Extrapulmonary Manifestations of Covid-19: A Review View PDF

*Antonio Montero
Center For Tropical Medicine And Emerging Infectious Diseases, School Of Medical Sciences, Faculty Of Medicine, National University Of Rosario, Argentina

*Corresponding Author:
Antonio Montero
Center For Tropical Medicine And Emerging Infectious Diseases, School Of Medical Sciences, Faculty Of Medicine, National University Of Rosario, Argentina
Email:amontero@sede.unr.edu.ar

Published on: 2021-12-03

Abstract

Coronavirus disease 2019 (covid-19) presents in a wide variety of clinical pictures ranging from completely asymptomatic or mild forms to rapidly progressive disease, including pulmonary and extrapulmonary manifestations. SARS-CoV-2 –the etiological agent of covid-19- access to their target cells via a transmembrane protein, the angiotensin-converting enzyme II (ACE2). ACE-2 is a type-I metallocarboxypeptidase with homology to ACE, an essential enzyme in the Renin-Angiotensin System [1]. This enzyme is expressed in vascular endothelial cells, renal tubular epithelium, Leydig cells in the testes, lungs, kidneys, brain, heart, vasculature, and gastrointestinal tract [2-7]. As such, the clinical manifestations of covid-19 are explained by the tissular distribution of ACE-2. Beyond the tissular affectation “per se”, another pathological feature is the “cytokine storm” phenomenon (CS).  CS is an exaggerated immune response characterized by a high level of circulating inflammatory cytokines sustained over time. It is rapidly progressive and has a high mortality.  CS has been detected in critical patients with covid-19 and it is considered a major cause of acute respiratory distress syndrome (ARDS) and multiorgan failure. Serum levels of proinflammatory cytokines are significantly increased in patients with ARDS, and their levels are positively correlated with mortality [8,9]. CS may also cause inflammation and injury of the Central Nervous System (CNS) Supporting this view, IL-6 levels positively correlate with covid-19 severity [10]. This syndrome has been described in sepsis, hemophagocytic syndrome and in other coronavirus infections like the severe acute respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS). Although lung involvement has been well described in many reports, extra-pulmonary manifestations are still poorly described. This paper will review the non-pulmonary manifestations of covid-19. Main extra-pulmonary symptoms comprise the neurologic, cardiac, ophthalmologic, muscular, hematologic, cutaneous, and gastrointestinal ones, as well as hepatic and renal involvement. Each one of these manifestations can arise during the disease evolution or constitute their initial manifestation.

Keywords

SARS-CoV-2, Angiotensin-Converting Enzyme II, Central Nervous System

Asymptomatic or oligosymptomatic forms

During an outbreak of covid-19 affecting a cruise-ship, more than 50% of infected people were asymptomatic or presymptomatic at the time of testing [11,12].   It was estimated that 18% of positive cases on board were “true asymptomatic”, defined as infected people who never developed symptoms [13].

Asymptomatic or oligosymptomatic subjects showed viral loads similar to those found in fully symptomatic people. It follows that the contagiousness of SARS-CoV-2 may be similar in symptomatic and asymptomatic patients [14-16].

Available data suggest that 12% of transmission occurs before an index case becomes symptomatic [17,18]. A study evaluating the value of symptom-based screening to identify infection in residents of a nursing facility found that over 50% of residents having a positive SARS-CoV-2 test were asymptomatic when the test was performed. Thus, infection-control strategies based solely on the detection of symptomatic cases are not enough to prevent transmission [19]. The role of asymptomatic cases must be always considered.

Symptomatic presentations

Neurological involvement

SARS-CoV-2 is a neurotropic virus capable to cause a variety of neurological complications as encephalitis, meningitis, toxic encephalopathy, acute cerebrovascular events, Bell´s palsy, or Guillain-Barré syndrome. More rarely, acute disseminated encephalomyelitis and peripheral neuropathy have also been described [20,21].

SARS-CoV-2 can reach the CNS through the olfactory nerve during the early stages of infection, causing inflammation and a demyelinating reaction [22,23]. This route of CNS invasion explains the loss of olfactory function frequently reported in covid-19 patients. Olfactory disorders affected 53% of the cases in a small cohort of Italian patients, with new anosmia emerging as a diagnostic criterion, especially in young oligosymptomatic people. Hematogenous spread is another mechanism for SARS-CoV-2 to reach the SNC [23-26].

In a series, 36.4% of patients developed headache, disturbed consciousness, epilepsy, and paresthesia [27]. Manifestations as acute cerebrovascular disease (ACVD), conscious disturbance, and muscle injury were more prevalent among severely ill covid-19-patients. Postmortem examination revealed brain tissue edema and partial neuronal degeneration [28].

Neurologic symptoms may also constitute the initial manifestation or appear later [29].

In a series of covid-19 patients with ARDS, neurological findings affected 14% of patients on admission to the intensive care unit (ICU), but 67% of patients leaving out ICU.

The main findings were agitation (69%), diffuse corticospinal tract signs with enhanced tendon reflexes, ankle clonus, bilateral extensor plantar reflexes (67%) or confusion (45%). Additionally, 33% of the discharged patients showed a dysexecutive syndrome consisting of inattention, disorientation, or poorly organized movements in response to a command. Silent acute ischemic strokes may occur. Magnetic resonance also revealed an enhancement in leptomeningeal spaces in 8 out of 13 patients and bilateral frontotemporal hypoperfusion in all of them [30]. However, it was difficult to distinguish whether these findings were covid-19 specific or were reflecting critical illness-related encephalopathy, cytokines storm, or drug toxicity.

Meningitis/encephalitis

Encephalitis is a syndrome characterized by altered mental status and various combinations of fever, seizures, neurologic deficits, and cerebrospinal fluid pleocytosis besides the neuroimaging and electroencephalographic abnormalities [31]. This entity refers to inflammatory lesions in the brain parenchyma caused by pathogens, including neuronal damage and nerve tissue lesions. It is characterized by the acute onset of symptoms including headache, fever, vomiting, convulsions, and sensory alteration.

SARS-CoV-2 was isolated from the cerebrospinal fluid of Covid-19 patients, suggesting a direct role for this virus as responsible for the encephalitis among covid-19 patients [32,33].

Of note, encephalitis can be the initial manifestation of covid-19 or presents with meningeal signs [34].

Infectious toxic encephalopathy

Infectious toxic encephalopathy (ATE) is a global cerebral dysfunction in absence of structural brain damage. Pathological changes consist of cerebral edema without evidence of inflammation or changes in the cerebrospinal fluid [35-37].

It constitutes a habitually reversible brain dysfunction caused by factors such as systemic toxemia, metabolic disorders, or hypoxia during an acute infection. Because of the frequent onset of respiratory insufficiency in covid-19 patients, hypoxia emerges as a major mechanism of neurological injury [38].

This syndrome is due to an interference with the function of the ascending reticular activating system, leading to impaired arousal and/or awareness. Its clinical picture is complex and diverse. Patients having a mild affectation may develop headaches, dysphoria, mental disorder, and delirium. More severe forms may present with disorientation, loss of consciousness, coma, and paralysis. In Covid-19, ATE can be the initial manifestation or develop during hospitalization [35].

Acute cerebrovascular disease

Covid-19 increases the risk of ACVD. Severe SARS-CoV-2 infection shows high plasmatic concentrations of D-dimer, thrombocytopenia, and severe platelet reduction. These factors are all capable of increase the risk of ACVD.

It is well known that respiratory infections increase the risk for acute cerebrovascular disease (ACVD) [39]. For instance, influenza virus infection can aggravate ischemic brain injury or increase the risk of cerebral hemorrhage by triggering a cytokine cascade.  

The binding of viral particles to ACE-2 into cerebral blood vessels might raise the intraluminal pressure leading to intracerebral hemorrhage [40]. Then, the diagnosis of SARS-CoV-2 must be considered in patients developing ACVD during the pandemic.

Covid-19 patients experiencing ACVD were significantly older, had severe clinical manifestations along with typical risk factors for cardiovascular disease including hypertension, diabetes and a previous medical record of ACVD [41].

Guillain–Barré syndrome (GB) has been reported in Covid-19 patients, being more likely to arise during the inflammatory period [42,43].

At least one case of Bell´s palsy complicating covid-19 has been reported [44].

Cardiac involvement

Coronary disease is associated with acute cardiac events and poor outcomes during influenza and other major respiratory viral infections [45-50]. Thus, it is not surprising that cardiac complications are associated with increased morbidity and mortality during Covid-19.

Cardiomyocytes carry ACE2 protein on their cell membranes, rending these cells susceptible to SARS-CoV-2 infection [29]. Necropsy studies showed myocardial infiltration of mononuclear cells but no viral inclusion bodies. However, direct myocardial injury by SARS-CoV-2 through ACE2 entry cannot be ruled out, since direct viral toxicity on cardiomyocytes has been seen in other viral infections such as coxsackievirus-induced myocarditis [51].

More than 50% of lethal cases showed high levels of high-sensitivity cardiac troponin-I. High levels of troponin-I have also be found in severe but recovered covid-19 cases and in non-survivors [52].

Raised levels of high-sensitivity troponin I, together with changes in the electrocardiogram or new echocardiographic abnormalities were detected in 7.2% of patients, but this figure climbs to 22% in subjects admitted to ICU [53].

Cardiac complications of covid-19 include the new onset of heart failure, arrhythmias, myocardial infarction, worsening of preexistent cardiac diseases, myocardial injury, myocarditis, pericarditis, or myopericarditis with reduced systolic function. New or worsening arrhythmia or myocardial infarctions are frequently seen in covid-19 pneumonia patients, with nearly 3% of them experiencing cardiac arrest [54].

Myocardial injury in Covid inpatients has been associated with increased mortality. A series including 416 patients documented myocardial injury in 19.7% of them. Patients with myocardial injury had higher leukocyte counts, besides with lower lymphocyte and platelets counts [55,56].

Patients admitted without cardiac involvement showed varied plasmatic troponin levels depending on their clinical course. Recovered subjects had a mean troponin level of 2.5 pg/mL by the 4th day of hospitalization, but this value raised to 8.8 pg/mL among non-survivors.

Mean troponin values did not change significantly in survivors (2.5 - 4.4 pg/mL). By opposite, these values rose progressively among non-survivors. This pattern might be reflecting myocardial damage more linked to CS than direct viral injury. The proper mechanism of myocardial damage mediated by cytokines remains unknown, although cardiomyocytes and endothelial cells may die in presence of inflammatory cytokines such as TNF-a [57,58].

Direct viral myocardial injury and stress cardiomyopathy is more prevalent among patients showing prominent cardiovascular symptoms on admission. At least one case of fulminant myocarditis has been reported in this subset of patients [59].  

Coronavirus infection can cause myocarditis or even congestive heart failure [60]. It is difficult to ascertain whether myocardial injury is due to direct viral replication in the myocardium, or it is mediated by systemic responses to respiratory failure or by harmful immune reactions ensuing from the viral infection [61].

Cases with rapid recovery of cardiac structure and function without clear reductions in viral load suggest that immune mechanisms or a CS may be involved in myocardial injury [62,63]. Severe hypoxia secondary to pulmonary involvement is also able to trigger serious inflammatory responses resulting in myocardial injury [64].

Direct viral damage of the macro- or microvascular circulation has been suggested as another mechanism for myocardial damage. Since ACE2 is expressed at the endothelium, infection of endothelial cells may contribute to vascular damage, local inflammation, and production of procoagulant factors predisposing to thrombosis. This mechanism has been demonstrated in myocardial infarction seen during influenza [65].

Some patients who complained of heart palpitations and chest tightness without respiratory symptoms were finally diagnosed as presenting covid-19 [53].

Drug-related heart damage is another concern of importance during covid-19 treatment. In a study of 138 patients, 89.9% received cardiotoxic antiviral drugs capable of causing cardiac insufficiency, arrhythmia, or other cardiovascular disorders [66,67].

Ophthalmologic manifestations

Ocular involvement during covid-19 is mild and infrequent [68]. In a small series of 38 patients, 31.6% of them presented ocular conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. Remarkably, conjunctival swabs have been positive for SARS-CoV-2 on RT-PCR in 16.7% of the patients. These findings suggest that tears may constitute a vehicle for SARS-CoV-2 transmission, mostly considering that SARS-CoV-2 is present in tears [69].

Patients with ocular symptoms were more likely to show higher leukocyte and neutrophil counts raised levels of procalcitonin, C-reactive protein, and lactate dehydrogenase in comparison with patients without ocular symptoms.

Muscular damage

Muscle symptoms are common in covid-19, which can reflect muscular damage. Patients with muscle pain had higher creatine kinase and lactate dehydrogenase levels. These findings were also more frequent in severe patients [70,71].

Muscle injury may be associated with the direct infection for SARS-CoV-2 via ACE2 protein present in the skeletal muscle cells, although the virus has not been detected in skeletal muscle by postmortem examination. Muscle injury may be also related to CS, since cytokines may damage muscular tissue.

Rhabdomyolysis has been described during the late stages of covid-19 in 0.2% of 1009 cases studied in China.

Hematological Disorders

Hematological markers

Hematological changes are frequent in covid-19 patients. These include lymphocytopenia and thrombocytopenia together with alterations of coagulation markers. Most patients have prolonged activated partial thromboplastin time and many of them have raised D-dimer levels. However, most patients have normal prothrombin time [72]. In a series of 1099 patients, 82.1% had lymphopenia; 36.2% thrombocytopenia, and 33.7% leukopenia [73]. These findings prevailed among severe cases. Thrombocytopenia can be also present on admission in up to 5% of the patients, but the platelet count usually did not felt beyond the limit of bleeding. Lymphopenia and thrombocytopenia are predominant in severe cases.

Damaged lung tissues and endothelial cells may activate platelets, resulting in aggregation and formation of microthrombi, thus increasing platelet consumption. Supporting this view, most patients with thrombocytopenia had simultaneously raised D-dimer levels and impaired coagulation times.

CS is likely to destroy the hematopoietic progenitor cells in bone marrow from severely ill patients, with a subsequent reduction in platelet production.

Secondary hemophagocytic lymphohistiocytosis due to excessive proliferation and activation of the mononuclear-macrophage system seems to be another mechanism responsible for thrombocytopenia [74]. This disorder presents with persistent fever, hyperferremia, cytopenia, and lung involvement, leading to high mortality. A study of 150 covid-19 patients identified high levels of ferritin as one of the death predictors [75].

During the covid-19 incubation, peripheral blood leukocyte and lymphocyte counts remain within normal limits. Nevertheless, 7 to 14 days after the onset of the symptoms a salient lymphopenia develops, frequently together with a pronounced systemic increase of inflammatory mediators and cytokines, which in severe cases resemble a CS [76].

Lymphocytes express the ACE2 receptor on their surface, allowing SARS-CoV-2 to infect and kill them. On the other hand, the higher levels of IL-6, IL-2, IL-7, granulocyte colony-stimulating factor, interferon-? inducible protein 10, Monocyte Chemoattractant Protein-1, Macrophage Inflammatory Protein and tumor necrosis factor (TNF)-? may promote lymphocyte apoptosis [77].

Coagulation disorders

Covid-19 was associated with a hypercoagulable state mirrored by a prolonged prothrombin time, elevated levels of D-dimer and fibrinogen.

A series of 560 patients showed raised levels of D-dimer in 46.4% of them. This alteration prevailed in severe cases rather than the milder ones. D-dimer levels also increased progressively in non-survivors but not in recovered patients [78,79].

Some evidence of disseminated intravascular coagulation was also found in 71.4% of non-survivors but in 0.6% of survivors [80,81].

Covid-19 patients are at high risk for venous thromboembolism (VTE). CS in severe covid-19 patients acts as a triggering stimulus for the coagulation cascade. IL-6 may activate the coagulation system and suppress the fibrinolytic system. Besides, Endothelial cells may be infected by SARS-CoV-2, causing endothelial injury that might be another inducer of hypercoagulation. In this setting, a feed-back loop may develop between cytokines providing a stimulus for coagulation that further amplifies the immune response.

Venous thromboembolism (VTE) affects 10% of inpatients with covid-19 raising the possible development of lethal pulmonary thromboembolism [82]. Hence, the indication of thromboprophylaxis is mandatory, especially in patients under mechanical ventilation, which constitutes a risk factor for endothelial damage.

Cutaneous manifestations

Galván-Casas et al described five patterns of skin manifestations in covid-19. Listed in frequency order they are:

  1. Acral areas of erythema with vesicles or pustules (Pseudochilblain) (47%).
  2. Maculopapular eruptions (47%).
  3. Urticarial lessons (19%).
  4. Livedo (6%).
  5. Necrosis (6%).

Vesicular eruptions may appear early in the course of the disease (15%) and they can be the initial manifestation of covid-19. By opposite, the pseudo-chilblain pattern tends to appear late during the disease (59%) being usually preceded by other symptoms [83].

Livedo and necrotic lesions were uncommon; they mainly affected elderly and severe patients. These might result from a direct viral injury of the endothelial cells [84].

A series of 88 patients found some skin involvement in 20.4% out of them. Cutaneous manifestations were erythematous rash (12.32%), widespread urticaria (2.64%), and chickenpox-like vesicles (0.88%), involving preferably the trunk.

The appearance of unexplained skin manifestations during a covid-19 epidemic must alert clinicians to rule-out this diagnosis.

Kawaski disease (KWD) is an acute vasculitis of unknown cause, being the leading cause of acquired heart disease in children from developed countries [85]. Jones VG, et al. (2020) [82], reported the first case of KWD in a SARS-CoV-2 infected child. Later, a cluster of eight KWD cases affecting previously-health children was found. SARS-CoV-2 was detected in three out of them, while other two children had strong evidence of direct familiar exposition to the virus.

All cases showed similar clinical pictures with high fever (38-40°C), rash, conjunctivitis, peripheral edema, muscle pain, and relevant gastrointestinal symptoms. They worsened toward a vasoplegic shock refractory to volume resuscitation and eventually required vasoactive drugs. One child died because of a refractory shock and a large cerebrovascular infarct.

The cause of the KWD in covid-19 patients is unknown, although it might be related to CS.

Gastrointestinal manifestations

The frequency of gastrointestinal symptoms in covid-19 patients ranges between 2% and 40% [77,86]. In a meta-analysis involving 60 studies and 4243 patients, 17.6% had gastrointestinal manifestations.

The prevalence of digestive symptoms in patients having mild forms of covid-19 versus those more severely ill was 11.8% and 17.1%, respectively [87]. However, there is no evidence linking the intensity of digestive symptoms with the severity of covid-19.

SARS-CoV-2 RNA was found in feces of 48.1% of the patients. Interestingly, 73% of them showed viral RNA in stools after their respiratory secretions became negative for viral RNA. Thus, negativization of viral RNA in respiratory secretions does not guarantee that the patient's feces will not remain infectious.

Gastrointestinal symptoms were the first manifestation of covid-19 in 16% of 1141 cases. Anorexia was the most frequent complaint, affecting up to 98% [88]. Nausea and vomiting affected 73% and 65% of cases respectively. Diarrhea and abdominal pain were reported in 37% and 25% respectively [89]. 

In another series, 15.3% of them presented viral RNA in stools. Viral RNA was detectable in the stools in 38.5% of patients with diarrhea but in 8.7% of patients without diarrhea [29,90].

Hepatic involvement

Liver impairment has been reported in up to 60% of patients of SARS and MERS-CoV [91,92].

A high proportion of covid-19 patients presented a mild increase of hepatic transaminases on admission.

In a study involving 417 patients, 76.3% had abnormal liver tests. Raised levels of aspartate aminotransferase (AST) were found in 62% of the patients admitted to an intensive care unit.

Abnormal liver tests became more pronounced during the second week of hospitalization. The percentage of patients showing a more than threefold increase of Alanine aminotransferase, AST, total bilirubin, and gamma-glutamyl transferase was 23.4%, 14.8%, 11.5%, and 24.4%, respectively [93].

Liver failure is rare in covid-19 being only found in the context of sepsis or multiple organ failure [94,95].

Examination of liver tissue in search for viral inclusions failed to demonstrate viral particles, suggesting that the viral titer was relatively low in hepatocytes [96].

These findings point to a multifactorial mechanism for hepatotoxity rather than a direct cytopathic action of SARS-CoV-2 on hepatocytes. Additional factors for liver damage are drugs, pneumonia-related hypoxia and CS [97].

Renal manifestations

Some kind of renal impairment is present in the majority of patients with covid-19 pneumonia. Although proteinuria, hematuria, and acute kidney injury (AKI) often resolved within 3 weeks after the onset of symptoms, they are associated with higher mortality.

In a series of 333 patients admitted because of covid-19 pneumonia, 75.4% showed signs of renal involvement, (proteinuria, 65.8% or hematuria, 41.7%). Both alterations were more prevalent in patients severe or critically ill (85.7% and 69.6%, respectively).

The incidence of AKI was 4.7% on admission but affected 42.9% of critically ill patients. Proteinuria and hematuria mostly prevailed in patients who developed AKI in comparison with patients without AKI (88.6% and 60% versus 63.1% and 41.7%, respectively). The rate of renal abnormalities found was in line with what has been found in other critical illnesses [97].

Mechanisms of renal damage in covid-19 belong to one of three categories:

  • Cytokine-mediated injury;
  • Related lung and kidney damage; or
  • Organ crosstalk, existing a significant amount of overlapping among these mechanisms.
  1. Cytokine mediated injury: AKI may appear as a consequence of intrarenal inflammation, increased vascular permeability, and cardiomyopathy, along with factors leading to a type 1 cardiorenal syndrome. This syndrome includes systemic endothelial injury, manifested as pleural effusions, edema, intra-abdominal hypertension, loss of fluids to a third-space, intravascular fluid depletion, and hypotension. Interestingly, some dialysis procedures have been proposed to remove cytokines in patients with sepsis which may potentially be beneficial in critically ill patients with covid-19.
  2. Related lung and kidney damage: CS is a factor for lung–kidney bidirectional damage. Injured renal tubular epithelium upregulates IL-6 synthesis, which in turn increases alveolar-capillary permeability leading to pulmonary hemorrhage. The resulting hypoxemia causes renal medullar hypoxia, and hence aggravating kidney damage.
  3. Organ crosstalk: Crosstalk is defined as the ability of different components of a given transduction pathway to induce changes in the components of another pathway. Heart–kidney crosstalk may play a role in the onset of AKI during covid-19. CS cardiomyopathy and acute viral myocarditis can both contribute to a cardiorenal syndrome, mediated by renal vein congestion with the subsequent hypotension and renal hypoperfusion and the ensuing reduction in the glomerular filtration rate. Other mechanisms for organ crosstalk are rhabdomyolysis -a well-known factor of tubular renal toxicity- or high peak airway pressure or intra-abdominal hypertension causing a renal compartmental syndrome.

Table 1: Extrapulmonary manifestations of covid-19 and their relative frequencies.

Involvement

% frequency

Asymptomatic-

18%

Gastrointestinal

2 - 40%

Neurologic

36%

Hematologic

     Lymphopenia

     Thrombocytopenia

     Leukopenia

 

82.1%

36.2%

33.7%

Ophthalmological

31.6%

Cardiac

7%

Rhabdomyolysis

0.2%

Cutaneous

 

Renal (on admission)

     Proteinuria

     Hematuria

Acute kidney injury

75.4%

     65.8%

     41.7%

      4.7%

Coagulation disorders

     Raised circulating D-dimer

          Severe cases

          Milder cases

          DIC*

 

46.4%

     59.0%

     43.2%

Non-survivors 71.0%

Survivors 0.6%

Abnormal liver tests

60%

*DIC: Disseminated Intravascular Coagulation.

Conclusion

Covid-19 is a systemic disease able to affect a wide range of organs and systems.

Three mechanisms may explain the multiorgan involvement of covid-19:

  • The tissular distribution of ACE-2 protein among different cell types. Since ACE-2 is the entry door for the virus, their distribution in different cells renders tissues more susceptible to SARS-CoV-2 infection.
  • CS leading to systemic involvement and multiorgan damage.
  • Organ crosstalk like the axis kidney-lung further contributing to multiorgan failure.

In essence, the entire clinical picture of covid-19 may be explained by the pattern of tissular distribution of receptors ACE-2.

Declarations

The author declare that he has no conflicts of interest, that the work has been approved by the ethics committee responsible in the workplace, and do not declare means of financing of the work carried out.

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