|Year : 2020 | Volume
| Issue : 1 | Page : 5-16
Understanding COVID-19: origin, symptoms and current treatment guidelines
Sandeep Singh1, Honey Goel2, Sonia Singh1, Ashok Kumar Tiwary3
1 Department of Physiotherapy, Punjabi University, Patiala, Punjab, India
2 Department of Pharmaceutical Sciences, Baba Farid University of Health Sciences, Faridkot, Punjab, India
3 Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
|Date of Submission||21-Apr-2020|
|Date of Decision||27-Apr-2020|
|Date of Acceptance||13-May-2020|
|Date of Web Publication||29-Jun-2020|
Dr. Sandeep Singh
Department of Physiotherapy, Punjabi University, Patiala - 147 002, Punjab
Source of Support: None, Conflict of Interest: None
2019-novel corona virus (nCoV) has come as an unexpected health emergency to the world. The highly contagious and unknown virus is still being studied for its origin, molecular structure and virulence as the globe faces numerous deaths every day. The situation is highly challenging because there is currently no vaccine available for 2019-nCoV as the virus had never infected humans. Every nation is facing multiple challenges of testing, diagnosing treating and containing the spread of COVID (as is 2019-nCoV infection commonly called). The economies of all nations have been ravaged due to the exigencies arising out of this extraordinary situation. In the midst of this global health emergency, it is essential to learn from the concurrent clinical cases and develop measures to detect, diagnose and treat the patients. This article aims at consolidating the existing knowledge with respect to the different aspects related to the COVID infection.
Keywords: COVID-19, diagnostic testing, physiotherapy, severe acute respiratory syndrome-coronaviruses 2, treatment
|How to cite this article:|
Singh S, Goel H, Singh S, Tiwary AK. Understanding COVID-19: origin, symptoms and current treatment guidelines. Physiother - J Indian Assoc Physiother 2020;14:5-16
|How to cite this URL:|
Singh S, Goel H, Singh S, Tiwary AK. Understanding COVID-19: origin, symptoms and current treatment guidelines. Physiother - J Indian Assoc Physiother [serial online] 2020 [cited 2020 Jul 6];14:5-16. Available from: http://www.pjiap.org/text.asp?2020/14/1/5/288359
| Introduction|| |
Wuhan, the People's Republic of China, reported the first case of now known as COVID-19 on December 31, 2019. Since then, COVID cases have continued increasing unabated, transgressing geographical boundaries, social status, and gender. The ongoing outbreak of novel coronavirus (2019-nCoV) has generated global socioeconomic concerns. The nCoV spread with such tenacious ferocity that the International Health Regulations Emergency Committee was forced to advise the WHO Director-General to declare the outbreak of 2019-nCoV a Public Health Emergency of International Concern on January 30, 2020. Currently, the entire world is experiencing vast devastation of human life and economy through numerous deaths and complete lockdown of almost all facilities in an attempt to contain the spread of virus.
Coronaviruses (CoVs) are regarded important for human and vertebrates due to their pathogenicity. They can infect respiratory, gastrointestinal, hepatic and central nervous system of human, livestock, birds, bat, mouse and many other wild animals.,, Severe acute respiratory syndrome (SARS), the first identified in 2002 and diagnosed in Southern China, occurred from a human CoV. Then, exactly 10 years after the SARS-CoV emergence with mortality rate of 10%, a new emerging CoV named Middle East respiratory syndrome (MERS-CoV) infected people with a high mortality rate of nearly 37% in the Middle East. Currently, the mortality rate of 2019-nCoV is estimated to be 2.0%. However, its transmissibility is higher. The mean R0(R0 is used to estimate the transmissibility of virus) of 2019-nCoV ranges from 3.3 to 5.5, and it appears (slightly) higher than those of SARS-CoV (2–5) and MERS-CoV (2.7–3.9). The subfamily Coronavirinae includes four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. The phylogenetic tree of the CoVs displays the evolutional relationships among common ancestors as shown in [Figure 1].
Protein sequence analysis shows that the 2019-nCoV possesses a typical genome structure of CoV and belongs to the cluster of betacoronaviruses. Typically, the nCoV possesses the largest genome among the known viruses. Different CoVs identified so far belong to one of four general (α, β, γ, and ∂) and effect diverse organisms [Table 1].
Before 2019, there were only six CoVs that were known to infect humans and cause respiratory diseases. 2019-nCoV can also infect the lower respiratory tract and cause pneumonia in humans but it seems that the symptoms are milder than SARS and MERS. This 2019-nCoV is the seventh member of the family of CoVs that infects humans.
| Clinical Findings|| |
The length of whole genome of SARS-CoV-2 is 29,727 nucleotides and the genome organization exhibits 79.0% nucleotide identity to SARS-CoV and 51.8% identity to MERS-CoV, which belongs to β-CoV genus. The genome sequence (SARS-CoV-2, Urbani strain-Accession number-AY278741) is open for public view at Gene Bank information on National Center for Biotechnology Information, National Library of Medicine.
Furthermore, it has been reported that 2019-nCoV is 96% identical across the entire genome to a bat CoV. This suggests that there is a high probability that this infection causing virus originated from bats. Thein vitro tests have shown that its inoculation onto surface layers of human airway epithelial cells causes cytopathic effects and cessation of the cilium beating of the cells.
Morphology and nature of severe acute respiratory syndrome coronavirus-2
It exhibits round or elliptic and often pleomorphic form and has a diameter of ~ 60–140 nm. Like other CoVs, it is sensitive to ultraviolet light and heat. Further, it can be inactivated by lipid solvents including ether (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid and chloroform except for chlorhexidine.
It is important to note that at present, there is no specific biochemical marker for identifying 2019-nCoV infection. Scientists have till now relied heavily on the concentration of various biochemical markers of infected patients to ascertain and correlate their clinical symptoms with severity of this viral infection. Blood analysis of 2019-nCoV-infected patients showed higher concentrations of plasma interleukin (IL)-1β, IL-1Rα, IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, interferon-γ, IP10, MCP1, MIP1A, MIP1B, platelet-derived growth factor, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor as compared to healthy individuals. Majority of these are indicative of inflammation and an increase in their concentration after 2019-nCoV infection is a response to the damage being done to the healthy cells of the body. Moreover, intensive care unit (ICU) patients showed higher plasma levels of IL-2, IL-7, IL-10, Granulocyte-colony stimulating factor (GCSF), IP10, MCP1, MIP1A and TNF-α than non-ICU patients. Patients requiring ICU admission have either advanced form of infection or have less innate immunity. Hence, these findings suggest that immunopathology may also play a relevant role in the development of disease severity.
| Clinical Symptoms of 2019-Novel Corona Virus Infection|| |
The general clinical symptoms of 2019-nCoV infection are similar to those of SARS-CoV and MERS-CoV. Most patients report fever, dry cough, shortness of breath (dyspnea) and bilateral ground-glass opacities on chest computed tomography (CT) scans. However, patients with 2019-nCoV infection rarely reported obvious upper respiratory signs and symptoms (such as snot, sneezing, or sore throat), indicating that the virus primarily infected the lower respiratory tract. In addition, about 20%–25% of 2019-nCoV patients experienced intestinal symptoms and signs (such as diarrhea), similarly to MERS-CoV or SARS-CoV. In severe 2019-nCoV infection cases, the symptoms included acute respiratory distress syndrome, septic shock, metabolic acidosis, bleeding and coagulation dysfunction. It is worth noting that severe and critically ill patients may have moderate to low fever during the course of the disease, even without obvious fever. Furthermore, like SARS-CoV and MERS-CoV, 2019-nCoV infections induce production of high levels of cytokines that are released as a response to viral infections by the cells of the immune system.,,
There is a difference in the viral load in various parts of the respiratory system between SARS-CoV and 2019-nCoV infection. SARS-CoV infection displayed an aberrant trait that the “viral load” in upper respiratory tract secretions was low in the first 5 days of illness, then increased progressively, and peaked early in the 2nd week. This gave some lead time to the health professionals because the transmission rate was relatively low in the 1st day of illness. Hence, detection and isolation of patients was easier for preventing transmission of infections. On the contrary, for 2019-nCoV, the incubation lasts for an average of 10 days (in a reported range of 2–14 days) from infection to appearance of symptoms. Even worse, 2019-nCoV is able to spread from one person to another even before any actual clinical manifestations.,,, This makes early detection of clinical symptoms and isolation of infected patients extremely challenging without extensive testing of all potential individuals having exposure to the virus. As a consequence, control of situation usually begins when it has already taken the form of an epidemic.
| Transmission Route|| |
An envelope-anchored spike protein mediates CoV entry into host cells by first binding to a host receptor and then fusing viral and host membranes. A defined receptor-binding domain (RBD) of SARS-CoV spike specifically recognizes its host receptor angiotensin-converting enzyme 2 (ACE2). The host that is susceptible to SARS-CoV infection is primarily determined by the affinity between the viral RBD and host ACE2 in the initial viral attachment step.
ACE2, a receptor for 2019-nCoV, is necessary for the viral entry of 2019-nCoV. The ubiquitous expression of ACE2 in various cells, such as heart, lung AT2 cells, upper esophagus, stratified epithelial cells, absorptive enterocytes of ileum and colon, may contribute to the multitissue infection of 2019-nCoV. Therefore, besides respiratory and bodily contact, fecal–oral transmission too is a potential route for 2019-nCoV infection.,,
| Origin of 2019-Novel Corona Virus|| |
A detailed computer-aided analysis of interactions between residues on the receptor-binding motifs of 2019-nCoV and ACE-2 analogs of various species has revealed that it uses civet ACE2 as its receptor, although it appears that 2019-nCoV RBD has not evolved adaptively for civet ACE2 binding. Moreover, 2019-nCoV likely does not use mouse or rat ACE2 as its receptor due to no significant virus-receptor interaction as judged by computational analysis. 2019-nCoV RBD likely recognizes ACE2 from pigs, ferrets, cats, orangutans, monkeys and humans with similar efficiencies, because these ACE2 molecules are identical or similar in the critical virus-binding residues. The situation involving bat ACE2 is complex because of the diversity of bat species. However, it still likely recognizes bat ACE2 as its receptor for ACE2 from Rhinolophus sinicus bats (which can be recognized by bat SARS-CoV strain Rs3367).
In the case of SARS-CoV, some of its critical receptor-binding motif residues were adapted to human ACE2, while some others were adapted to civet ACE2. This type of partial viral adaptation to two host species promoted virus replication and cross-species transmission between the two host species. However, in the case of 2019-nCoV, no strong evidence for adaptive mutations in its critical receptor-binding motif residues that would specifically promote viral binding to civet ACE2 have been identified. Hence, either palm civets were not intermediate hosts for 2019-nCoV, or they passed 2019-nCoV to humans quickly before 2019-nCoV had any chance to adapt to civet ACE2.
Bats are less likely to have direct contact with human, and thus, direct transmission of the virus from bat to human is unlikely. Although SARS-CoV and MERS-CoV originated from bats, they were transmitted to humans via intermediate host civets and camels, respectively. Therefore, 2019-nCoV could have also originated from bat but was then transmitted to humans via an intermediate host in the market. Recently, 2019-nCoV virus that was isolated from pangolins was found to have 99% similarity with the genomic sequence of the isolated strain of 2019-nCoV that had infected humans. Hence, it could be possible that the transmission and evolution path of 2019-nCoV was from bat-CoV to pangolins (the intermediate hosts), from where it infected humans.
However, it is a matter of deep investigation to locate the origin and intermediate hosts of 2019-nCoV before it infected humans. The fact that mutations were not detected in receptor-binding motif residues on 2019-nCoV for binding to civet ACE2 and the former's genomic sequence was found identical to that isolated from pangolins, makes it even more difficult to pin point the exact source and intermediate host. Most importantly, the computer-aided structural analysis has predicted that a single mutation may significantly enhance the binding affinity between 2019-nCoV RBD and human ACE2. Thus, 2019-nCoV evolution in patients should be closely monitored for the emergence of novel mutations at the 501 position (to a lesser extent, also the 494 position).
Two most important inferences could be logically drawn from limited reports available so for on 2019-nCoV. Prima facie it seems less convincing that the culinary interests of inhabitants of Wuhan could have contributed to this disaster. This contention arises from the fact that the natives should have acquired immunity against this virus over the period as they would have been consuming civets and pangolins since long. Therefore, it would be appropriate presently to apprehend that the route of infection was bats to pangolins to human. However, whether bats infect pangolins with 2019-nCoV does require deep contemplation. Second, nonsignificant virus-receptor interaction between 2019-nCoV and rat and mouse ACE2 suggests that these cannot be used for developing experimental model for research.
| Diagnosis|| |
In wake of global health crisis inflicted by the outbreak of COVID-19 disease, foremost priority of any nation of world today is to contain spread of this highly contagious disease. Since definitive treatment and vaccine remains unavailable, diagnostic testing plays a pivotal role in this crisis contributing to patient screening, early identification, and diagnosis of COVID-19 even monitoring treatment, as well as in epidemiologic surveillance. Early diagnosis is key to halt transmission the COVID-19 as it will assist in early treatment, reducing the mortality, thus decreasing the burden on health-care systems allowing them to deal effectively with epidemic. Clinical diagnosis of the COVID-19 can be made taking manifestation into consideration (fever, dry cough, dyspnea, ad other upper respiratory symptoms), epidemiological risk (travel history to COVID-19-affected region), and other factors including age and comorbidities.
Since the clinical symptoms and signs of patients infected with SARS-CoV-2 are highly atypical and mimic features of respiratory infections caused by other viruses such as parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, and SARS-CoV,, COVID-19 requires confirmatory laboratory diagnosis. Further, keeping in view the present scenario, in order to decrease the pace of progression of pandemic, many health organizations are clamoring for conduction of early laboratory testing to confirm the diagnosis of COVID-19 suspected cases so that necessary intervention (isolation/quarantine) could be taken. The important diagnostic tests include (i) nucleic acid amplification test (NAAT), (ii) serological tests, (iii) chest radiographs and CT scans, and (iv) others.
- The basis of NAAT test is to find the virus in the secretions of patient by detecting presence of genetic material (nucleic acid) of SARS-CoV2 virus. The most common and effective method recommended by the WHO for nucleic acid detection of SARS-CoV-2 is real-time quantitative polymerase chain reaction (RT-qPCR). In this test, upper airway specimen (pharyngeal swabs, nasal swabs, nasopharyngeal secretions) as well as lower airway specimen (sputum, bronchoalveolar lavage fluid) and even blood or fecal samples are collected. Extraction of RNA is done. The protocol has been published by the WHO for using RT-qPCR. The extracted RNA is transcribed into DNA by adding enzymes. This DNA is put into a RT-qPCR machine that essentially xeroxes the DNA, making thousands of copies of genetic material. Further few specific genes of 2019-nCoV, namely the open reading frame la/b, nucleocapsid protein (N), envelope protein (E) genes, and RNA dependent RNA polymerase genes, are searched for confirming COVID-19. Results are positive if two genes are present, not conclusive if one gene is present and negative if no gene is present.,, Though RT-qPCR test suffer certain shortcomings such as biological safety hazards due to sample collection or transportation. cumbersome nucleic acid detection operations and long waiting time for results but still RT-qPCR remains gold standard test for diagnosis of COVID-19 as it can detect virus at an early stage of infection. Shortage of RT-qPCR kits is being experienced due to unprecedented rise in infected cases. Thus, it becomes necessary to prioritize who gets tested according to health objectives of the nation and testing is recommended for individual with high index of suspicion. The Indian Council of Medical Research (ICMR), New Delhi, has also developed diagnostic strategy for testing, which is being revised and updated time to time as new information about 2019-nCoV emerges (https://icmr.nic.in/content/covid-19)
- Serological tests: Serology-based tests analyze the serum component of whole blood to detect presence of antibodies to know whether person has been exposed to a corona virus. These tests include colloidal gold immunochromatography, enzyme-linked immunosorbent assay, immunofluorescence assay, and chemiluminescence immunoassay. Two antibodies develop in the body against viral infection, i.e., immunoglobulin (IgM) antibodies and IgG antibodies. Detection of IgM antibodies reflects recent exposure whereas IgG antibodies indicate viral exposure some time ago. Detection of both IgM and IgG provides information on virus infection time course. IgM becomes detectable around 3–5 days after onset; IgG reaches a titration of at least 4-fold increase during convalescence compared with the acute phase. During follow-up monitoring, IgM is detec[table 10] days after symptom onset and IgG is detec[table 12] days after symptom onset. A positive interpretation of antibody test has been defined as a positive IgM or an increased IgG titer (>4-fold than that in the acute phase). In cases where NAAT reports have been negative, but there is a strong epidemiological link to COVID-19 infection, IgM and IgG testing validated serology tests (in the acute and convalescent phase) could support diagnosis. However, few authorities question the usefulness of serological testing in COVID-19 diagnosis and monitoring as these tests detect infection after 7–10 days of exposure to virus and they also may cross-react with serologic responses to seasonal CoVs. Overlooking these limitations, serological tests could prove highly valuable in point-of-care testing as they are rapid, simple to use, and provide results within 15 min. Therefore, rapid antibody tests with high sensitivity and specificity will quickly identify 2019-nCoV in infected patients and would give impetus to containment efforts for COVID-19 disease. The ICMR has made significant progress in this direction and validated five rapid antibody tests (list of tests released on April 2, 2020). Most significant benefit of serological assays would be in determining who developed immunity to COVID-19. This knowledge would help in identifying individuals who showed strong immunological response to 2019-nCoV and could then serve as donors for the generation of convalescent serum therapeutics. Additional usefulness of these tests would be for deploying immunologically strong health-care workers in high viral risk areas to prevent inadvertent spread of the virus
- Chest radiographs and CT scans: Chest radiographs are not especially sensitive for COVID-19 and have little diagnostic value in early stages, whereas CT findings may be present even before symptom onset. CT is significantly more sensitive than RT-qPCR, but not much specific as many of its imaging features can easily be confused with other disease process such as H1N1, SARS, MERS, and seasonal flu., Chest CT or X-ray is not currently recommend as a diagnostic method. The American College of Radiology recommends not to use CT scan for screening or primary testing for diagnosis of COVID-19. According to the Center for Disease Control and Prevention, viral testing needs to be conducted for diagnosis confirmation even if a chest CT or X-ray suggests COVID-19. Notwithstanding reservations for using CT scan for initial diagnosis COVID-19 infection, it is very valuable for monitoring disease progression of severely ill patients and categorization of clinical syndromes
- Other laboratory tests: In the early stage of the disease, close check should be kept on absolute value of lymphocytes. If it is <0.8 × 109/L, or the numbers of CD4 and CD8 T cells are significantly decreased, it is generally recommend to recheck the routine blood changes after 3 days., More laboratory tests for checking the status of 2019-nCoV infection include blood gas analysis, function tests of liver and kidney, myocardial enzyme, myoglobin, erythrocyte sedimentation rate, alanine aminotransferase, cardiac troponin, C-reactive protein, procalcitonin, lactate, D-dimer, coagulation image, urine routine test, inflammatory factors (IL-6, IL-10, TNF-α), 11 items of tuberculosis subgroup, complement, and anti-acid staining. Aforementionedin vitro laboratory tests beyond being valuable in etiological diagnosis of COVID-19 are critical for assessing disease severity and monitoring therapeutic intervention. Many of these tests have been implicated in unfavorable COVID-19 progression wherein they provide important prognostic information.,, Emerging evidence suggests that severe COVID-19 patients are at risk for cytokine storm syndrome which could be major cause of mortality. Cytokine tests, particularly IL-6, assesses hyperinflammation in severe patients and would be instrumental in checking rise of COVID-19 mortality.,
| Treatment|| |
Severity of the COVID-19 disease has been classified into four types:
- Mild cases: Having mild clinical symptoms and pneumonia manifestations not present in imaging
- Moderate cases: Having symptoms such as fever and respiratory tract symptoms, etc., and pneumonia manifestations seen in imaging
- Severe cases: Dyspnea, hypoxia, or >50% lung involvement on imaging
- Critical cases: Respiratory failure, shock, or multiorgan system dysfunction; about 80% of COVID-19 patients develop only mild or uncomplicated illness and approximately 14% patients develop severe disease requiring hospitalization and oxygen support, while 5% require admission to an ICU., In severe cases of COVID-19, many complications may develop such as acute respiratory disease syndrome (ARDS), sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury.
Further, clinical course of COVID-19 disease can progress through six clinical syndromes outlined by the World Health Organization, which include mild illness, pneumonia, severe pneumonia, ARDS, sepsis, and septic shock. Treatment of patient is mainly based on syndrome differentiation of disease.
| Supportive Treatment|| |
Many patients with a mild illness and without underlying risk factors (lung or heart disease, renal failure, or immunocompromising conditions) of developing complications may not be hospitalized owing to limited health-care resources and care to them can be provided at home that too by family members. The decision to monitor a patient in the inpatient or outpatient requires careful clinical judgment and will depend on whether the residential setting is suitable for providing care and whether patient and the family are capable of adhering to the precautions that will be recommended as part of home care isolation (e.g., hand hygiene, respiratory hygiene, environmental cleaning, and limitations on movement around or from the house). Home management is mainly supportive with proper nutrition, hydration, antipyretics (especially paracetamol recommended), and analgesics. Further, given the possible risk of progression to severe illness in the 2nd week after symptom onset, health-care workers should monitor the patient closely and provision for immediate hospitalization should be well in place., The detail guidelines about home care management of COVID-19 patients have been developed by the WHO.
Few COVID-19 patients will require hospitalization for management (inpatient) as the disease develops and complications including pneumonia, hypoxemic respiratory failure/ARDS, sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney injury, and secondary bacterial infections set in., As of now, currently, no specific treatment for COVID-19 is approved. Inpatient management of COVID-19 provides supportive management of the most common complications of severe COVID-19.
The WHO has developed guidelines on the basis of scientific evidence derived from the treatment of previous epidemics from human corona viruses (SARS and MERS). This guideline provides recommendations for the management of adults, pregnant, and children with COVID-19. Recently, on March 31, 2020, the Government of India also released national guidelines on clinical management of COVID-19, which aim to provide clinicians with updated interim guidance on timely, effective, and safe supportive management of patients with COVID-19. Important strategies of these guidelines are discussed as follows:
I. For management of severe COVID-19
- Provide airway management and oxygen therapy during resuscitation to target SpO2≥94% to patients with severe acute respiratory infection (SARI) exhibiting emergency signs (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma, or convulsions)
- In patients with SARI but having no evidence of shock, administer conservative fluid management with intravenous fluid. Aggressive fluid resuscitation needs to be avoided as it may worsen oxygenation.
- Administer appropriate empiric antimicrobials within 1 h of identification of sepsis to treat all likely pathogens causing SARI
- Avoid routine corticosteroids for the treatment of viral pneumonia or ARDS unless they are indicated for another reason as the lack of evidence survival benefit and can cause possible harm
- Patients to be closely monitored for signs of clinical deterioration, such as rapidly progressive respiratory failure and sepsis, and provide supportive care interventions immediately as supportive therapies are the cornerstone of therapy to improve chance of survival of COVID-19 patient.
II. For management of critical COVID-19: Acute respiratory distress syndrome
- When a patient with respiratory distress is failing standard oxygen therapy, severe hypoxemic respiratory failure needs to be recognized and preparation to provide advanced oxygen/ventilatory support is done
- When respiratory distress and/or hypoxemia of the patient cannot be alleviated after receiving standard oxygen therapy, high-flow nasal cannula oxygen (HFNO) therapy or noninvasive ventilation (NIV) is considered
- Patients receiving a trial of HFNO or NIV should be in a monitored setting, and in case the patient acutely deteriorates or does not improve in about 1 h, tracheal intubation and invasive mechanical ventilation should be instituted in a timely manner. Patients with hemodynamic instability, multiorgan failure, or abnormal mental status should not receive NIV
- Mechanical ventilation to be implemented using lower tidal volumes (4–8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure <30 cm H2O)
- In patients with severe ARDS, prone ventilation for >12 h per day is recommended
- In patients with moderate or severe ARDS, higher positive end-expiratory pressure (PEEP) instead of lower PEEP is suggested to maintain driving pressure
- In moderate or severe ARDS (PaO2/FiO2<150), neuromuscular blockade by continuous infusion should not be routinely used
- Never disconnect patient from ventilator rather use in-line catheters for airway suctioning and clamp endotracheal tube when disconnection is required, as it would result into atelectasis
- Patients with refractory hypoxemia despite lung protective ventilation should be referred to settings having access to expertise in extracorporeal life support.
III. Management of critical illness: Septic shock
- When infection is suspected or confirmed, monitor and try to recognize signs of septic shock using values of mean arterial pressure and serum lactate levels. Standard care should start within 1 h of recognition which includes antimicrobial therapy and initiation of fluid bolus and vasopressors for hypotension. Detailed guidelines from the Surviving Sepsis Campaign and WHO are available for the management of septic shock in adults
- Hemodynamic support is essential for resuscitation of adults from septic shock. In the first 15–30 min, give patient 250–500 mL isotonic crystalloid fluid as rapid bolus and reassess for signs of fluid overload after each bolus. Do not use hypotonic crystalloids, starches, or gelatins for resuscitation
- Fluid resuscitation may lead to volume overload, including respiratory failure. If there is no response to fluid loading and signs of volume overload appear (for example, jugular venous distension, crackles on lung auscultation, pulmonary edema on imaging, or hepatomegaly in children), reduce or discontinue fluid administration. This step is particularly important where mechanical ventilation is not available
- Administer vasopressors (norepinephrine, epinephrine, and vasopressin) when shock persists during or after fluid resuscitation. The initial blood pressure target is mean arterial pressure (MAP) ≥65 mmHg in adults
- If signs of poor perfusion and cardiac dysfunction persist despite achieving MAP target with fluids and vasopressors, consider an inotrope such as dobutamine.
Other therapeutic measures
Glucocorticoids can be administered only for 3–5 days in patients with progressive deterioration of oxygenation indicators, rapid worsening on imaging and excessive activation of the body's inflammatory response. The dose should not exceed the equivalent of methylprednisolone 1–2 mg/kg/day as larger dose of glucocorticoid will delay the removal of CoV due to immunosuppressive effects. Psychological support through counseling should be provided to patients who suffer from anxiety and fear.
Physiotherapy as supportive treatment
Expertise and knowledge of physiotherapists can be utilized at various levels and settings and they can contribute significantly in stabilizing a 2019-nCoV patient. In primary care settings, physiotherapists can manage and share workload and can help in triage and early identification of cases. In community care (i.e., in the home), they can help in educating patients, serve as care givers, and contribute in workforce planning. In acute care (i.e., the hospital setting), the physiotherapy emphasis will be on the management of respiratory symptoms and prevention of complications.,
Physiotherapy can be beneficial in the respiratory treatment and physical rehabilitation of patients with COVID-19. Not all COVID-19 positive patients develop high secretion loads, so respiratory physiotherapy is indicated only for selected patients, however those patients who have pre-existing respiratory conditions require personalized physiotherapy treatments which may include mechanical airway clearance or use of oscillating devices. In this scenario, it is important to take clearance of critical care consultants after discussing with them the risk and benefit of continuing with the physiotherapy.,
During the acute phase of COVID 19, physiotherapy interventions that could potentially increase the risk of breathing should be avoided. However, once patient is stable and if respiratory physiotherapy is strongly indicated, the main goal is to mobilize secretions and ease the work of breathing. Interventions may include techniques such as positioning, autogenic drainage, deep breathing exercises, breath stacking, active cycle of breathing mobilization, and manual techniques (e.g., percussion, vibrations, and assisted cough) to aid sputum expectoration. It is necessary for physiotherapist to protect himself/herself from contamination by following recommendation regarding the use personal protective equipment.
In the mechanically ventilated COVID-19 patients, important physiotherapy methods include positioning with regular turning which are vital to prevent atelectasis, optimize ventilation, and prevent pressure sores. Patients can be positioned in lateral positioning, but prone positioning is well recognized to treat hypoxemic respiratory failure. It is highly recommended to deliver ventilation to patients with ARDS in the prone position. Prone ventilation is found to enhance lung mechanics and gas exchange, thus increasing oxygenation and improving outcomes.,,
Physiotherapists can play a key role in the prevention of a range of complications including ventilator-associated pneumonias, secondary infections, contractures, or pressure areas/sores. Further, the main role of the physiotherapist in the management of COVID-19 patients will be witnessed in recovery phase (rehabilitation phase) of COVID-19 patients. Physiotherapy in this phase focusses on early mobilization of patient, returning to functional activities, so that duration of hospital stay is reduced and functional decline is minimized. This phase starts from rehabilitation and exercise within the ICU to ward-based rehabilitation. Physiotherapist uses diverse methods such as passive, active-assisted, active, or resisted joint range of motion exercises to maintain or improve joint integrity and range of motion and muscle strength and mobilization exercise programs such as bed mobility, movement transition, tilt table standing, and upper limb or lower limb ergometry.,, An international team of expert researchers and clinicians within the intensive care and acute cardiorespiratory fields has developed recommendation to provide information to physiotherapists about the potential role of physiotherapy in the management of hospital-admitted patients with confirmed and/or suspected COVID-19. For detailed information about physiotherapy role in COVID-19 patient management, one can refer these guidelines available at: Physiotherapy Management for COVID-19 in the Acute Hospital Setting: Recommendations to Guide Clinical Practice.
| Therapeutic Intervention|| |
Since 2019-nCoV has not been found before in humans, there is no vaccine or special treatment for it so far. The number of cases is increasing rapidly. The need of the hour is to intensify testing and isolating all diagnosed cases as soon as possible in order to cut off the source of infection. Several drugs are under clinical trial and compassionate use protocols based onin vitro activity (against SARS-CoV-2 on limited clinical experience). However, the following line of drug/therapies has been utilized for the treatment of COVID 19, until the approved, efficacious therapy is developed.
- Chloroquine –In vitro and limited clinical data suggest potential benefit
- Hydroxychloroquine –In vitro and limited clinical data suggest potential benefit
- Lopinavir – Ritonavir-role in the treatment of COVID-19 is unclear. Preclinical data suggested potential benefit; however, more recent data have failed to confirm
- Remdesivir – Investigational and available only through expanded access and study protocols; several large clinical trials are underway
- Azithromycin – Used in some protocols based on theoretical mechanism and limited preliminary data as adjunct therapy
- Tocilizumab – Immunomodulating agent used in some protocols based on theoretical mechanism and limited preliminary data as adjunct therapy
- COVID-19 convalescent plasma – Investigational use is being studied
- Corticosteroid therapy is not recommended for viral pneumonia; however, use may be considered for patients with refractory shock or acute respiratory distress syndrome.
| Preventive Measures Based on the Who Guidelines|| |
- Prevent close contact with subjects suffering from acute respiratory infections
- Frequently wash hands especially after contact with infected people or their environment
- Evade unprotected contact with farm or wild animals
- People with symptoms of acute airway infection should keep their distance, cover coughs or sneezes with disposable tissues or clothes, and wash their hands
- Strengthen, in particular, in emergency medicine departments, the application of strict hygiene measures for the prevention and control of infections
- Individuals that are immunocompromised should avoid public gatherings.
| Potential Risks and Challenges in the Development of Human Vaccines|| |
The development of safe, effective, and stable vaccines is a lengthy process. In addition, it should also be effective against various mutated strains in order to be useful to the infected patients. This makes the task even more challenging. Traditional drug or vaccine development processes are not viable during such suddenly emerging epidemics.
It is pertinent to note here that animal vaccination against some animal CoVs are available. Live or attenuated virus vaccine is effective against porcine epidemic diarrhea virus and avian infectious bronchitis virus. However, in the development of human vaccines (especially live virus or attenuated CoV), the potential risk would be the recombination of genomes of vaccine strains with wild type CoVs. Hence, killed or subunit vaccines containing spike glycoprotein or along with some other viral proteins might prevent the complications such as lower respiratory tract disease in humans. It has been reported that some vaccines against feline CoVs augmented the severity of the disease rather than reduction, when the vaccinated animals were exposed to wild type/form of CoVs. This challenge could be another obstacle in the smooth translation of vaccine development for humans.
Therefore, the first option available could be to systematically screen existing drugs to determine whether they have activity against the 2019-nCoV. Such screening practices have found that nelfinavir has potential antiviral activity against 2019-nCoV. Based on previous studies, an anti-HIV drug named Kaletra (composed of two protease inhibitors, ritonavir and lopinavir) can be screened as they had displayed therapeutic efficiency on SARS and MERS. More recently, Kaletra was also recommended to treat Wuhan pneumonia by the National Health Commission of the People's Republic of China. Patients with SARS or MERS have been treated with several drugs including ribavirin, interferon, lopinavir-ritonavir, and corticosteroids, but the efficacy of certain drugs is still controversial.
Other antiviral drugs, such as US Food and Drug Administration (FDA)-approved drugs including ribavirin, penciclovir, nitrazine, nalfamusta, and chloroquine, are being evaluated by measuring the effects of these compounds on cytotoxicity, virus yield, and infection rate of 2019-nCoV. Recent results have shown that remdesivir and chloroquine are effective in controlling 2019-nCoV infectionin vitro and may be evaluated in human patients with 2019-nCoV disease. Currently, remdesivir is in clinical research phase for the treatment of Ebola virus infection. Moreover, the fifth edition of infection prevention and control guidance has announced that severe and critically ill patients could be treated with recovery plasma.,
The drug favilavir (marketed by the name Avigan) developed by Fugifilm Toyama Chemicals, Japan, has become the first ever antiviral medicine to be approved for use as a treatment for Covid-19 in China. It was earlier used for treating influenza in Japan and China. This approval is based on the reports of patients in Shenzhen where patients receiving favilavir turned negative for CoV after a median of 4 days after becoming positive as compared to 11 patients who did not receive the drug. Furthermore, X-rays of chest showed improvements in 91% of the patients as compared to 62% of the patients who did not receive the drug. However, the USA has not yet approved this drug for the treatment of CoV. Nevertheless, clinical trials are going on in Japan to see if it can be used for preventing the virus from multiplying in the patients suffering from mild-to-moderate symptoms.
Another important development has been reported from the University of Pittsburgh's Center for Vaccine Research (CVR), USA. They are developing a SARS-CoV-2 vaccine using a measles vector (a measles vaccine tailored to express SARS-CoV-2 proteins on its surface). This is aimed to be sued for generating immunity to the virus. CVR is a part of an international consortium led by Institut Pasteur (Paris, France) in collaboration with Themis Bioscience GmbH (Vienna, Austria). It is expected that the vaccine shall be ready by April 2020 and will undergo trails in 60–80 human volunteers in Europe by the end of this year. The Coalition for Epidemic Preparedness Innovations, an international intergovernmental organization, has committed about United States Dollar 5 million to the consortium for this purpose.
Working on immediate need awaiting development of new treatments, Roche (Basel, Switzerland) has been given permission by the US-FDA to initiate randomized, double-blind, placebo-controlled Phase III clinical trial in collaboration with the Biomedical Advanced Research and Development Authority to evaluate the safety and efficacy of Actemra/Ro-Actemra (having tocilizumab) in hospitalized adult patients with severe COVID0-19 pneumonia. Actemra/Ro-Actemra was the first approved anti-IL-6 receptor available for the treatment of adult patients suffering from moderate-to-severe active rheumatoid arthritis.
| Future Possible Targets or Interventions|| |
Some of the potential targets for the development of future drugs against SARS-CoV-2 could be among protease inhibitors (which prevent processing of the RNA polymerase or cleavage of the viral S glycoprotein), CoV acetylesterase inhibitors (which limit viral replication) likely as neuraminidase inhibitors which inhibit the replication of influenza virus A and B. Further, inhibitors of membrane fusion may be potentially useful in blocking viral entry as do several new drugs against HIV. Therefore, antibodies against viral S glycoprotein or the unidentified receptor for the SARS-CoV-2 could also block entry of the virus.
| Conclusions|| |
The primary job seems to track the origin of the human pathogen and learn from experiences of various nations. Human activities, including unlimited invasion of natural habitats of animals, consumption of some of these animals, have probably given rise to such emergency situations. Adaption of viruses from natural hosts to humans has been happening and seems to be escalating. Seemingly trivial, invisible viruses can have devastating effects on the entire human race not sparing ones who were not perpetuators of the chain. People who had not visited the Wuhan animal market have also been diagnosed positive for 2019-nCoV. This was possible through human-to-human contact even at very far off countries. These findings indicate the virulence of 2019-nCoV and its stable nature even after exposure to various environment conditions. Therefore, there is an immediate need to investigate the animal etiology, recognize, and eliminate the chances of high risk pathogens from entering human chain. Complete ban on consumption of animals posing high risk of such infections, maintaining constant vigil on such highly virulent infective organisms especially from the wild, may help in reducing such episodes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wang LF, Shi Z, Zhang S, Field H, Daszak P, Eaton BT. Review of bats and SARS. Emerg Infect Dis 2006;12:1834-40.
Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, et al
. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 2013;503:535-8.
Chen Y, Guo D. Molecular mechanisms of coronavirus RNA capping and methylation. Virol Sin 2016;31:3-11.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al
. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74.
Lin Q, Chiu AP, Zhao S, He D. Modeling the spread of middle east respiratory syndrome coronavirus in Saudi Arabia. Stat Methods Med Res 2018;27:1968-78.
Ren LL, Wang YM, Wu ZQ, Xiang ZC, Guo L, Xu T, et al
. Identification of a novel coronavirus causing severe pneumonia in humans: A descriptive study. Chin Med J 2020;1:133:1015-24. [doi: 10.1097/CM9.0000000000000722].
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al
. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al
. A novel coronavirus from patients with pneumonia in China, 2019. N
Engl J Med 2020;382:727-33.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al
. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020;395:514-23.
Chen C, Zhang XR, Ju ZY, He WF. Advances in the research of cytokine storm mechanism induced by corona virus disease 2019 and the corresponding immunotherapies. Chin J Burns 2020;1:36.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
Hoffmann M, Kleine WH, Krüger N, Müller M. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv 2020. [doi.org/10.1101/2020.01.31.929042].
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al
. A new coronavirus associated with human respiratory disease in China. Nature 2020;579:265-9.
Letko M, Munster V. Functional assessment of cell entry and receptor usage for lineage B β-coronaviruses, including 2019-nCoV. Nat Microbiol 2020;5:562-9.
Holshue ML, De Bolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al
. First case of 2019 novel coronavirus in the United States. N
Engl J Med 2020;382:929-36.
Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, et al
. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:1-3. [doi.org/10.1186/s40779-020-00246-8].
Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 2020;10:102-8. [doi.org/10.1016/j.jpha. 2020.03.001].
Hongliu C, Yu C, Zuobing C, Qiang F, Wei LI, Shaohua H, et al
. Diagnosis and Treatment. Handbook of COVIO-19 Prevention and Treatment. In: Tingbo L, editor. Handbook of COVIO-19 Prevention and Treatment. Hangzhou: TheFirst Affiliated Hospital, Zhejiang University School of Medicine (FAHZU); 2020. p. 19-24.
Li Z, Yi Y, Luo X, Xiong N, Liu Y, Li S, et al
. Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis. J Med Virol 2020; [doi: 10.1002/jmv.25727].
National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia. National Health Commission and State Administration of Traditional Chinese Medicine; 2020. Available from: http://www.kankyokansen.org/upl oads/uploads/files/jsipc/protocol_V7.pdf
. [Last accessed on 2020 Apr 04].
Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al
. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: A report of 1014 Cases. Radiology 2020. [doi: 10.1148/radiol. 2020200642].
Li T. Diagnosis and clinical management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: An operational recommendation of Peking Union Medical College Hospital (V2. 0) Working Group of 2019 Novel Coronavirus, Peking Union Medical College Hospital. Emerg Microbes Infect 2020;9:582-5.
Lippi G, Plebani M. The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. Clin Chem Lab Med 2020. [doi.org/10.1515/cclm-2020-0240].
Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med 2020. [doi.org/10.1515/cclm-2020-0198].
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al
. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
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 2020;323:1239-42.
Feng Z, Li Q, Zhang Y, Wu Z, Dong X, Ma H, et al
. The novel coronavirus pneumonia emergency response epidemiology team. Vital surveillances: The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) – China, 2020. China CDC Wkly 2020;2:113.
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al
. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475-81. [doi: 10.1016/S2213-2600 (20) 30079-5].
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al
. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al
. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock. Intensive Care Med 2017;43:304-77.
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di NR. Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/
. [Last accessed on 2020 Mar 31].
Thomas P, Baldwin C, Bissett B, Boden I, Gosselink R, Granger CL, et al
. Physiotherapy management for COVID-19 in the acute hospital setting. Recommendations to guide clinical practice. J Physiother 2020;66:73-82. [doi.org/10.1016/j.jphys. 2020.03.011]. Available from: https://www.sciencedirect.com/science/article/pii/S183695532030028X
. [Last accessed on 2020 Apr 05].
Lazzeri M, Lanza A, Bellini R, Bellofiore A, Cecchetto S, Colombo A, et al
. Respiratory physiotherapy in patients with COVID-19 infection in acute setting: A position paper of the Italian Association of Respiratory Physiotherapists (ARIR). Monaldi Arch Chest Dis 2020;90:163-68. [doi.org/10.4081/monaldi. 2020.1285].
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS Coronavirus. J Virol 2020;94:1-9. [doi: 10.1128/JVI.00127-20].
Arabi YM, Asiri AY, Assiri AM, Jokhdar HA, Alothman A, Balkhy HH, et al
. Treatment of middle east respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): Statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials 2020;21:1-8.
Wang ML, Cao R, Zhang L, Yang XL, Liu J, Xu MY, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
. Cell Res 2020;30:269-71.