| Abstract|| |
COVID-19 pandemic caused by SARS-CoV-2 virus has been around for 2 years causing significant health-care catastrophes in most parts of the world. The understanding of COVID-19 continues to expand, with multiple newer developments such as the presence of asymptomatic cases, feco-oral transmission, and endothelial dysfunction. The existing classification was developed before this current understanding. With the availability of recent literature evidences, we have attempted a classification encompassing pathogenesis and clinical features for better understanding of the disease process. The pathogenesis of COVID-19 continues to evolve. The spiked protein of the SARS-CoV-2 virus binds to ACE2 receptors causes direct cytopathic damage and hyperinflammatory injury. In addition to alveolar cells, ACE2 is also distributed in gastrointestinal tract and vascular endothelium. ACE2–SARS-CoV-2 interaction engulfs the receptors leading to depletion. Accumulation of Ang2 via AT1 receptor (AT1R) binding causes upregulation of macrophage activity leading to pro-inflammatory cytokine release. Interleukin-6 (IL-6) has been attributed to cause hyperinflammatory syndrome in COVID-19. In addition, it also causes severe widespread endothelial injury through soluble IL-6 receptors. Thrombotic complications occur following the cleavage and activation of von Willebrand factor. Based on the above understanding, clinical features, organ involvement, risk stratification, and disease severity, we have classified COVID-19 patients into asymptomatic, pulmonary, GI, and systemic COVID-19 (S-COVID-19). Studies show that the infectivity and prognosis are different and distinct amongst these groups. Systemic-COVID-19 patients are more likely to be critically ill with multi-organ dysfunction and thrombo-embolic complications.
Keywords: ACE2, asymptomatic COVID, COVID-19 classification, GI-COVID, IL6, SARS-CoV-2
|How to cite this article:|
Jothimani D, Venugopal R, Manoharan S, Danielraj S, Palanichamy S, Narasimhan G, Kaliamoorthy I, Rela M. COVID-19: Time for a clinical classification?. Indian J Pathol Microbiol 2022;65:902-6
|How to cite this URL:|
Jothimani D, Venugopal R, Manoharan S, Danielraj S, Palanichamy S, Narasimhan G, Kaliamoorthy I, Rela M. COVID-19: Time for a clinical classification?. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Nov 30];65:902-6. Available from: https://www.ijpmonline.org/text.asp?2022/65/4/902/359361
| Introduction|| |
COVID-19 has been around for more than 23 months causing significant health-care catastrophes in most parts of the world. There are several caveats in the understanding of COVID-19 since the beginning of this pandemic. First, unlike the earlier studies on COVID-19, the recent ones describe heterogeneous clinical presentation from mild disease to severe life-threatening complications, particularly in high-risk patients. Second, SARS-CoV-2 utilizes ACE2 receptors which initially was described in alveolar cells, but later studies identified in other organ systems including gastrointestinal tract and vascular endothelium.,, Third, the sensitivity of SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) is around 50–60%. Fourth, disease transmission is predominantly through aerosol droplets but later studies recognized other modalities of disease transmission, for example, feco-oral route.,, Fifth, all patients with COVID-19 were considered to develop clinical symptoms. However, a number of recent studies clearly identified asymptomatic patients.,, Sixth, patients with COVID-19 are now recognized to possess prothrombotic features. Finally, there are no definitive curative therapies available to treat COVID-19. Current treatment approach involves corticosteroids, immunomodulators, antivirals, and anticoagulants. These features add more confusion to the existing conundrum. The understanding of pathogenesis of COVID-19 is continuing to evolve. It is known that spiked protein of the SARS-CoV-2 virus binds to ACE2 receptors leading to activation of orchestrated tissue injury by direct cytopathic effect and through hyperactivation of pro-inflammatory pathway., ACE2, by default, is the receptor for angiotensin 2 (Ang2).
Initially, studies showed higher expression of ACE2 in type 2 alveolar cells. Subsequent studies identified ACE2 in myocardial cells, proximal tubular cells of the kidney, bladder urothelial cells, oral mucosa, ileum, esophageal epithelial cells, and liver. In the liver, ACE2 expression was observed in the endothelial cells of hepatic and portal vasculatures and in cholangiocytes. Interleukin-6 (IL-6) has been found to play a vital role in driving inflammation, particularly in patients with severe COVID-19 [Figure 1].
|Figure 1: Pathophysiology of COVID-19. IL6: Interleukin 6, sIL6R: soluble IL-6 receptor, ADAM 17: a disintegrin and metalloproteinase 17, vWF: von Willebrand Factor, Gp130: glycoprotein 130|
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Binding of SARS-CoV-2 with ACE2 receptors' vascular endothelium causes widespread disruption and damage to the endothelial lining. Presence of endothelial damage results in cleavage and release of von Willebrand factor (vWF) from its inactive form from the endothelial layer causing extensive platelet aggregation and activation of coagulation cascade leading to widespread thrombosis.
With the availability of enormous evidences and understanding of the literature, we believe this is an appropriate time to attempt a classification encompassing pathogenesis and clinical features is probably a better way to understand the disease process.
| Current COVID-19 Classification|| |
The current classification by the Chinese CDC was published in February 2020 [Table 1], at the early stages of the pandemic that describes the disease severity. This is useful in hospitalized patients, with a focus on respiratory symptoms and related complications. It may identify patients who require high dependency or intensive care unit. This existing classification does not consider asymptomatic patients, those with gastrointestinal manifestations, and most importantly thrombotic complications. In addition, it doesn't correlate with clinical and pathological features. With the enormity of rapidly expanding COVID-19 literature, there is a definite need for a better classification.
| Clinical Classification Of COVID-19|| |
Considering the above viral and host immune pathogenic factors, we propose a COVID-19 classification based on the organ system (s) involved [Table 2]; [Figure 2]. Our current classification encompasses the natural history of the disease, risk stratification, and clinicopathological characteristics along with possible treatment and outcomes. It is likely that infectivity and prognosis are probably different and distinct amongst these groups.
| Asymptomatic COVID-19|| |
Asymptomatic COVID-19 (A-COVID-19) refers to the presence of disease in the absence of clinical symptoms and is increasingly recognized.
These patients may have a different clinical profile and viral kinetics compared with those who have symptoms. A study from China followed 31 A-COVID-positive patients and found that 22 patients developed mild symptoms and 9 remained symptom free throughout and cleared the virus. The cycle threshold (Ct), an indirect measurement of viral load during amplification, was significantly different between symptomatic and asymptomatic patients (34.5 vs. 39.0). Moreover, the viral loads of these patients peaked at different times (second week vs. first week) indicating differential viral load in asymptomatic and symptomatic patients, in support of our clinical classification.
Accurate estimation of prevalence of A-COVID-19 may be difficult because of absence of symptoms to trigger testing. Most of the asymptomatic patients are diagnosed through contact tracing. There is a wide variation in the prevalence of A-COVID-19 in various studies ranging from 1.6% to 56.5%. Contact tracing and close follow-up of A-COVID-19 patients are probably required to know the exact prevalence. In an attempt to identify the true prevalence of A-COVID infection, Kim et al. followed 213 COVID-19-positive patients from a community isolation facility and found 19.2% patients remained asymptomatic throughout. Based on a study from repatriated Japanese, using the Bayes equation, asymptomatic ratio was estimated to be 30.8%.
A-COVID-19 patients transmit virus. Reproduction number (R) is the number of new cases per index case. A recent study clarified that risk of disease transmission (secondary cases: Rs) from a symptomatic patient was 0.78 and from an asymptomatic patient was 0.20 indicating that symptomatic cases were more infectious than asymptomatic patients. Secondary cases from an asymptomatic case will more often be asymptomatic. At least 50% of secondary cases from primary asymptomatic cases remained asymptomatic, in comparison to 15% from symptomatic index cases. Another study showed that an asymptomatic person can infect five people.
Despite the lack of symptoms, A-COVID-19 patients may have radiological and biochemical changes associated with the disease. A study from Wuhan with 58 A-COVID-19-positive patients showed 94.8% of them had ground-glass opacity. Subsequently, 16 patients (27.6%) developed symptoms with elevated C-reactive protein and lymphopenia; however, majority of them remained asymptomatic.
Evidences suggest that patients with high ACE2 receptors likely to have less severe disease. It is possible that A-COVID-19 patients have a combination of low viral load and high ACE2 receptors and is therefore likely to clear the virus. These patients do not require treatment but should be managed with self-quarantine and self-monitoring for symptoms.
| Pulmonary COVID-19|| |
Lungs harbor high amount of ACE2 receptors but may not be higher compared to the GI system or the endothelium. Transmission occurring by viral inhalation through droplets (>5–10 μm in diameter particles) from sneezing/coughing results in lower respiratory tract infection (pulmonary COVID-19 [P-COVID-19]). Most of these patients have fever, cough, and occasional breathing difficulties akin to other viral pneumonitis. X-ray or CT imaging of chest may show ground-glass appearance., Diagnosis is by nasopharyngeal swab RT-PCR for SARS-CoV-2 RNA. However, due to limited sensitivity of the polymerase chain reaction (PCR) test, many centers perform CT chest for better sensitivity.,, Most of these patients were treated with HCQ in the first half of this pandemic. However, there is more evidence for a short course of corticosteroids in this cohort of patients with better results. Role of antiviral drugs such as Remdisivir or Lopinavir–Ritonavir is unclear.,,
The severity associated with P-COVID-19 is probably related to the presence of limited number of ACE2 receptors particularly in patients with advanced age and comorbidities. Moreover, the regenerative capacity of the lungs is quite poor. This leads to rapid depletion of ACE2 receptors following SARS-CoV-2 viral infection and causes accumulation of Ang2. Excess Ang2 along with SARS-CoV-2 leads to destruction of alveolar cells causing edema and inflammatory cell infiltrates constituting to acute respiratory distress syndrome (ARDS) in severe cases. Similarly, if the endothelial damage is restricted to alveolar capillaries, it may result in vascular leakage and edema leading to the development of ARDS.,
| GI-COVID-19|| |
Apart from respiratory tract, SARS-CoV-2 can affect the gastrointestinal system. These patients often present with anorexia (39.9–50.2%), diarrhea (2–50%), nausea and vomiting (6.5–66.7%), and occasional abdominal discomfort. These patients may acquire the disease through feco-oral contamination. However, some patients may have mixed pulmonary and GI-COVID-19 where respiratory symptoms predominate. Between 3% and 79% of patients with COVID-19 have GI symptoms. Xiao and colleagues have shown that 53.42% of patients with respiratory illness had positive stool sample, of which 23.29% had stool positivity even after testing negative for nasopharyngeal swab. Postmortem analysis showed occasional lymphocytic infiltration in squamous epithelia of esophagus and extensive plasma cell and lymphocytic infiltration in gastric, duodenal, and rectal lamina propria. Gastric and intestinal epithelial cell cytoplasm and cilia of glandular epithelial cells showed positivity in ACE2 staining.
As discussed earlier, ACE2 distribution in the GI tract is quite extensive. This widespread distribution of ACE2 makes GI-COVID-19 predominantly a milder disease. Moreover, liver cells and GI tract mucosal layer continues to regenerate following injury due to SARS-CoV-2 virus. This high restorative capacity and development of new cells will continue to harbor the virus for a longer period of time. Literature supports our hypothesis as patients may continue to shed the virus in stools for a longer period following COVID-19 infection., On similar lines, liver could potentially harbor the virus for longer duration and these patients may continue to shed the virus in stools leading to feco-oral transmission as seen in patients with other RNA viral infections, for example, hepatitis E. Moreover, these patients are less likely to develop systemic complications such as ARDS or cytokine storm (CS). Low levels of viral shedding may lead to asymptomatic disease in the community, which may spread herd immunity.
| S-COVID-19|| |
This is a severe disease as a result of widespread endothelial injury leading to accelerated systemic inflammatory response secondary to macrophage activation syndrome and hemophagocytic lymphohistiocytosis. “CS” or, better termed, “COVID-19 shock syndrome” is the clinical manifestation of S-COVID-19 characterized by tachycardia, vasodilatation, hypotension, acidosis, acute kidney injury, and in worst cases multi-organ failure. Moreover, extensive endothelial disruption leads to activation of vWF resulting thrombotic and thromboembolic complications. Biochemical parameters show elevated ferritin, CRP, and IL-6. Studies are required to assess and clarify the viremic nature of these patients. Clearly, this syndrome is associated with a poor clinical outcome. These patients require aggressive therapy often in the intensive care with high-flow oxygen, intravenous fluids, corticosteroid therapy, and therapeutic heparinization. They may require invasive ventilation, airway protection, and multi-organ support.
| Conclusion|| |
With the intensity of COVID-19 pandemic continuing to increase in several countries, we are in need of a better understanding of COVID-19, so that treatment can be streamlined according to the clinical characteristics of COVID-19 and to channelize resources accordingly. Our classification incorporates clinical symptoms, pathogenesis, organs involved, and disease severity. Clearly, more studies are required in stratify COVID-19 in order to manage these patients effectively. Until then, measures to reduce disease spread such as social distancing, hand hygiene, facemask, and lockdown are the only ways to mitigate disease transmission.
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Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, 7, CLC Works Road, Chrompet, Chennai - 600044, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]