I hope everyone is staying safe and healthy in these strange times. This is the second blog I'm writing about SARS CoV-2 which causes COVID1-19. The information below is a summary from some calls I've been on with various physicians and scientists, some on the frontline of COVID-19 as well as review of preprint and preleminary data that have not been certified by peer review and should not be solely related to make clinical judgment or guide clinical practice or health related behaviors but merely to get better insight into this rapidly developing pandemic. The information is rapidly changing as the number of new cases as well as the number of recovered cases increase. By the time you read this, some of the information might have already been changed or be outdated. Kudos to all of us who have been practicing social distancing which has shown to help delay the peak, especially in California and Washington State and help flatten the curve. I apologize if the information is too scientific since the data coming out is now more specific to pathophysiology of the virus. If you need more general information about SARS-CoV-2 and COVID-19, please see last week's blog post.
Social Distancing: Mathematical models have run to investigate the effectiveness of social distancing interventions lasting 6 weeks in a mid-size city in the US. Results suggest that social distancing interventions can avert cases by 20% and hospitalizations by 90% even with modest compliance within adults as long as intervention is kept in place, but the epidemic can rebound once the intervention is lifted. However, social distancing can buy us time for the hospitals to get ready and the community to get ready with testing and contact tracing of all suspected cases to mitigate transmission of SARS-CoV-2. As we've seen, early mandatory social distancing in California and Washington State has been effective based on some early, preliminary data. California and Washington State "were the first to report community cases of COVID-19 and were also the first in the nation to mandate residents stay at home to keep physically apart. New analysis from academics and federal and local officials indicates the moves bought those communities precious time - and may have also "flattened the curve" of infections for the long haul.
While insufficient testing limits the full picture, it's now clear that the disease is spreading at different speeds in different places in the United States. California and Washington continue to see new cases and deaths, but so far they haven't come in the spikes seen in parts of the East Coast and Midwest. Even still, social distancing efforts need to continue for several more weeks to be effective, experts say." Per COVID-19 Projections from IHME, as of today we expect to reach "peak resource use" in California on April 26 while April 9th in New York and April 15 for the entire US on average. This means we have bought ourselves some time to get ready for the surge and utilization of hospital use.
Comorbidities that were found to cause the worse disease include: higher BMI (overweight and obesity), cardiovascular disease (heart disease), chronic obstructive pulmonary disease (asthma and emphysema), diabetes, high blood pressure and/or cancer other than skin. Overall 45.4% of adults who reported any of the 6 comorbidities, had increased rate of complications from 19.8% for ages 18-29 to 80.7% for ages 80+ years.
In another study, it was found that hypertension, diabetes, and coronary artery disease can affect the severity of COVID-19. It may be related to the imbalance of ACE2(angiotensin converting enzyme 2) and the cytokine storm induced by Glocolipid metabolic disorders.
Smoking cessation and as well as cessation of vaping can also significantly reduce severity of COVID-19 infecion, hospitalization and need for intubation as well as recovery in severe cases.
Symptoms: the most common symptoms in patients who tested positive for COVID-19 was fever (83%), cough (38%), fatigue (15%) and breathing difficulties (14%). Other symptoms including nasal congestion, dizziness and chills were less frequently reported. Since unfortunately testing is yet to become available to us here in Santa Monica in an outpatient setting, my recommendation to my patients is that in mild to moderate cases to self quarantine at home and only go to the emergency room for persistent fever(above 101) that does not respond well to acetaminophen (Tylnol) and worsening shortness of breath.
SARS-CoV-2 IgG-IgM test kit yields a sensitivity of 85.6% and specificity of 91%. PPV was 95.1%, NPV 82.7% and accuracy was 88.3% in one study. Accuracy in mild/common and severe/critical subgroup were 73.9% and 97.7%.
The high sensitivity and specificity, ease of use of the IgG/IgM kits plus short turnaround time and no specific requirements for additional equipment or skilled technicians collectively contributed to its competence for mass testing. It cannot take the place of SARS-CoV-2 nucleic acid RT-PCR which is currently avaialble but can be served as a complementary option for the RT-PCR testing and combination of the two tests could provide insight into SARS-CoV 2 infection diagnosis.
The anti-nucleocapsid-protein IgM started on day 7 and positive rate peaked on day 28, while that of IgG was on day 10. IgM and IgG appear earlier, and their titers are significantly higher in severe patients than non-severe patients.
SARS-CoV-2 IgG antibody tended to be higher in female patients compared to males. Most of the female patients generated a high level of the IgG antibody in severe status. In addition, the generation of IgG antibody in female tended to be stronger than male patients in disease early phase. Therefore the SARS-CoV-2 IgG antibody generation in male and female patients may account for the different outcomes of COVID-19 between gender.
Hopefully we will have the rapid IgG/IgM testing available to SJPP physicians at Providence St John soon and can start testing healthcare workers, prior sick patients and symptoamtic patients and ideally be able to recommend more directed self quarantine, similar to what was done in South Korea which flattended their curve the earliest.
C-reactive Protein measurements was found to be elevated in 73% of patients. Progression to acute respiratory distress syndrome (ARDS) was the most common complication of patients testing positive for COVID-19 (33%). CT images displayed ground-glass opafication pattern (80%) as well as bilateral lung involvement (71%). Development of ARDS may play a role in estimating disease progression and mortality risk. Early detection of elevations in serum CRP, combined with a clinical COVID-19 symptom presentation (especially fever) may be used as a surrogate marker for presence and severity of disease. Clinially, we can use CRP in symptomatic patients to decide as one of the markers for hospitalization and recovery of the patient.
IL-6: Levels of serum IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. Elevated IL-6 was strongly associated with the need tor mechanical ventilation. In addition, the maximal IL-6 for each patient during disease, predicted respiratory failure with high accuracy. This indicates in the current, overwhelmed intensive care units, IL-6 is an effective marker that might be able to predict upcoming respiratory failure with high accuracy and help physicians correctly allocate patients at an early stage. Anti-IL-6 tocilizumab (Actemra) maybe beneficial and be efficacious and safe in preleminary investigation. Tocilizumab has also been shown to successfully treat COVID-19 in patients with Myeloma as well as a study of 20 critically ill COVID-19 patients in China who were treated in February and have now fully recovered.
Update on Angiotensin receptor blockers and ACE inhibitors (ARBs and ACEIs): ACEI and ARB usage is associated with improved inflammatory status and clinical outcomes in COVID-19 Patients with Hypertension: patients on ARBs/ACEs have had significantly lower concentration of CRP and procalcitonin, marker for pneumonia and inflammation than patients who are not on these meds. There has also been lower proportion of critical patients and a lower death rate (4.7% vs 13.3%) observed in ARBs/ACEs group than non-ARBs/ACEs group but the differences failed to reach statistical difference. What these teaches us is to NOT take patients off of these drugs as of now and also not to switch patients to these drugs yet. Use your clinical judgment for management of hypertension and do not use management of COVID-19 as a reason to start or stop ARB or ACEI.
Possible promising treatment with hrsARB2: "A University of British Columbia investigator led an international team that has discovered an experimental drug that effectively blocks the cellular door to SARS-CoV-2 used to infect its hosts (humans). The team points out that ACE2 is identified as a key receptor for SARS-CoV-2 infections, and hence the possibility of inhibiting this interaction could be used to treat patients with COVID-19. The team’s study reveals that clinical grade human recombinant soluble ACE2 (hrsACE2) reduces SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. They highlight an equivalent mouse rsACE2 had no effect. Based on this and other findings, the team declared that hrsACE2 can materially block early stages of SARS-CoV-2 infections."
QT Prolongation in hydroxychloroquine/azhithromycin protocol: QTc prolonged maximally from baseline between days 3 and 4. in 30% of patients QTc increased by greater than 40ms. in 11% of patients, QTc increased >500 ms, representing high risk group for arrhythmia. Development of acute renal failure, not baseline QTc was a strong predictor of extreme QTc prolongation.
Viral Shedding: The medial duration of SARS-CoV-2 RNA shedding was 12 days in nasopharyngeal swabs, 19 days in sputum and 18 days in stools. Only 5.6% of urine and 5.7% of plasma were viral positive. Prolonged viral shedding was observed in severe patients than that of non-severe patients. Cough but not Fever aligned with viral shedding in clinical respiratory specimens, meanwhile the positive stool-RNA appeared to align with the proportion who concurrently had cough and sputum production but not diarrhea. Stronger antibody response was associated with delayed viral clearance and disease severity.
Convalescent Plasma: is a technology that was used to some degree in a form in 1918 for the Spanish Influenza. In a study where 10 severe patients confirmed by real-time viral RNA received 200 ml of convalescent plasma (CP) derived from recently recovered donors with the neuralizing antibody titres above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. After convalescent plasma transfusion, the level of neutralizing antibody increased oxygen saturation within 3 days. Several parameters tended to improve as compared to pre-transfusion, including increased white blood cell count and decreased CRP. Radiological examinations showed varying degrees of absorption of lung lesions within 7 days. The viral load was undetectable after transfusion in 7 patients who had previously high viral load in their blood. No severe adverse effects were observed. Even though convalescent plasma from one person can treat one sick person, it can also be used to immunize up 60 people for at least short term which can be used for healthcare workers on the frontline.
Amplifying Monoclonal antibodies as well as preparations generated in certain animal hosts, such as genetically engineered cows that produce human antibody are also in the works and might be available by summer.
Even though we need to continue to practice social distancing, wash our hands and avoid touching our face, maybe helped by wearing a mask or something to cover out mouth while outside and keep at least 6 feet between us and our fellow walkers, we need to eat right and help populate good gut bacteria, aka our best line of defense and immune system, also to limit alcohol intake to 1 drinks per night and to continue to try to get 7-8 hours of sleep to keep our Natural killer cells up and practice daily meditation or gratitude, all practices that have shown to help our immune system fight optimally and reduce risk of viral and bacterial infections. This is now a community spread infection and unfortunately as time goes by, you or a loved one might be infected with SARS CoV 2. If you have symptoms of persistent fever, loss of sense of smell and taste and shortness of breath, contact your primary care physician who most likely will be offering a Telemedicine visit to guide you regarding further testing and management of your symptoms.
Stay healthy and live with passion,
Pouya Shafipour, MD