Atypical Complications during the Course of COVID-19: A Comprehensive Review

COVID-19 is primarily a respiratory disease, but numerous studies have indicated the involvement of various organ systems during the course of illness. We conducted a comprehensive review of atypical complications of COVID-19 with their incidence range (IR) and their impact on hospitalization and mortality rates. We identified 97 studies, including 55 research articles and 42 case studies. We reviewed four major body organ systems for various types of atypical complications: (i) Gastro-intestinal (GI) and hepatobiliary system, e.g., bowel ischemia/infarction (IR: 1.49–83.87%), GI bleeding/hemorrhage (IR: 0.47–10.6%), hepatic ischemia (IR: 1.0–7.4%); (ii) Neurological system, e.g., acute ischemic stroke/cerebral venous sinus thrombosis/cerebral hemorrhage (IR: 0.5–90.9%), anosmia (IR: 4.9–79.6%), dysgeusia (IR: 2.8–83.38%), encephalopathy/encephalitis with or without fever and hypoxia (IR: 0.19–35.2%); (iii) Renal system, e.g., acute kidney injury (AKI)/acute renal failure (IR: 0.5–68.8%); (iv) Cardiovascular system, e.g., acute cardiac injury/non-coronary myocardial injury (IR: 7.2–55.56%), arrhythmia/ventricular tachycardia/ventricular fibrillation (IR: 5.9–16.7%), and coagulopathy/venous thromboembolism (IR: 19–34.4%). This review encourages and informs healthcare practitioners to keenly monitor COVID-19 survivors for these atypical complications in all major organ systems and not only treat the respiratory symptoms of patients. Post-COVID effects should be monitored, and follow-up of patients should be performed on a regular basis to check for long-term complications.


Introduction
Coronavirus disease 2019, or COVID-19, is an exceedingly transmissible viral illness that is acquired by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).It has had a disastrous consequence on the world, culminating in over six million deaths around the globe.Succeeding the early cases of this dominating respiratory viral disease, which were reported in December 2019 in Wuhan, Hubei Province, China, SARS-CoV-2 swiftly promulgated around the globe in a brief period of time.As a result, the World Health Organization (WHO) was forced to announce it as a global pandemic on 11 March 2020, and trials for the first human vaccine for COVID-19 started with the modern mRNA vaccine.By April 2020, 1 million cases were reported, and the WHO released guidance for mask-wearing.The major countries affected included the USA, the UK, India, Russia, and Vietnam.By September 2020, 1 million deaths were recorded.In November 2020, vaccine trials of Pfizer and BioNTech showed 90% efficacy.By April 2021, one billion doses of COVID-19 vaccination were given all across the world.According to recent data, three million new cases and more than 23,000 deaths have been reported from 13 March to 9 April 2023, a decline of 28% and 30%, respectively, in comparison to the preceding 28 days.As of 9 April 2023, over 762 million confirmed cases and over 6.8 million deaths have been reported all over the world [1][2][3].
According to its structure and phylogenetics, SARS-CoV-2 is identical to MERS-CoV and SARS-CoV.It is made up of four major structural proteins: membrane protein (M), nucleocapsid (N), envelope (E), and spike (S), together with sixteen nonstructural proteins and five to eight accessory proteins [4].The surface spike glycoprotein (S) consists of an S1 subunit, which is divided further into the receptor-binding domain (RBD) and the N-terminal domain (NTD), which aids the virus to enter into the host cell and acts as a prospective target for neutralization concerning vaccines or antisera [5].SARS-CoV-2 gains access into the host cell once its spike (S protein) abundantly binds to angiotensinconverting enzyme 2 (ACE2) receptors present on the respiratory epithelium, for example, type II alveolar epithelial cells.The amino acid site of the spike RBD permits functional processing of a similar kind in the presence of the human enzyme furin, which allows the amalgamation of viral and cell membranes, a vital transit for the virus's entry into the cell.This is followed by the subsequent endocytosis and viral replication along with virion assembly [6].In addition to the respiratory epithelium, ACE2 receptors are also present in other organs such as enterocytes and the proximal tubular cells present inside the kidney, ileum, upper esophagus, myocardial cells, and the urothelial cells that make up the bladder [7].
Primarily, COVID-19 is considered a viral respiratory as well as vascular disease, as SARS-CoV-2 principally targets the respiratory and vascular systems.In spite of the fact that the respiratory system is the main target of SARS-CoV-2, it causes atypical complications in systems such as the renal, cardiovascular, hepatobiliary, gastrointestinal tract (GI), and central nervous systems [8].SARS-CoV-2-prompted organ dysfunction, by and large, is possibly described by one or a combination of the suggested mechanisms, such as dysregulation of the renin-angiotensin-aldosterone system (RAAS), direct viral toxicity, dysregulation of the immune system, ischemic injury resulting from thrombo-inflammation, thrombosis, and vasculitis [9].
Considering the large volume of research data on the atypical complications of COVID-19, it is crucial to perform an overview so that current literature can be organized and identified to underline the scope of priority for successful clinical management and effective decision making by healthcare practitioners to not only curb the impact of these atypical complications on the patient's quality of life but also to reduce the economic burden on the healthcare system.Previously, there have been a few reviews on extrapulmonary manifestations [8,[10][11][12][13], but the types of complications and their overall effect on hospitalization and mortality rates have never been explored.In addition, a large number of reviews exist on manifestations in individual organ systems of the body [14][15][16][17][18][19], but no study has ever attempted to gather information in a single article through extensive research on major organ systems.Furthermore, there are other infections that can cause atypical complications, i.e., dengue and Varicella-Zoster virus infections are well known to cause dementia, chronic encephalitis, aseptic meningitis, multiple sclerosis, acute pancreatitis, and myopericarditis [20][21][22][23][24][25] and such complications further accelerate patient hospitalization and rates of morbidity and mortality, which, in turn, render a huge burden on the healthcare system.eligibility.Finally, 55 research studies and 42 case reports were included in this review.The current review has identified complications pertaining to four major organ systems: (1) Gastrointestinal/hepatobiliary system, (2) neurological system, (3) renal system, and (4) cardiovascular system.Details of complications identified from the selected studies along with underlying pathophysiology and management considerations are described below.

Summary of Included Studies
Of 65,179 total studies, 17,880 studies were initially selected.Of these, 4365 studies were excluded after abstract screening.A total of 1513 full-text articles were assessed for eligibility.Finally, 55 research studies and 42 case reports were included in this review.The current review has identified complications pertaining to four major organ systems: (1) Gastrointestinal/hepatobiliary system, (2) neurological system, (3) renal system, and (4) cardiovascular system.Details of complications identified from the selected studies along with underlying pathophysiology and management considerations are described below.

Underlying Pathophysiology
The underlying pathophysiology related to GI damage among COVID-19 patients is most likely multifactorial.The most credible mechanism is direct virus-mediated tissue damage due to the existence of ACE2 receptors in the glandular cells of the intestine [26][27][28][29], in addition to the assimilation of the viral nucleocapsid protein among the epithelial cells of the stomach, duodenum, and rectum, as well as glandular enterocytes [27].Additionally, diffused endothelial inflammation among the submucosal vessels of the small intestine in histopathological evidence and mesenteric ischemia suggest microvascular small-bowel injury [30].The existence of infiltrating lymphocytes and plasma cells and interstitial edema in the gastric, duodenal, and rectal lamina propria of COVID-19 patients provides support for tissue damage mediated by inflammation [27].It has also been suggested that the GI manifestations and severe disease progression are contributed by the modification of the intestinal flora caused by the virus [31].

Management Considerations
Specific management considerations should be considered by health practitioners, which should include differential diagnosis for COVID-19 among patients suffering from isolated GI symptoms in the non-appearance of respiratory symptoms [32].Practitioners should prioritize testing for COVID-19 among patients presenting both GI and respiratory symptoms if testing resources are limited [33], and diagnostic endoscopy should only be utilized for emergency therapeutic reasons such as biliary obstruction or large-volume GI bleeding [34,35].Hepatic transaminases should be monitored longitudinally, in particular among patients who are given investigational treatments.Decreased levels should not particularly be considered a contraindication when treating with tocilizumab, lopinavir, and remdesivir [36].

Underlying Pathophysiology
The underlying pathophysiological mechanisms proposed include direct invasion of neural parenchyma cells by the virus.The central nervous system is assessed by SARS-CoV-2 through the lamina cribrosa, olfactory bulb, and nasal mucosa or transport through the retrograde axonal.In the respiratory tree, ACE2 receptors are highly expressed in nasal epithelial cells [57,58], which may justify the symptoms of modified smell or taste mostly reported in outpatients retrospectively with SARS-CoV-2 [59][60][61].The other complications are attributed to the neurovirulence of SARS-CoV-2, which reflects the prothrombotic and proinflammatory cascade resulting in cytokine storm [62], which in turn produces effects on the blood-brain barrier and brain vasculature.This has been particularly observed in critical patients experiencing toxic-metabolic prolongation of multi-organ dysfunction.

Management Considerations
Specific management considerations for health practitioners include continuous conformity to the guidelines established for acute ischemic stroke (thrombectomy and thrombolysis) [63].Guidelines for the monitoring of post-acute care for pandemic restrictions should be adopted.A remote video assessment, whenever feasible, should be considered for hospitalized patients with symptoms that might be related to stroke [64].A delayed or extended-interval dosing of long-term immunomodulatory therapies should be considered in diseases such as multiple sclerosis in SARS-CoV-2 patients [65].We included 16 studies reporting renal complications among COVID-19 patients.A total of seven renal complications were noted in research studies.The major complication was acute kidney injury (AKI)/acute renal failure (IR: 0.5-68.8%).Other complications included electrolyte disturbances (incidence: 7.2%, 23%), acidosis (incidence: 9%, 12%), proteinuria (incidence: 6.5%, 43.9%), hematuria (incidence: 26.7%), alkalosis (incidence: 28%) and continuous renal replacement therapy clotting due to hypertriglyceridemia. All-cause mortality ranged from 1.4% to 52.4%, whereas 9% to 93.6% of patients were still hospitalized due to at least one complication.Mortality rates caused by AKI/kidney disease ranged between 16.1% and 66.35%, and patients still hospitalized due to them varied significantly.In one retrospective cohort study, 50% of non-survivors died due to acute kidney injury [86].In one retrospective case series, mortality was observed among patients with acidosis (12%), alkalosis (28%), AKI (25%), and hyperkalemia (23%) [87] (Table 5).In Figure 3, the prevalence in terms of the maximum percentage of renal complications among different studies was presented.

Underlying Pathophysiology
Several possible pathophysiological mechanisms have been identified for renal abnormalities.Firstly, the virus may infect the renal cells directly, as evidenced by the existence of ACE2 receptors on them and histopathological findings [88][89][90].Secondly, microvascular dysfunction is incidental to endothelial damage as demonstrated by renal lymphocytic endothelialitis, and moreover to the inclusion of particles of the virus in the endothelium of glomerular capillary cells [30].Thirdly, cytokine storm may have a vital role in the immunopathology of AKI [91].Another likely mechanism for glomerular injury is arbitrated by specific immunological effector mechanisms induced by the virus or viral antigen immunocomplexes [88].In addition, proteinuria is not considered the classic We included seven case reports comprising seven patients in the current review.These case reports reported a total of eight renal complications.The major complications identified were renal/splenic/cerebral infarct or aortic thrombosis (57.14%).Rare complications were catastrophic thrombotic syndrome (14.29%), glomerulonephritis (14.29%), polycystic kidney disease (14.29%),IgA neuropathy (14.29%), and spinal epidural abscess (14.29%).Of the seven patients in these case reports, 71.43% (n = 5/7) were cured/improved, one patient died, and one patient was discharged but not completely cured (Table 6).

Underlying Pathophysiology
Several possible pathophysiological mechanisms have been identified for renal abnormalities.Firstly, the virus may infect the renal cells directly, as evidenced by the existence of ACE2 receptors on them and histopathological findings [88][89][90].Secondly, microvascular dysfunction is incidental to endothelial damage as demonstrated by renal lymphocytic endothelialitis, and moreover to the inclusion of particles of the virus in the endothelium of glomerular capillary cells [30].Thirdly, cytokine storm may have a vital role in the immunopathology of AKI [91].Another likely mechanism for glomerular injury is arbitrated by specific immunological effector mechanisms induced by the virus or viral antigen immunocomplexes [88].In addition, proteinuria is not considered the classic manifestation of AKI; short-term heavy albuminuria might arise from direct podocyte injury or endothelial dysfunction.Other causative etiologies for renal injury include acute respiratory distress syndrome, interstitial nephritis, volume depletion, and rhabdomyolysis [92].

Management Considerations
Specific management considerations by health practitioners for managing renal complications should include evaluation of the albumin-to-creatinine ratio and complete urine analysis, providing the coalition of hematuria and proteinuria with the outcomes [93,94].Empirical systemic low-dose anticoagulants, when initiating and also in the routine management of RRT extracorporeal circuits, should be considered [95].Consideration should be taken to co-localize patients requiring RRT, and a shared protocol for RRT should be used [96].Additionally, acute peritoneal dialysis among select patients should be considered so as to minimize the requirement of personnel [96].We have included 18 research studies reporting cardiovascular complications.In total, 15 complications were uncovered from these research studies.The major complications in research studies included acute cardiac injury/non-coronary myocardial injury (IR: 7.2-55.56%),arrhythmia/ventricular tachycardia/ventricular fibrillation (IR: 5.9-16.7%),coagulopathy/venous thromboembolism (IR: 19-34.4%),and myocardial infarction/heart failure (IR: 23.0-44.44%).Other complications included acute coronary syndrome and cardiac insufficiency (incidence: 0.96% and 17.4%).In one study, disseminated intravascular coagulation was seen in 71.4% of the non-survivors.All-cause mortality ranged from 4.3% to 45%, and among in-hospital patients, it ranged from 6.7% to 76.7%.In one retrospective case series, 77% of acute cardiac injury patients and 49% of heart failure patients did not survive [87] (Table 7).In Figure 4, the prevalence in terms of the maximum percentage of cardiovascular complications among different studies was presented.

Complications
We have included 18 research studies reporting cardiovascular complications.In total, 15 complications were uncovered from these research studies.The major complications in research studies included acute cardiac injury/non-coronary myocardial injury (IR: 7.2-55.56%),arrhythmia/ventricular tachycardia/ventricular fibrillation (IR: 5.9-16.7%),coagulopathy/venous thromboembolism (IR: 19-34.4%),and myocardial infarction/heart failure (IR: 23.0-44.44%).Other complications included acute coronary syndrome and cardiac insufficiency (incidence: 0.96% and 17.4%).In one study, disseminated intravascular coagulation was seen in 71.4% of the non-survivors.All-cause mortality ranged from 4.3% to 45%, and among in-hospital patients, it ranged from 6.7% to 76.7%.In one retrospective case series, 77% of acute cardiac injury patients and 49% of heart failure patients did not survive [87] (Table 7).In Figure 4, the prevalence in terms of the maximum percentage of cardiovascular complications among different studies was presented.We have also included 11 case reports (11 patients) reporting cardiovascular complications.From case reports, a total of 10 cardiovascular complications were identified.Major complications in case reports were fulminant myocarditis (27.27%) and Takotsubo syndrome (18.18%).Other complications included myopericarditis complicated by cardiac tamponade (9.09%) and isolated hemorrhagic pericardial effusion with tamponade (9.09%).Of the twelve patients in case reports, five patients (33.33%) improved/were cured and were discharged from the hospitals, while two patients (16.67%) died (Table 8).

Underlying Pathophysiology
The underlying pathophysiology of CV complications is most likely multifactorial.ACE2 is highly expressed in endothelial cells, fibroblasts, and myocytes of the CV tissue [90,117], and direct viral injury is one possible mechanism.Myocarditis, MI, and circulatory failure may develop due to viral load and inflammatory infiltrates, as evidenced by some autopsy studies [118][119][120] and pathological reports [121,122].In addition, endothelial damage mediated by viruses [30] and cytokine storms can be another assumed underlying mechanism for myocardial injury [123].In general, viral infections further predispose patients to MI [124], and this risk is elevated in COVID-19 patients, with evidence of unjustifiably escalated hypercoagulability, which induces MI mediated by thrombotic events.Furthermore, isolated right ventricular malfunction may arise due to pulmonary thromboembolism [125,126] and increased pulmonary vascular pressures due to ARDS [127].We have also included 11 case reports (11 patients) reporting cardiovascular complications.From case reports, a total of 10 cardiovascular complications were identified.Major complications in case reports were fulminant myocarditis (27.27%) and Takotsubo syndrome (18.18%).Other complications included myopericarditis complicated by cardiac tamponade (9.09%) and isolated hemorrhagic pericardial effusion with tamponade (9.09%).Of the twelve patients in case reports, five patients (33.33%) improved/were cured and were discharged from the hospitals, while two patients (16.67%) died (Table 8).

Underlying Pathophysiology
The underlying pathophysiology of CV complications is most likely multifactorial.ACE2 is highly expressed in endothelial cells, fibroblasts, and myocytes of the CV tissue [90,117], and direct viral injury is one possible mechanism.Myocarditis, MI, and circulatory failure may develop due to viral load and inflammatory infiltrates, as evidenced by some autopsy studies [118][119][120] and pathological reports [121,122].In addition, endothelial damage mediated by viruses [30] and cytokine storms can be another assumed underlying mechanism for myocardial injury [123].In general, viral infections further predispose patients to MI [124], and this risk is elevated in COVID-19 patients, with evidence of unjustifiably escalated hypercoagulability, which induces MI mediated by thrombotic events.Furthermore, isolated right ventricular malfunction may arise due to pulmonary thromboembolism [125,126] and increased pulmonary vascular pressures due to ARDS [127].

Management Considerations
Important management considerations for CV complications by health practitioners should not include the discontinuation of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers in patients who are already using them at home, and assessment should be made on the basis of individual patient condition [128,129].Furthermore, those who have torsades de pointes risk and are treated with drugs for QTc prolongation should be monitored by telemetry, and an electrocardiogram should be performed [130].Above all, in order to minimize the viral transmission risk, the utility of diagnostic modalities (endomyocardial biopsies, invasive hemodynamic assessments, and cardiac imaging) should be considered carefully [131,132].The preferred approach for most patients with ST-segment elevation MI is primary percutaneous coronary intervention.Furthermore, fibrinolytic therapy in specific patients should be considered if personal protective supplies are unavailable [133][134][135].

Limitations and Strengths
There are several limitations in this review that must be taken into account.First, we did not perform a meta-analysis due to the large heterogeneity and variations in data collection and study designs.Secondly, a quality assessment of the studies was not performed.Thirdly, it might be possible that a confirmed diagnosis of these complications is lacking in primary studies.Lastly, due to the large body of available literature, complications related to only four major organ systems were covered in the current review.There are certain strengths of the present review that cannot be neglected.Firstly, according to our knowledge, this is the first review that points out the unusual complications in key organ systems after COVID-19.Secondly, the compilation of a large amount of evidence in a single article provides information on the range of incidences of atypical complications caused by the COVID-19 virus and their impact on hospitalization and mortality rates.Thirdly, the findings of the current review highlight the importance of the consideration of other organ systems during the management of COVID-19 infection.

Future Prospects
Since the commencement of the SARS-CoV-2 pandemic, an exceeding number of evidence has concentrated on the quick diagnosis, evolution, and divergence of new therapies.Nevertheless, it has been found in various studies, including the current review, that SARS-CoV-2 is not just a respiratory disease.Elevated levels of endogenous chemical substances generated in reaction to inflammation developed by the virus have the potential to generate disturbances and alterations in target tissues all over the human body, which even surpass the protective barriers of innate tissue immunity.Moreover, the cytokine storm developed during sepsis, which also has pleiotropic capabilities, interacts with respective high-density receptors, vasculature, and immune cells.In addition, the overexpression of angiotensin-converting enzyme II receptors (hACE2-R) in numerous tissues permits the virus to proliferate to the vascular system and extend into the entire human body.A vicious cycle develops, which entails the generation of chemical mediators, a decrease in the density of the hACE2-R receptors, and elevated levels of angiotensin II, producing both inflammatory and vascular effects.Moreover, this mechanism prompts the generation of additional hACE2-R via positive feedback.These frequently stimulated cycles multiply the proliferation of infection and consequent expansion in angiotensin II, which widely contribute to the pathophysiological mechanisms of SARS-CoV-2 and generate increased inflammation, vasoconstriction, and fibrosis.This necessitates the focus of healthcare practitioners on not only the respiratory syndrome caused by this virus but also on monitoring for atypical complications in all major body systems and following up on patients for post-COVID and long-COVID health issues, which at times are entirely asymptomatic in nature.Hence, there is a need for a multidisciplinary approach.Moreover, further research is required to identify actual differences as there is a wide variability across studies.Also, the impact of novel variants on long-COVID development and which individuals will be at the most risk will need future study and research.

Conclusions
This article reviewed four major organ systems to determine the burden of atypical complications.Major gastric complications found in research studies are bowel ischemia/infarction, GI bleeding, and hepatic ischemia/injury/infarct due to thromboembolism of the portal system.Major neurological complications included acute ischemic stroke, cerebral venous sinus thrombosis, cerebral hemorrhage, anosmia, and dysgeusia.Major renal complications included acute kidney injury (AKI) and acute renal failure.Major cardiovascular complications included acute cardiac injury/non-coronary myocardial injury, arrhythmia/ventricular tachycardia/ventricular fibrillation, coagulopathy/venous thromboembolism, and myocardial infarction/heart failure.The major complications found in these organ systems in case reports were bowel ischemia/hepatic ischemia, acute pancreatitis, bowel perforation, encephalopathy/encephalitis, Guillain-Barré Syndrome,

Figure 1 .
Figure 1.Prevalence of gastrointestinal complications among COVID-19 patients (prevalence represents the maximum percentage reported in the literature).

Figure 1 .
Figure 1.Prevalence of gastrointestinal complications among COVID-19 patients (prevalence represents the maximum percentage reported in the literature).

Figure 2 .
Figure 2. Prevalence of neurological complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Figure 2 .
Figure 2. Prevalence of neurological complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Figure 3 .
Figure 3. Prevalence of renal complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Figure 3 .
Figure 3. Prevalence of renal complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Figure 4 .
Figure 4. Prevalence of cardiovascular complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Figure 4 .
Figure 4. Prevalence of cardiovascular complications among COVID-19 patients (prevalence represents maximum percentage reported in the literature).

Table 1 .
Summary of research studies reporting gastrointestinal complications in COVID-19 patients.

Table 2 .
Summary of case studies reporting gastrointestinal complications in COVID-19 patients.

Table 3 .
Summary of research studies reporting neurological complications in COVID-19 patients.

Table 4 .
Summary of case studies reporting neurological complications in COVID-19 patients.

Table 5 .
Summary of research studies reporting renal complications in COVID-19 patients.

Table 6 .
Summary of case studies reporting renal complications in COVID-19 patients.

Table 7 .
Summary of research studies reporting cardiovascular complications in COVID-19 patients.

Table 8 .
Summary of case studies reporting cardiovascular complications in COVID-19 patients.