et al (2021) has observed that cardiomyocytes are infected in patients with Covid-19 myocarditis and established an engineered heart tissue model of Covid-19 myocar-dial pathology. The authors also described the mechanisms of viral pathogenesis, and demonstrated that cardiomyocyte SARS-CoV-2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death [17]. These results suggest direct infection of cardiomyocytes in the pathogenesis of Covid-19 myocardial pathology and delivers a model system. More pathological studies and autopsy series will be helpful to explain the competence of Covid-19 in direct infection of myocardium and causing myocarditis.

A cohort study conducted post Covid-19 infection in 1597 US competitive athletes, showed 37 athletes (2.3%) with clinical and subclinical myocarditis [18]. A case series showed low prevalence of myocarditis (1.4%) among the student athletes recovering from Covid-19, based on the MRI findings [19]. Systemic responses to the vaccine, which were typically mild and transient were reported among the younger population and more often after the second dose [20, 21]. Abu et al (2021) from Israel reported six cases of myocarditis post BNT162b2 vaccination. Myocarditis was reported in five patients after the second dose of vaccination and in one patient after the first dose of the vaccine. All of them were males with an average age of 23 years. Myocarditis was diagnosed in all patients through routine clinical and laboratory inves-tigations which included troponin and C- reactive protein levels for common etiologies of myocarditis. Myocarditis diagnosis was established after cardiac MRI. There was no indication of Covid-19 infection. None of the patients had any clinical sign or laboratory finding compatible with autoimmune disease nor had a history of an exposure to new drugs or toxins prior to onset of their symptoms. The clinical course was mild in all the six patients [22]. Further studies on endomyocardial biopsy and autopsy are required for a well understanding of the pathogenesis of clinically suspected myocarditis in the course of SARS-CoV-2 infection.

2.2 Acute kidney injury (AKI)

In critically ill Covid-19 patients, acute kidney injury (AKI), an unexpected decrease in kidney function has appeared as a serious impairment. The SARS-CoV-2 virus enter tubular cells through the angiotensin-converting enzyme 2 (ACE2) receptor. Angiotensin converting enzyme 2 (ACE2) is present in podocytes, mesangial cells, parietal epithelium of the bowman’s capsule, proximal cells and the collecting duct of the kidney [23]. SARS-CoV-2 can straight infect podocytes and tubular epithelial cells [23, 24]. The initial reports across the world showed that the incidence rate of AKI as <5% surpassing to 25% [25-28]. The occurrence of AKI in SARS patients with normal kidney function is reported to be 6.7%, which might be due to acute tubular necrosis (ATN) and occasional rhabdomyolysis [29]. A meta-analysis showed increased mortality rate in Covid-19 patients with AKI and incidence of AKI was also higher in severe cases [30]. Post-mortem histology of kidneys has confirmed thrombi and erythrocyte aggregates obstructing peritubular capillaries and impacting intrarenal microcirculation. Renal histology reports confirmed pigmented tubular casts containing high levels of creatine phosphokinase [31]. Collapsing glomerulopathy, a hostile variant of focal segmental glomerulosclerosis through high rates of podocyte injury and depletion was reported in renal biopsies of patients with SARS-CoV-2 infection related AKI [32]. Proteinuria and haematuria are the conditions reported in patients with SARS-CoV-2 infection related AKI [33]. ERA-EDTA Registry results show a high mortality due to Covid-19 in dialysis patients and kidney transplant recipients across Europe [34].

However, whether AKI leads to increased mortality in patients with Covid-19 remains unknown [35, 36]. Severe renal impairment has been reported in half of the Covid-19 patients in the Middle East. Diabetes and hypertension were the most common existing comorbidities among them [37]. Ali et al (2020) from Iran reported Acute kidney injury in pregnant women following SARS-CoV-2 infection [38]. Isil et al (2021) found abnormal renal imaging in a patient with only mild form of Covid-19 [39]. Two paediatric cases showed acute necrotizing glomeru-lonephritis associated with Covid-19 infection [40]. Acute kidney injury (AKI) has become an area of concern in Covid-19 patients and has increased the risk of mortality [33, 27]. The case reports and autopsy series of covid-19, demonstrate specific causes of AKI such as volume depletion, multiorgan failure, viral infection resulting in kidney tubular injury, thrombotic vascular processes, glomerulone-phritis, or rhabdomyolysis [31, 32, 41]. Pre-existing comorbidities along with genetic makeup may play a role in resulting condition. According to Pan et al (2020) the expression of the ACE2 receptor in renal podocytes and proximal tubule cells was more definite in occidental subjects than in Asians, signifying the ethnic difference [42]. Severe Covid-19 infection may damage the kidney and cause acute tubular necrosis (ATN), leading to proteinuria, haem-aturia, and elevated serum creatinine. The deposition of immune complexes of viral antigen or virus-induced specific immunological effector mechanisms specific to T-cell lymphocytes or antibodies can induce inflammatory processes and leads to further kidney damage.

2.3 Delirium as a presenting sign of Covid-19

Covid-19 infection has several neurological manifest-tations, for a detailed review the reader is referred to Sultana and Ananthapur (2020) [43]. In the present section, the focus is on delirium as a presenting sign of Covid-19. Delirium is defined as an acute con-fused state, characterized by compromised cognition, psychomotor disorders, inattention, and a fluctuating course [44]. Delirium is arbitrated by several mech-anisms which include oxidative stress, inflammation, neuronal aging, cellular signalling and messaging dysregulation [45], which lead to neurotransmitter imbalances of acetylcholine, melatonin, dopamine, glutamine, GABA, serotonin, and histamine [46]. Covid-19 infection has systemic effects throughout the body, including the brain [47-49]. The WHO recognized altered consciousness and confusion as core symptoms of Covid-19 [50]. The foremost question still remains unanswered is whether deli-rium in Covid-19 characterizes a primary manifest-tation, signalling invasion of the brain by the virus, or it simply establishes a secondary encephalopathy caused by inflammation or further systemic effects of the virus. Altered consciousness exists as a neuro-logic manifestation of Covid-19, extending from drowsiness to confusion, delirium, lethargy and coma, in nearly 15% of hospitalized Covid-19 patients [51]. Delirium might depend on the direct effects of SARS-CoV-2 infection, likely viral invasion to the central nervous system (CNS), secondary encephalopathy due to systemic inflame-mation, or other precipitating factors, such as prolonged duration of hospital stay, urinary retention, constipation, pain, and various metabolic abnormal-lities that occur during severe infection [52, 53]. Neurotransmitter imbalance, pro-inflammatory cyto-kines, tissue hypoxia, and sleep deprivation play imp-ortant role in the pathomechanism of delirium.

A recent review on psychiatric and neuropsychiatric appearances of Covid-19 and other coronaviruses showed high rates of delirium [54]. A systematic review and meta-analysis showed that the presence of delirium is associated with increased risk of mortality in hospitalized older adults with Covid-19 [55]. A multicentric cohort study stated that the acute brain dysfunction was extremely predominant and exten-ded in critically ill Covid-19 patients and use of benzodiazepine, lack of family visitation was recognized as modifiable risk factors for delirium [56]. A cohort study of 322 hospitalised and 535 community-based older adults revealed probable delirium as a presenting symptom of Covid-19 in frail and older adults [57]. According to a study pre-existing cognitive impairment was the main risk factor for delirium in older patients with Covid-19. Delirium was related with increased in-hospital mortality, but not with the length of stay [58]. Walid et al (2020) presented a unique case of delirium, otherwise asymptomatic for Covid-19 [59]. Delirium was common and seen frequently without other typical symptoms of Covid-19, and associated with poor hospital outcomes and mortality in older adults [60, 61]. A case report described, delirium as the only first manifestation of Covid-19 without obvious lung disease [62]. Acute onset of altered mental status and delirium with normal respiration and metabolic balance in the first 48 hours was reported in two Covid-19 infected cases [63]. The existence of delirium is an important factor in predicting worse functional outcomes in patients with Covid-19 [64]. Although several studies from all over the world have reported delirium as the presenting sign of Covid-19, the existing diagnosis criteria do not include delirium as the first presenting symptom of Covid-19, thus leading to under diagnosis of Covid-19 infection. There is lack of concern and attention towards the implications of delirium in identification and management of Covid-19 situation. Under detection of delirium as a primary manifestation of Covid-19 may result in under diagnosis of Covid-19 infection, which further enhance the spread of infection and mortality. In long term, it might lead to cognitive and functional decline [65]. Taking the results of published literature into due consideration, it is necessary to include delirium in the list of presenting signs of Covid-19 infection for better diagnosis and management of the condition.

2.4 Gastrointestinal symptoms associated with Covid-19

Gastrointestinal signs are accompanied by inflame-mation and intestinal damage due to loss of intestinal barrier integrity and gut microbes which activate innate and adaptive immune cells to release prion-flammatory cytokines into the circulatory system, resulting in systemic inflammation. In a study of 206 patients with mild Covid-19 infection, 48 patients presented only digestive symptoms, disclosing that patients with gastrointestinal symptoms had a lengthier duration between symptom onset and viral clearance and faecal virus-positive compared with respiratory symptoms [66]. According to a systematic metanalysis the frequency of diarrhoea was as low as 2% and up to 50% in Covid-19 positive cases [67]. Receptors for transmembrane protease serine 2 (TMRPSS2), an enzyme expressed in the small intestinal epithelial cells are used by SARS-CoV-2 to get entry into the infected cells [67]. The SARS-CoV-2 activity might cause ACE2 alterations in the gut that intensify the susceptibility to intestinal inflammation and diarrhoea. In enterocytes, esophagus and lungs a high co-expression of ACE2 and TMPRSS2 was detected [68]. ACE2 and TMPRSS2 transcripts co-expression was maximum in the small intestine, 20% in enterocytes and 5% in the colon cells, as studied by a single-cell RNA sequencing in the gastrointestinal tract [69]. ACE2 also shows substantial influence on the intestinal microbiota composition [70]. Changes in the immune system result in variations in the intestinal flora, and coronavirus infection also persuades bacterial changes that might alter the gut-brain axis. A meta transcriptional analysis found that 36 differentially expressed genes are associated with immune pathways and cytokine signalling such as interferon gamma and severity of Covid-19 [71]. A metanalysis of 1,810 paediatric Covid-19 patients, reveals an incidence of gastrointestinal symptoms in 6% of the patients with higher occurrence of fever (55%), cough (45%), and dyspnea (19%) [72]. In a pool of 371 children comprised in 14 studies, 7.4% showed gastrointestinal symptoms such as vomiting, diarrhoea and abdominal pain [73]. Even rare manifestations of SARS-CoV-2 infection have also been reported in children, with substantial mucosal inflammation being seen in the acute phase, with terminal ileitis related with symptoms of fever and abdominal pain impersonating an unusual appendi-citis [74]. Identification of gastrointestinal symptoms relating to SARS-CoV-2 infection can aid in designing new treatments targeting gut microbiota, to combat associated symptoms in Covid-19 treatment.

3. Post Covid-19 Recovery Complication

3.1 Mucormycosis

Covid-19 pandemic has resulted in an innumerable clinical manifestations and complications. The emer-gence of second wave added a new post Covid-19 recovery complication to the existing clinical mani-festations of Covid-19 in the form of mucormycosis, popularly known as black fungus. Mucormycosis a rare fungal infection pronounced by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae. The utmost medical presentation of mucormycosis is rhino-orbitalcerebral infection, believed to be secondary to inhalation of spores into the paranasal sinuses of the host [75]. Predisposing conditions for mucormycosis include diabetes, systemic cortico-steroid use, neutropenia, hematologic malignancies, stem cell transplant, and immunocompromised individuals [76]. Around seventy percent of rhino-orbitalcerebral mucormy-cosis cases are found in patients with diabetes mellitus, majority of them had also established ketoacidosis at the time of exhibition. Infection typically presents by acute sinusitis, fever, nasal congestion, purulent nasal discharge and headache. Obtundation is resulted due to the spread of infection from the ethmoid sinus to the frontal lobe. The fungi gain entry into the host through inhalation into the paranasal sinuses and might eventually spread to the sphenoid sinus, palate and cavernous sinus. Clinical features include blurry vision, inflammation around the orbit, sinusitis, facial pain or numbness, head-ache, proptosis, ophtha-lmoplegia, or even periorbital cellulitis [77, 78].

Mucormycosis is caused due to fungi Mucorales. Depending on the site of infection the clinical manifestations are cutaneous, pulmonary, sinusitis, gastrointestinal, or even dissemination. Rhinocerebral mucormycosis is well-known in diabetic patients [79]. Rhinocerebral mucormycosis presents black necrotic eschars due to tissue necrosis from angio-invasion and subsequent thrombosis. Early diagnosis and treatment are very important to prevent morbidity and mortality. The major investigative modalities for mucormycosis include histopathology, direct micro-scopy, and culture from clinical specimens [80]. The incidence rate of mucormycosis differs from 0.005 to 1.7 per million population. It is very difficult to diagnose mucormycosis. Initial diagnosis and treat-ment are crucial, as a delay of even 6 days is related with a doubling of 30- day mortality from 35% to 66% [81]. Mucormycosis condition is encountered in immunocompromised patients. The early clinical symptoms suspected for diagnosis include unilateral facial pain or swelling, orbital swelling, or proptosis. Though tissue necrosis is a delayed sign, it is considered as hallmark of mucormycosis, resulting from angioinvasion and vascular thrombosis.

Amanda Werthman-Ehrenreich reported the first case of mucormycosis with orbital compartment syndrome in a patient with Covid-19 infection [82]. Akshay et al [83] reported the first case of mucormycosis in a heart transplant recipient prior to Covid-19. The patient was diabetic, and on immunosuppressive and corticosteroid medication and later passed away [83]. Andre et al reported pulmonary aspergillosis and mucormycosis in a Covid-19 patient [84]. Ricardo et al from Chile reported 16 cases of Covid-19 associated invasive mold infection (CAIMI) among 146 nonimmuno compromised patients with severe Covid-19 [85]. Nariman et al reported Covid-19 associated pulmonary mucormycosis in a 44-year-old hyperglycaemic hispanic female [86]. Amirreza et al reported one case of rhino-orbitocerebral mucorm-ycosis and another case of rhino-orbital mucorm-ycosis among the two cases of Covid-19 under corticosteroid [87]. The first report of gastrointestinal mucormycosis in Brasil was resported by Epifanio et l in an 86 years old male patient [88]. Acute invasive rhino-orbital mucormycosis in a patient with covid -19 associated acute respiratory distress syndrome was reported from California, USA [89]. A case of rhinocerebral mucormycosis coexisting with Covid-19 pneumonia in a 41-year-old man with a history of type 1 diabetes mellitus (T1DM) was presented by Kirill et al [90]. A 53-year-old male patient with secondary acute myeloid leukemia (AML) infected with Covid-19 was diagnosed with mucormycosis postmortem [91]. A fatal Case of Rhizopus azygos-porus pneumonia after Covid-19 infection was reported in a 56-year-old man treated with methy-lprednisolone and tocilizumab [92]. Fatal rhino-orbital mucormycosis was described in a 24-year-old female diabetic patient with Covid-19 [93].

Aastha et al from Mumbai, India reported Sino-orbital mucormycosis in a Covid-19 patient [94]. Deepak et al from Chandigarh, India described a case of probable pulmonary mucormycosis in a 55-year-old man with diabetes, end-stage kidney disease, and Covid-19 [95]. Marina et al from Karnataka, India reported a case of paranasal mucormycosis in Covid-19 patient [96]. Rhino-orbital mucormycosis associ-ated With Covid-19 was diagnosed in a 60-year-old male, diabetic patient from Lilavati Hospital and Research Centre, Mumbai, India [97]. Sharma et al from Jaipur, India studied the likely association between invasive fungal sinusitis (mucormycosis) and coronavirus disease and found twenty-three patients with mucormycosis. The ethmoids (100 %) were the most common sinuses affected. Intra-orbital extension was observed in 43.47 % of cases, while intracranial extension was seen only in 8.69 %. 21 cases out of 23 were diabetic, out of them 12 were having uncontrolled diabetes. All of them were on steroid treatment [98]. Uncontrolled diabetes, overuse of steroids and immunosuppressive nature of virus are the contributing factors for the spread of mucormycosis. In patients suspected for mucorm-ycosis, quick diagnosis and treatment should be started especially in patients with poorly controlled diabetes mellitus due to angio invasive nature and rapid disease progression that contribute to the severity of the infection. Treatment of mucormycosis should include multidisciplinary approach which includes prompt diagnosis and treatment with anti-fungals and surgical interventions. After the diag-nosis is confirmed, empiric antifungal treatment should be started. Prompt surgical opinion should also be sought.

4. Conclusion

Understanding Covid-19 infection and its effect on multiorgan is still obscure. A presumptive diagnosis should be made on the presenting signs and symp-toms of SARS-CoV-2 infection. There is a paucity of controlled randomized studies to clearly understand the effect of Covid-19 infection on multiorgan. Further studies are needed for the better under-standing of Covid-19 infection and its effect on multiorgan. It is important for the emergency clini-cians to be aware of the multiorgan complic-ations arising out of Covid-19 infection while treating the patients and management of the condition to reduce the mortality rate.

Acknowledgements

Dr. Shehnaz Sultana would like to thank Department of Science and Technology (DST), New Delhi for providing women scientist fellowship under DST (WOS-A) scheme.Grateful thanks are due to Sri.Mahendra Ranka, Chairman, BMMT and Mrs.G. Sunita Kumar, Chairman,MAA Hospitals, Hyderabad for their encouragement.

Conflicts of Interest

None to declare.

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323 (2020): 1239-1242.
2. Mehta P, Mcauley DF, Brown M, et al. Correspondence COVID-19: consider cyto-kine storm syndromes and immunosup-pression. Lancet 395 (2020): 1033-1034.
3. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol (2020).
4. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8 (2020): 420-422.
5. Jia-Hui Zeng, Ying-Xia Liu, Jing Yuan, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection 48 (2020): 773-777.
6. Caforio ALP, Pankuweit S, Arbustini E, et
7. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 34 (2013): 2636-2648.
8. Gheblawi M, Wang K, Viveiros A, et al. Angiotensin converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 126 (2020): 1456-1474.
9. Tavazzi G, Pellegrini C, Maurelli M, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 22 (2020): 911-915.
10. Sala S, Peretto G, Gramegna M, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J 41 (2020): 1861-1862.
11. Guo T, Fan Y, Chen M, et al. Cardio-vascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol (2020).
12. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 46 (2020): 846-848.
13. Selman Kesici, Hayrettin Hakan Aykan, Diclehan Orhan, et al. Fulminant COVID-19-relatedmyocarditis in an infant. Cardio-vascular flashlight (2020).
14. Jeanne Bordet, Stéphanie Perrier, Catherine Olexa, et al. Paediatric multisystem inflame-matory syndrome associated with COVID-19: filling the gap between myocarditis and Kawasaki?. European Journal of Pediatrics 180 (2021): 877-884.
15. Joanne S Chiu, Manuella Lahoud-Rahme, David Schaffer, et al. Kawasaki Disease Features and Myocarditis in a Patient with COVID-19. Pediatric Cardiology 41 (2020): 1526-1528.
16. Jamie SY Ho, Ching-Hui Sia, Mark YY Chan, et al. Coronavirus-induced myocar-ditis: A meta-summary of cases. Heart & Lung 49 (2020): 681-685.
17. Marc K Halushka, Richard S Vander Heide. Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmo-rtem examinations. Cardiovascular Patho---logy 50 (2021): 107300.
18. Adam L Bailey, Oleksandr Dmytrenko, Lina Greenberg, et al. SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. J Am Coll Cardiol Basic Trans Science 6 (2021): 331-345.
19. Curt J Daniels, Saurabh Rajpal, Joel T Greenshields, et al. Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes with Recent SARS-CoV-2 Infection Results from the Big Ten COVID-19 Cardiac Registry. JAMA Cardiol (2021).
20. Jitka Starekova, David A Bluemke, William S Bradham. Evaluation forMyocarditis in Competitive Student Athletes Recovering from Coronavirus Disease 2019 With Cardiac Magnetic Resonance Imaging. JAMA Cardiol (2021).
21. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383 (2020): 2603-2615.
22. Walsh EE, Frenck RW, Jr., Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 383 (2020): 2439-2450.
23. Abu Mouch S, Roguin A, Hellou E, et al. Myocarditis following COVID-19 mRNA vaccination. Vaccine (2021).
24. Martinez-Rojas MA. Vega-Vega O, Bobadilla NA. Is the kidney a target of SARS-CoV-2?. Am J Physiol Ren Physiol 318 (2020): F1454-F1462.
25. Diao B,Wang C,Wang R, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. medRxiv (2020).
26. GuanWJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 382 (2020): 1708-1720.
27. Arentz M, YimE, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA 323 (2020): 1612-1614.
28. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Nephro (2020):31(6);1157-1165.
29. Wang L, Li X, Chen H, et al. Coronavirus Disease 19 Infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China. Am J Nephrol 51 (2020): 343-348.
30. Chu KH, Tsang WK, Tang CS, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int 67 (2005): 698e705.
31. Nicola Brienza, Filomena Puntillo, Stefano Romagnoli, et al. Acute Kidney Injury in Coronavirus Disease 2019 Infected Patients: A Meta-Analytic Study. Blood Purif 50 (2021): 35-41.
32. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 post mortem findings of patients with COVID-19 in China. Kidney Int 98 (2020): 219-222.
33. Peleg Y, Kudose S, D’Agati V, et al. Acute kidney injury due to collapsing glomer-ulopathy following COVID-19 infection. Kidney Int. Rep 5 (2020): 940-945.
34. Cheng Y, Luo R,Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 97 (2020): 829-838.
35. Kitty J Jager, Anneke Kramer, Nicholas C, et al. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe. Kidney Interna-tional 98 (2020): 1540-1548.
36. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395 (2020): 1054e1062.
37. Zhen Li, Ming Wu, Jiwei Yao, et al. Anti -2019-nCoV Volunteers, Caution on kidney dysfunctions of 2019-nCoV patients. MedR-xiv (2020).
38. Ibrahim Y Hachim, Mahmood Y Hachim, Kashif Bin Naeem, et al. Kidney Dysfunction among COVID-19 Patients in the United Arab Emirates. Oman Med J 36(2021): e221.
39. Ali Taghizadieh, Haleh Mikaeili, Majid Ahmadi, et al. Acute kidney injury in preg-nant women following SARS-CoV-2 infect-ion: A case report from Iran. Respiratory Medicine Case Reports 30 (2020): 101090
40. Isil Basara Akin, Canan Altay, Oya Eren Kutsoylu, et al. Possible radiologic renal signs of COVID-19. Abdominal Radiology 46 (2021): 692-695.
41. Mitra Basiratnia, Dorna Derakhshan, Babak Shirazi Yeganeh, et al. Acute necrotizing glomerulonephritis associated with COVID-19 infection: report of two pediatric cases. Pediatric Nephrology 36 (2021): 1019-1023.
42. Gross O, Moerer O, Weber M, et al. COVID -19-associated nephritis: early warning for disease severity and complications?. Lancet (2020).
43. Pan XW, Xu D, Zhang H, et al. Identi-fication of a potential mechanism of acute kidney injury during the COVID-19 out-break: a study based on single-cell transcri-ptome analysis. Intensive Care Med 46 (2020): 1114-1116.
44. Shehnaz Sultana, Venkateshwari Anantha-pur. COVID-19 and its impact on neurolo-gical manifestations and mental health: the present scenario. Neurological Sciences 41 (2020): 3015-3020.
45. Eubank K, Covinsky K. Delirium severity in the hospitalized patient: Time to pay attention. Annals of Internal Medicine 160 (2014): 574-575.
46. Yelizaveta S, Miller A, Lolak S, et al. Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale. Journal of Neuro-psychiatry and Clinical Neuroscience 27 (2015): 365-370.
47. Maldonado J. Pathoetiological model of delirium: A comprehensive understanding of the neurobiology of delirium and an evi-dence-based approach to prevention and treatment. Critical Care Clinician 24 (2008): 789-856.
48. Puelles VG, Lütgehetmann M, Linden-meyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2, N. Engl. J. Med (2020).
49. Li MY, Li L, Zhang Y, et al Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues, Infect Dis. Poverty 9 (2020): 45.
50. Zhang Y, Geng X, Tan Y, et al. New understanding of the damage of SARS-CoV-2 infection outside the respiratory system, Biomed. Pharmacother 127 (2020): 110195.
51. World Health Organization and International Severe Acute Respiratory and Emerging Infection Consortium. COVId-19 Core Case Report Form (2020).
52. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology 77 (2020): 683-690.
53. Beach S R, Praschan N C, Hogan C, et al. Delirium in COVID-19: A case series and exploration of potential mechanisms for central nervous system involvement. Gene-ral Hospital Psychiatry 65 (2020): 47-53.
54. Zambrelli E, Canevini M, Gambini O, et al. Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients? Sleep Medicine 70 (2020): 111.
55. Rogers JP, Chesney E, Oliver D, et al. Psychiatric and neuropsychiatric presentat-ions associated with severe coronavirus infe-ctions: a systematic review and meta-analy-sis with comparison to the COVID-19 pand-emic, Lancet Psychiatry 7 (2020): 611-627.
56. Raymond Pranata, Ian Huang, Michael Anthonius Lim, et al. Delirium and Morta-lity in Coronavirus Disease 2019 (COVID-19) – A Systematic Review and Meta-analysis. Archives of Gerontology and Geriatrics 95 (2021): 104388.
57. Brenda T Pun, Rafael Badenes, Gabriel Heras La Calle, et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study. Lancet Respir Med 9 (2021): 239-250.
58. Maria Beatrice Zazzara, Rose S Penfold, Amy L Roberts, et al. Probable delirium is a presenting symptom of COVID-19 in frail, older adults: a cohort study of 322 hospit-alised and 535 community-based older adults. Age and Ageing 50 (2021): 40-48.
59. Aline Mendes, François R Herrmann, Samuel Périvier, et al. Delirium in Older Patients With COVID-19: Prevalence, Risk Factors, and Clinical Relevance. Gerontol A Biol Sci Med Sci 76 (2021): e142-e146.
60. Walid A Alkeridy, Ibrahim Almaghlouth, Rashed Alrashed, et al. A Unique Presen-tation of Delirium in a Patient with Other-wise Asymptomatic COVID-19. The Ameri-can Geriatrics society 68 (2020): 1382-1384.
61. Maura Kennedy, Benjamin K I Helfand, Ray Yun Gou, et al. Delirium in Older Patients With COVID-19 Presenting to the Eme-rgency Department. JAMA Network Open 3 (2020): e2029540.
62. Paola Rebora, Renzo Rozzini, Angelo Bianchetti, et al. Delirium in Patients with SARS-CoV-2 Infection: A Multicenter Study. The American Geriatrics Society 69 (2021): 293-299.
63. Isabel Butt, Vijay Sawlani, Tarekegn Geberhiwot. Prolonged confusional state as first manifestation of COVID-19. Annals of Clinical and Translational Neurology 7 (2020): 1450-1452.
64. Akram A Hosseinia, Ashit K Shetty, Nikola Sprigg, et al. Delirium as a presenting feature in COVID-19: Neuroinvasive infect-ion or autoimmune encephalopathy?. Brain, Behavior, and Immunity 88 (2020): 68-70.
65. Benjamin C Mcloughlin, Amy Miles, Thomas E Webb, et al. Functional and cognitive outcomes after COVID-19 delir-ium. European Geriatric Medicine 11 (2020): 857-862.
66. Servick K. For survivors of severe COVID-19, beating the virus is just the beginning. Science (2020).
67. Han C, Duan C, Zhang S, et al. Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes. Am J Gastroenterol 115 (2020): 916-923.
68. D’Amico F, Baumgart DC, Danese S, et al. Diarrhea during COVID-19 infection: patho-genesis, epidemiology, prevention, and management. Clin Gastroenterol Hepatol 18(2020): 1663-1672.
69. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV- 2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181 (2020): 271-280, e8.
70. Lee JJ, Kopetz S, Vilar E, Shen JP, Chen K, Maitra A. Relative abundance of SARS-CoV-2 entry genes in the enterocytes of the lower gastrointestinal tract. Genes (Basel) 11 (2020): 645.
71. Cole-Jeffrey CT, Liu M, Katovich MJ, et al. ACE2 and microbiota: emerging targets for cardiopulmonary disease therapy. J Cardio-vasc Pharmacol 66 (2015): 540-550.
72. Gu S, Chen Y, Wu Z, et al. Alterations of the gut microbiota in patients with COVID-19 or H1N1 Influenza. Clin Infect Dis 4 (2020): ciaa709.
73. Badal S, Bajgain BT, Badal S, et al. Prevalence, clinical characteristics and out-come of pediatric COVID-19: a systematic review and meta-analysis. J Clin Virol 135 (2020): 104715.
74. Ding Y, Yan H, Guo W. Clinical characteristics of children with COVID-19: a meta-analysis. Front Ped 8 (2020): 431.
75. Tullie L, Ford K, Bisharat M, et al. Gastro-intestinal features in children with COVID-19: an observation of varied presentation in eight children. Lancet Child Adolesc Health 4 (2020): e19-e20.
76. Cox G. Mucormycosis UpToDate (2020).
77. Serris A, Danion F, Lanternier F. Disease entities in mucormycosis. J Fungi 5 (2019): 23.
78. Riley TT, Muzny CA, Swiatlo E, et al. Breaking the mold: a review of mucor-mycosis and current pharmacological treat-ment options. Ann Pharmacother 50 (2016): 747-757.
79. Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 19 (2019): e405-e421.
80. Ali Asghar S, Majid Z, Tahir F, et al. Rhinooculo cerebral mucormycosis resistant to amphotericin B in a young patient with diabetic ketoacidosis. Cureus 11 (2019): e4295.
81. Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: pathophy-siology, presentation, and management. Clin Microbiol Rev 18 (2005): 556-569.
82. Jeong W, Keighley C, Wolfe R, et al. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports. Clin Micro-biol Infect 25 (2019):;26-34.
83. Amanda Werthman-Ehrenreich. Mucormyc-osis with orbital compartment syndrome in a patient with COVID-19. American Journal of Emergency Medicine 42 (2021): 264.e5-264.e8
84. Akshay Khatri, Kai-Ming Chang, Ilan Berlinrut, et al. Mucormycosis after Coro-navirus disease 2019 infection in a heart transplant recipient – Case report and review of literature. Journal of Medical Mycology 31 (2021): 101125.
85. Andre K Johnson, Zeron Ghazarian, Kristina D Cendrowski, et al. Persichino. Pulmonary aspergillosis and mucormycosis in a patient with COVID-19. Medical Mycology Case Reports 32 (2021): 64-67.
86. Ricardo Rabagliati, Nicolás Rodríguez, Carolina Núñez, et al. COVID-19–Asso-ciated Mold Infection in Critically Ill Patients, Chile. Emerging Infectious Diseases 27 (2021).
87. Nariman Khan, Christina G Gutierrez, David Villafuerte Martinez, et al. A case report of COVID-19 associated pulmonary mucormycosis. Arch Clin Cases 7 (2020): 46-51.
88. Amirreza Veisi, Abbas Bagheri, Mohammad Eshaghi, et al. Rhino-orbital mucormycosis during steroid therapy in COVID-19 patie-nts: A case report. European Journal of Oph-thalmology (2020): 11206721211009450.
89. Epifanio Silvino do Monte Junior, Marcos Eduardo Lera dos Santos, Igor Braga Ribeiro, et al. Rare and Fatal Gastro-intestinal Mucormycosis (Zygomycosis) in a COVID-19 Patient: A Case Report. Clin Endosc 53 (2020): 746-749.
90. Zesemayat K Mekonnen, Davin C Ashraf, Tyler Jankowski, et al. Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respira-tory Distress Syndrome. Ophthalmic Plast Reconstr Surg 37 (2021): e40-e42.
91. Kirill Alekseyev, Lidiya Didenko, Bilal Chaudhry. Rhinocerebral Mucormycosis and COVID-19 Pneumonia. J Med Cases 12(2021): 85-89.
92. Christoph Zurl, Martin Hoenigl, Eduard Schulz, et al. Autopsy Proven Pulmonary Mucormycosis Due to Rhizopus micro-sporus in a Critically Ill COVID-19 Patient with Underlying Hematological Malignancy. J. Fungi 7 (2021): 88.
93. Anubhav Kanwar, Alex Jordan, Scott Olewiler, et al. A Fatal Case of Rhizopus azygosporus Pneumonia Following COVID-19. J. Fungi 7 (2021): 174.
94. Waizel-Haiat S, Guerrero-Paz J, Sanchez-Hurtado L, et al. A Case of Fatal Rhino-Orbital Mucormycosis Associated with New Onset Diabetic Ketoacidosis and COVID-19. Cureus 13 (2021): e13163.
95. Aastha Maini, Gaurav Tomar, Deepak Khanna, et al. Sino-orbital mucormycosis in a COVID-19 patient: A case report. International Journal of Surgery Case Reports 82 (2021): 105957.
96. Deepak Garg, Valliappan Muthu, Inderpaul Singh Sehgal, et al. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Revi-ew of Literature. Mycopathologia 186 (2021): 289-298.
97. Marina Saldanha, Rashmitha Reddy, Mark Jittu Vincent. Paranasal Mucormycosis in COVID-19 Patient. Indian J Otolaryngol Head Neck Surg (2021).
98. Mehta S, Pandey A. Rhino-Orbital Mucor-mycosis Associated With COVID-19. Cureus 12 (2020): e10726.
99. Sharma S, Grover M, Bhargava S, et al. Post coronavirus disease mucormycosis: a deadly addition to the pandemic spectrum. J Laryngol Otol (2021): 1-6.