key: cord-0710499-yhynqeo1
authors: Zaim, Sevim; Chong, Jun Heng; Sankaranarayanan, Vissagan; Harky, Amer
title: COVID-19 and Multi-Organ Response
date: 2020-04-28
journal: Curr Probl Cardiol
DOI: 10.1016/j.cpcardiol.2020.100618
sha: a8920a3bf63ad590706a6c954cd31eb4a7600aae
doc_id: 710499
cord_uid: yhynqeo1

Abstract Since the outbreak and rapid spread of COVID-19 starting late December 2019, it has been apparent that disease prognosis has largely been influenced by multi-organ involvement. Comorbidities such as cardiovascular diseases have been the most common risk factors for severity and mortality. The hyperinflammatory response of the body, coupled with the plausible direct effects of SARS-CoV-2 on body-wide organs via ACE2, has been associated with complications of the disease. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure have precipitated death. Acknowledging the comorbidities and potential organ injuries throughout the course of COVID-19 is therefore crucial in the clinical management of patients. This paper aims to add onto the ever-emerging landscape of medical knowledge on COVID-19, encapsulating its multi-organ impact.

A novel coronavirus, designated the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late December 2019 from a cluster of pneumonia cases epidemiologically linked to a wet market in Wuhan, China. 1 The disease, now known as COVID-19, has since spread rampantly leading to a worldwide pandemic which has precipitated draconian measures to limit its transmission.

COVID-19 has demonstrated a wide spectrum of clinical manifestations, from asymptomatic or paucisymptomatic forms, to severe viral pneumonia with respiratory failure, multi-organ and systemic dysfunctions in terms of sepsis and septic shock, and death. 2, 3 This paper aims to encapsulate the multi-organ impact of COVID-19 reported since its outbreak. All the relevant articles were identified and screened by three authors; the results are summarized in narrative manner in each relevant section within the text of this review. A summary table of each section is provided where appropriate.

Epidemiology A timeline of the outbreak is summarized in Table 1 . As of 11 th April 2020, 1,610,909 confirmed cases worldwide have been reported. 4 Early investigations reported a basic reproductive number (R 0 ) ranging between 1.4-3.9, while a mean incubation period of 5.2 days 5 ranging between 1-14 days. 6 According to the World Health Organization (WHO) 4 , the current estimated global mortality is 99,690 (6.19% of confirmed cases) (Figure 1 ), the proportion of which may vary based on demographics of a location. All ages are susceptible to infection, and viral shedding may occur in asymptomatic individuals. 7 The risk factors for poor prognosis include advancing age and comorbidities 8 , while mortality is associated with age, high Sequential Organ Failure Assessment (SOFA) score and D-dimer levels of >1 μg/mL on admission 9 .

Virology SARS-CoV-2 is an enveloped, positive-sense RNA virus, and belongs to the β-coronavirus genus (sarbecovirus subgenus, orthonavirinae subfamily). 1 It represents the 7 th member of the Coronaviridae family known to infect humans. Its counterparts include 4 strains of low pathogenicity (229E, OC43, NL63 and HKU1), as well as 2 other β-coronaviruses which caused the previous outbreaks of severe and potentially fatal respiratory tract infections -SARS-CoV and MERS-CoV. 10 SARS-CoV-2 more closely resembles SARS-CoV (79% sequence identity) than MERS-CoV (50% sequence identity). 11 It also shares the same cellular receptor as SARS-CoV which is the angiotensin-converting enzyme 2 (ACE2) receptor. 12 ACE2 receptors are enriched in alveolar epithelial type II cells of lung tissues 13 , as well as extrapulmonary tissues such as the heart, endothelium, kidneys and intestines 14, 15 , which might play a role in the multi-organ effects of COVID-19.

Current evidence indicates an initial animal-to-human transmission from wild animals traded at the Huanan seafood market in Wuhan. The origin and mechanism of which remain to be clarified -while some genomic studies suggested bats as the natural reservoir 16 , others suggested pangolins 17 . As the outbreak progressed, person-to-person transmission remains the main mode of spread. This is through (1) respiratory droplets released via coughing or sneezing (2) aerosol, typically during aerosol-generating clinical procedures and (3) mucosal membrane contact with fomites. 18, 19 Faecal-oral transmission has been speculated 20 , given the detection of viral RNA in stools, reported GI symptoms, and ACE2 expression along the GI-tract. 21 No evidence of intrauterine or transplacental transmission has been reported. [22] [23] [24] 

In a study that analysed 138 COVID-19 patients 25 , the most common clinical features were fever (99%), fatigue (70%), dry cough (59%), anorexia (40%), myalgias (40%), dyspnoea (31%) and sputum production (27%). Other cohort studies have reported a similar range of clinical findings. 3, [26] [27] [28] However, fever might not be a universal finding, with one study reporting only 20% of their patients with very low grade fever (<100.4°F/38°C) and another 2 reporting fever in 44% of patients. Headache, sore throat and rhinorrhoea have also been noted as less common symptoms. 29 Although not highlighted in the aforementioned studies, anosmia and dysgeusia (smell and taste disorders) have been reported as well ( Table 2) . 29 

The most frequent, serious manifestation of COVID-19 infection seems to be pneumonia, which is characterised by cough, fever, dyspnoea and bilateral infiltrates displayed on radiographic chest imaging. Unfortunately, there are no specific clinical features that discern COVID-19 from other viral respiratory illnesses. 29 Although most patients will only experience mild symptoms of the disease, some patients will experience rapid progression of their symptoms over the span of a week (Table 3) . 3, 25 One study 30 found that 17% of their patients developed Acute Respiratory Distress Syndrome (ARDS) and among these, 65% rapidly worsened and died from multiple organ failure. In a study focusing on the associated risk factors 31 , it was reported that ARDS was greatly associated with older age (>65 years old), Diabetes Mellitus (DM) and hypertension. For most cases, bilateral lower zone consolidation (identified through chest x-ray) peaked at 10-12 days from symptom onset. 32 Radiological manifestations COVID-19 infection shares similar radiological features 33 to those of other viral pneumonia. 34 The hallmarks of COVID-19 on Computed Topography (CT) imaging were bilateral and peripheral ground-glass opacities (GGOs), and consolidative pulmonary opacities. Crazy paving patterns have also been observed. 27 A staging system for using CT images has been reported 33 and is summarized in Table 4 .

Interestingly, the development of pleural effusions and progression to a mixed pattern of GGOs and consolidative opacities have been reported in late-stages. 35 

Patients with existing cardiovascular disease (CVD) are at a greater risk of suffering from severe COVID-19 and having poorer prognosis. A meta-analysis comprising of 46,248 patients with confirmed COVID-19 found that the most common co-morbidities were hypertension (17%), diabetes (8%) and CVD (5%). 36 CVD and hypertension have also been more prevalent in the severe patient group as compared to non-severe cases (odds ratio of 3.42 and 2.36, respectively). 36 Existing CVD is also associated with higher mortality which is summarised in Table 5 . 16 On the other hand, it is widely agreed that COVID-19 can also have adverse effects on cardiovascular health itself, causing or aggravating damage to the heart.

There are reports of cardiogenic involvement in patients without known CVD 37 as well as cases with solely cardiac presentations. 38, 39 

The exact mechanism of cardiovascular involvement in COVID- 19 is not yet well understood, however elevated cardiac biomarker levels are commonly seen. In a study by Wang et al., 7.2% of patients had either elevated troponin levels or new electrocardiography or echocardiography abnormalities suggestive of cardiac injury. 25 ACE2 is highly expressed in the heart, providing opportunity for ACE2-dependent myocardial infection. Cytokine storm from systemic inflammation and the hypoxic state from ARDS inducing excessive extracellular calcium levels leading to myocyte apoptosis are also possible mechanisms of damage. 40 Surge in cytokine levels due to hyperinflammatory response or secondary hemophagocytic lymphohistiocytosis and increased myocardial demand in the setting of acute infection can lead to atherosclerotic plaque instability and myocardial injury, increasing the risk of acute myocardial infarction. 41 Blood pressure abnormalities can also be seen in response to the illness. 41 Additionally, palpitations due to arrhythmia have been observed. 41, 42 The type of arrhythmias are variable and aetiology can be multi-factorial, ranging from hypoxic state due to ARDS to myocarditis. 41 Hu et al. and

Zeng et al. also reported patients with reduced ejection fraction and heart enlargement. 39, 43 Therefore, possible long-term effects of COVID-19 on cardiovascular system such as risk of heart failure should be considered and further investigated.

Effects of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) on COVID-19 susceptibility and prognosis have been controversial. Some evidence suggests that increasing ACE2 expressions facilitate COVID-19 infection 44 , while others suggest potential beneficial effects of reducing lung injury. 45 Therefore, changes to their standard indications on the basis of COVID-19 is not currently recommended. 40

Acute Kidney Injury (AKI) is the abrupt loss of kidney function that develops within 7 days, its incidence has been observed with SARS and MERS-CoV. 46 The reported data of AKI in COVID-19 patients are compiled in Table 6 .

Although the exact pathogenesis of kidney involvement in COVID-19 infection is unclear, it is reported that AKI in COVID-19 accompanies sepsis, multi-organ failure and shock, suggesting the cause of AKI to be Acute Tubular Necrosis (ATN). 29 Alternatively, a study based on single-cell transcriptome analysis 47 proved ACE2 receptor expression in kidney cells, suggesting the plausibility of direct renal cellular damage from SARS-CoV-2. This is further supported by the recent detection of SARS-CoV-2 in a urine sample from an infected patient. 46 Findings of one of the first systematic investigations of kidney function in COVID-19 patients 48 are summarised in Table 7 .

In some patients, the metabolic consequences of AKI cannot be adequately controlled with conservative management; hence renal replacement therapy (RRT) can be required. There is little to no evidence that the starting time 49 , modality 50 and dose 51 of RRT has any difference in outcomes. However, convection therapies are known to cause filter clots and use consumables (e.g. tubing and dialysate/replacement solution bags), which can increase costs and exacerbate the issues faced by an overwhelmed hospital. Continuous RRT (CRRT) has been successfully applied in the treatment of SARS 52 , MERS 53 and sepsis 46 . A hemofiltration dose of 6 L/min removed pro-inflammatory cytokines and improved SOFA score at day 7 in septic patients 54 , suggesting the effectiveness of CRRT in the management of renal manifestations in COVID-19.

Gastrointestinal symptoms A significant number of patients reported gastrointestinal (GI) symptoms such as diarrhoea, nausea, vomiting and abdominal pain, with some reporting these symptoms as their sole presenting complaint. 32 The incidence of GI symptoms, alongside the detection of SARS-CoV-2 RNA in stool samples of infected patients 55 , suggest that ACE2 receptors highly expressed in the GI tract are another target for SARS-CoV-2 infection. patients. 56 Immune system response:

The immune response is undeniably one of the key determiners of the susceptibility and severity of the disease. While weakened immune system can increase the risk of severe COVID-19, hyperinflammatory response to the infection can be responsible for the commonly seen complications by causing organ damage.

The surge in inflammatory parameters like IL-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α and tumour necrosis factor-α can be caused by an imbalanced immune response leading to cytokine storm or secondary hemophagocytic lymphohistiocytosis. 57 Along with typical cardinal features like hyperferritinaemia, cytopenia and unremitting fever; pulmonary and cardiac involvement including ARDS and acute coronary syndrome can also result from hypercytokinaemia. 57, 58 Moreover, accumulating evidence suggests that this hyperinflammatory state can be predictors of morbidity and mortality in a significant subgroup of patients. 57 In a multicentre retrospective study, it was found that ferritin and IL-6 levels were more elevated in the nonsurvivor group as compared to the survivors. 59 This is also supported by findings of Qin et al.

who recently discovered that severe cases had higher neutrophil-lymphocyte ratio, lower percentages of basophils, eosinophils and monocytes, as well as elevated inflammatory biomarkers and cytokines. Additionally, the number of suppressor and helper T cells, B cells and NK cells were decreased in the severe group. 60 Septic shock is also reported in 4-8% of patients in several case series. 61 Therefore, it is paramount for all patients with severe COVID-19 to be screened for hyperinflammation using ferritin levels, platelet count and erythrocyte sedimentation rate along with the HScore. 57, 62 Once identified, therapeutic approach is to suppress the immune system. However, it is a difficult decision to determine whether anti-inflammatory effects of treatment outweigh the risk of impairing the immune system that is trying to fight the infection. In addition to the options of steroids and intravenous immunoglobulins, IL-6 receptor antagonist monoclonal antibodies like tocilizumab and sarilumab, anakinra, JAK inhibitors and CCR5 antagonists are also in the clinical trial stage for treatment of cytokine release syndrome in COVID- 19. 61 Other organ involvement

It has been suggested that viral invasion of the central nervous system by SARS-CoV2 is possible by the synapse-connected route observed with other coronaviruses such as SARS-CoV and can lead to several neurological complications including ataxia, seizures, neuralgia, unconsciousness, acute cerebrovascular disease and encephalopathy. 61 

Disseminated intravascular coagulation is another common complication of COVID-19 reported in 71.4% of non-survivors compared to only 0.6% of survivors. 65 It has also been found that use of anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) improved outcomes in severe cases with coagulopathy. 66 

One case of rhabdomyolysis as a potential late complication of COVID-19 has been reported in China. The possibility of under-diagnosis due to muscle pains being a common symptom of COVID-19 as well as creatine kinase (CK) and myoglobin levels not being routinely tested is also highlighted in the letter. 67

Current interventions are supportive, as effective anti-viral treatment has not yet been identified. The clinical management of adult patients are guided by international guidelines as well as local experience and regional outcomes. 68, 69 Patients with signs of pneumonia and those of the high-risk group are indicated for hospitalization. Those with mild flu-like symptoms are discharged, supplemented with symptomatic treatment and advised to return in case of illness worsening. Additional rescue interventions include extra-corporeal membrane oxygenation (ECMO).

Upon recognition of sepsis, standard care 72 is to be commenced as soon as possible. This includes initiation of fluid bolus and vasopressors for hypotension. Prophylaxis against venous thromboembolism is strongly recommended, LMWH preferred over unfractionated heparin, as well as non-pharmacological modalities such as intermittent pneumatic compression stockings. As mentioned above, acute kidney injury can be managed by CRRT. Intermittent RRT has been suggested to be as effective. 72 Cardiac support can be managed with direct input from the cardiology team and inotropic support if required.

Routine corticosteroids are not recommended, unless for trial purposes or for other indications such as adrenal insufficiency, asthma or COPD.

Multi-organ involvement has been apparent since the emergence of COVID-19 -the rapidity of disease progression is widely influenced by the presence of comorbidities and of extrapulmonary organ injuries. Acute respiratory distress syndrome, heart failure, renal failure, shock, and multi-organ failure precipitate death. Full attention to the comorbidities and potential organ injuries is therefore crucial in the implementation of preventative and protective measures. Acknowledging this could help in triaging the management of individual patients, minimizing the risk of decompensation. Alongside the rapid pace at which scientific results are shared, this paper hopes to add onto the ever-emerging landscape of medical knowledge on COVID-19. Estimated hazard ratio indicates that the mortality risk of COVID-19 patients with AKI is ~5.3x (p < 0.001) higher than the mortality risk of COVID-19 patients without AKI. Conclusions: BUN and SCr are key predictors of AKI and they were found to be significantly higher in non-severe cases of COVID-19 compared to other commonly known pneumonia. Both high levels of BUN and SCr were commonly observed in severe and deceased cases across the course of COVID-19. Unlike BUN, for other pneumonia cases, there were no reported elevated SCr levels. Occurrence of kidney dysfunction in COVID-19 patients could be due to kidney-lung crosstalk 76 for the following reasons: renal cells have the potential to be target sites for SARS-CoV-2 and inflammatory responses following lung impairments could damage the kidney, where this kidney-lung crosstalk could lead to a "cytokine storm" that acutely induces multi-organ failure and death. Furthermore, direct renal cellular damage is consistent with another report 77 which found acute renal tubular damage in 6 COVID-19 cases from the histological analysis of renal cell autopsies.

Legend BUN -Blood Urea Nitrogen SCr -Serum Creatinine

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