How Do Clinical Characteristics of COVID-19 Infection Differ Between Symptomatic and Asymptomatic Patients?
BACKGROUND AND PURPOSE:
Yang et al. (JAMA Netw Open., 2020) describe clinical characteristics of both symptomatic and asymptomatic patients with confirmed SARS-CoV-2 infection
METHODS:
Case series (December 24, 2019, to February 24, 2020)
Setting
Wuhan, China
Participants
Consecutive hospitalized cases with lab confirmed COVID-19
Recruited from 26 cluster cases who had
Confirmed history of exposure to the Hunan seafood market or
Close contact with another patient who had been hospitalized for COVID-19
Study design
RT-PCR on nasopharyngeal swabs was performed every 24 to 48 hours
CT scan: On admission with a second chest CT at 4 to 6 days and third CT at 6 to 7 days after the second scan
Additional CT for worsening status
CD4+T lymphocyte count was tested every 5 to 6 days
RESULTS:
78 patients
Median (IQR) number of patients per cluster: 3 (2-3) patients
Range: 2 to 10 patients per cluster
Symptomatic vs asymptomatic
Symptomatic cases: 57.7% of cases (45 patients)
Asymptomatic: 42.3% of cases (33 patients)
Patients who were asymptomatic tended to
Be younger (P < 0.001)
Asymptomatic: median (IQR) age 37 (26 to 45) years
Symptomatic: 56 (34 to 63) years
Be women (P = 0.002)
Asymptomatic: 66.7% were women (22 patients)
Symptomatic: 31.0% were women (14 patients)
Not have biochemical evidence of liver injury (P = 0.03)
Asymptomatic: 3% had a liver injury (1 patient)
Symptomatic: 20.0% had a liver injury (9 patients)
Have higher CD4+T lymphocyte counts (P = 0.001)
Asymptomatic: median (IQR) 719 (538 to 963) per uL
Symptomatic: 474 (354 to 811) per ul
Have faster lung recovery based on CT scan (P = 0.001)
Asymptomatic: median (IQR) duration 9 (6 to 18) days
Symptomatic: 15 (11 to 18) days
Have a shorter duration of viral shedding on nasopharyngeal swabs (P = 0.001)
Asymptomatic: median (IQR) duration 8 (3 to 12) days
Symptomatic: 19 (16 to 24) days
Have more stable SARS-CoV-2 testing results
Asymptomatic: 12.1% had fluctuated results (4 patients)
Symptomatic: 33.3% had fluctuated results (15 patients)
CONCLUSION:
Compared to symptomatic COVID-19 patients, asymptomatic patients experienced less organ injury and CT scans improved more rapidly
Consumption of CD4 lymphocytes was lower, suggesting less damage to the immune system
Asymptomatic patients appear to have a shorter duration of viral shedding, suggesting that they may be infectious for a shorter period of time
Cord prolapse (was induced for worsening respiratory status): 1 patient
Vaginal delivery: 1 patient
CONCLUSION:
2 patients (1 pregnant, 1 postpartum) hospitalized with COVID-19 died following ICU admission
15% of patients admitted to ICU and 25% of patients on mechanical ventilation
The authors state
…pregnant and postpartum women admitted to the ICU with COVID-19 are at risk for maternal death, which may occur even in the absence of significant baseline comorbidities
Is There a ‘Preeclampsia-Like’ Syndrome in Pregnant Women with COVID-19?
PURPOSE:
There is overlapping symptomatology between preeclampsia (PE) and COVID-19 including liver injury and coagulopathy
Being able to differentiate between the two could have significant implications for clinical care as PE with severe features usually requires delivery
Mendoza et al. (BJOG, 2020) sought to investigate pregnancies with COVID-19 and determine, based on clinical, ultrasound and biochemical findings if patients with true PE vs ‘PE-like’ features could be distinguished
METHODS:
Prospective observational study
Tertiary referral hospital
Participants
Singleton pregnancies
Confirmed or suspected COVID-19
>20w0d gestation
Classified in to two groups: Severe vs nonsevere COVID-19, based on presence of severe pneumonia
Aside from clinical outcomes, the following ultrasound and biochemical parameters were also assessed in patients with suspected PE
“UtAPI >95th centile for gestational age, and sFlt-1/PlGF values ≥85 (at <34 weeks) or ≥110 (at ≥34 weeks) were considered highly suggestive of underlying placental disease”
RESULTS:
42 consecutive pregnancies were recruited
Nonsevere: 34
Severe (requiring ICU admission): 8
Clinical course of severe group
Prior to onset of severe pneumonia, all 8 women were normotensive and only 1 patient had elevated UtAPI
Median age of severe cases (39.4 years) were significantly higher than nonsevere (30.9 years); p=0.006
Following severe pneumonia onset, 6 women (14.3% of total cohort) met PE criteria including
New onset hypertension and proteinuria and/or thrombocytopenia and/or elevated liver enzymes
No cases met diagnostic criteria in the nonsevere group
All required antihypertensive medication
Only 1 patient had abnormal LDH level >600 UI/L, sFlt-1/PlGF, and UtAPI
4 cesarean births
HELLP syndrome (1 case)
Worsening COVID-19 (3 cases)
Two cases were still pregnant after recovery from severe pneumonia
PE-like syndrome resolved in both cases
CONCLUSION:
Pregnant women with severe COVID-19 can develop a PE-like syndrome
The authors suggest that only 1 out of the 8 cases demonstrated ultrasound and biochemical features compatible with placental dysfunction
PE-like syndrome vs PE could possibly be differentiated based on these biochemical markers (sFlt-1/PlGF, LDH) and Doppler (UtAPI) features
Based on the resolution in 2 of the cases, the authors state that
PE-like syndrome might not be an indication for earlier delivery in itself since it might not be a placental complication and could resolve spontaneously after recovery from severe pneumonia.
The ‘Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial’ is a national program in the UK to study multiple potential therapies for SARS-CoV-2 infection. The program involves thousands of doctors, nurses, pharmacists, and research personnel. The dexamethasone branch of the RECOVERY Trial program was halted on June 8th because the steering committee felt there was sufficient evidence to make a determination whether there was benefit to this therapy. The chief investigators, Professors Horby and Landray, reported the findings on June 16, 2020.
The preliminary results found that
Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001)
Methods
Randomized controlled trial (RCT)
Participants
Patients hospitalized with COVID-19
Randomization
Dexamethasone 6 mg daily (oral or IV) vs usual care alone
Primary Outcomes
Within 28 days after randomization: Death | Discharge | Need for ventilation | Need for renal replacement therapy
Additional data collected
Age | Sex | Major co-morbidity | Pregnancy | COVID-19 onset date and severity
Results
Dexamethasone group: 2104 patients | Usual care alone: 4321 patients
Usual care group
28-day mortality rates
Requiring ventilation: 41%
Oxygen only: 25%
No respiratory intervention: 13%
Dexamethasone group: Reduction in deaths vs usual care alone
Requiring ventilation: Rate ratio (RR) 0.65 (95% CI, 0.48 to 0.88]; p=0.0003)
Oxygen only: RR 0.80 (95% CI, 0.67 to 0.96; p=0.0021)
No respiratory intervention: RR 1.22 (95% CI, 0.86 to 1.75; p=0.14)
Need to treat
Ventilated patients: 1 death would be prevented by treatment of approximately 8 patients
Oxygen alone: 1 death prevented by treatment of approximately 25 patients
KEY POINTS:
Reduction in deaths for hospitalized patients with COVID-19 with the use of low dose dexamethasone
Reduced deaths by one-third in ventilated patients
Reduced deaths by 20% for oxygen only patients
No benefit for patients not requiring respiratory support
Full report will be published
Professor Hornsby, one of the chief investigators states that
…dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide
FDA Revokes Hydroxychloroquine and Chloroquine EUA for the Treatment of COVID-19
SUMMARY:
The FDA has revoked the Emergency Use Authorization (EUA) for chloroquine phosphate and hydroxychloroquine sulfate. Based on the available data, these medications do not appear to be effective in the treatment of COVID-19 and also present harms, specifically related to cardiac arrhythmias.
An EUA is different than a full FDA approval
EUA based on an FDA evaluation of evidence and risks vs potential or known benefits of “unproven” products during an emergency
Chloroquine phosphate and hydroxychloroquine sulfate, donated to the Strategic National Stockpile, received an EUA to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible
Based on benefits/harms analysis, these medications no longer meet the EUA requirements
KEY POINTS:
Research has demonstrated the following regarding hydroxychloroquine and chloroquine (see ‘Related ObG Entries’ below)
Hydroxychloroquine showed no benefit on mortality or in speeding recovery (RCT)
Suggested dosing regimens for chloroquine and hydroxychloroquine are unlikely to kill or inhibit the virus that causes COVID-19
“The totality of scientific evidence currently available indicate a lack of benefit”
FDA approved use of chloroquine and hydroxychloroquine
Still both FDA-approved to treat or prevent malaria
Hydroxychloroquine is also approved to treat autoimmune conditions such as chronic discoid lupus erythematosus, systemic lupus erythematosus in adults, and rheumatoid arthritis
Note: “FDA approved products may be prescribed by physicians for off-label uses if they determine it is appropriate for treating their patients, including during COVID”
Possible Drug Interaction with Remdesivir
The FDA also released a warning regarding a potential drug interaction between remdesivir and chloroquine and hydroxychloroquine
Data derived from a non-clinical laboratory study demonstrated possible reduction in the antiviral activity of remdesivir activity when co-administered with these medications
The FDA is not currently aware of reduced activity in the clinical setting and continues to evaluate data on this subject
Neonatal Infection: COVID-19 and Risk for Vertical Transmission
PURPOSE:
Walker et al. (BJOG, 2020) sought to investigate the risk for vertical transmission in women with COVID-19 around the time of delivery
A systematic analysis was performed, including an effort to address duplicate reporting in previous studies
METHODS:
Systematic review and critical analysis (Search from April through May, 2020)
Authors sought out full text copies of any studies that may be eligible for inclusion
Eligibility criteria for studies
Pregnant women with confirmed (positive test or high clinical suspicion) COVID-19
Case reports or case series | No language restriction
Rates of infection were determined for the following
Mode of birth (cesarean or vaginal)
Breast or formula feeding
Rooming in or isolation
Studies underwent disambiguation to avoid duplication of patients among different reports
RESULTS:
49 studies included
666 neonates | 655 pregnant women
11 twins
Infected neonates: 4%
Duplicate pregnancies (in Chinese data) were identified and were properly accounted for in subsequent analyses
Mode of Delivery
Neonatal infection rates based on mode of delivery
Vaginal delivery: 2.7%
Cesarean: 5.3%
Breast vs Formula Feeding
Among neonates with confirmed COVID-19
Breast fed: 7
Formula: 3
Expressed breast milk: 1
Unreported: 17
Rooming In vs Isolation
Among neonates with confirmed COVID-19
Isolated: 7
Rooming in: 5
Not reported: 16
CONCLUSION:
Overall, there was a low rate of neonatal infection following maternal COVID-19 infection
There does not appear to be a greater risk for vertical SARS-CoV-2 transmission based on mode of delivery, breast feeding or rooming in
The authors acknowledge limitations including
Not all newborns tested for SARS-CoV-2
Case series have possibility of bias | More severe cases are more likely to be reported
“…disappointing that details of outcome and care” were not available and should be considered a “missed opportunity”
Due to low newborn infection rate, ‘n’ of infected neonates is still relatively small and appropriate caution should be used in interpreting the data
The authors conclude that
There is no evidence that isolating the baby away from the mother is beneficial if such precautions are taken, and encouraging the baby to spend time with its mother is likely to help with breastfeeding and bonding
We recommend that separation only occurs where this is necessary for clinical indications
Do Warmer Temperatures Decrease the Incidence of COVID-19?
BACKGROUND AND PURPOSE:
Sehra et al. (Clinical Infectious Diseases, 2020) investigated the effects of temperature, precipitation, and UV Light on community transmission of SARS-CoV-2
METHODS:
Observational analysis of case data
Data analyzed (January 22 to April 3, 2020)
Daily reported cases of SARS-CoV-2 and daily weather patterns across the US
Analysis
Null hypothesis: There is no association between daily temperatures and COVID-19 spread
Modeling techniques were used to investigate whether daily maximum temperature, precipitation, UV Index and the SARS-CoV-2 incidence 5 days later were related
Sensitivity analyses to assess transmission lags were performed at 3 days, 7 days and 9 days
RESULTS:
974 daily observations
Max temperature of >52°F associated with a lower rate of new cases at 5 days
Incidence rate ratio (IRR) 0.85 (95% CI 0.76 to 0.96; p = 0.009)
Temperature
Temperature <52°F was inversely associated with case rate at 5 days
IRR 0.98 (95% CI 0.97 to 0.99; p = 0.001)
Modeling results: Rate of new cases was lower for theoretical states where daily temperature remained >52°F
At this temperature threshold, modeling predicted that there would be 23-fewer cases per-million per-day by 25 days of the epidemic
UV Index
A 1-unit higher UV index associated with a lower rate at 5 days
IRR 0.97(95% CI 0.95 to 0.99; p = 0.004)
Precipitation
Precipitation was not associated with a greater rate of cases at 5 days
IRR 0.98 (95% CI 0.89 to 1.08; p = 0.65)
CONCLUSION:
COVID-19 incidence was lower at warmer vs cooler temperatures
Incidence declined with increasing temperature until 52°F
The authors state that while statistically significant, the actual association is small and therefore
…unlikely to provide significant effect beyond current strategies for mitigation
…although there is an association between daily temperature and subsequent case volume the disease may continue to spread in the United States even in periods of warmer weather
Remdesivir RCT Results: 5 or 10 Day Treatment for Severe COVID-19?
BACKGROUND AND PURPOSE:
Remdesivir is an RNA polymerase inhibitor that has antiviral activity against RNA viruses, possibly including SARS-CoV-2
Goldman et al. (NEJM, 2020) sought to evaluate the efficacy and safety of a 5-day vs 10-day course of remdesivir for the treatment of severe COVID-19
METHODS:
Randomized, open-label, phase III clinical trial (RCT)
Participants
Hospitalized COVID-19 (confirmed) patients
Oxygen saturation <94% on room air
Radiologic evidence of pneumonia
Intervention
5 days IV remdesivir
10 days IV remdesivir
Study design
Patients were randomly assigned 1:1
All patients received
200 mg of remdesivir on day 1
100 mg of remdesivir on all subsequent days
Primary outcome
Clinical status on day 1 using a 7-point ordinal scale from days 1 to 14 or until discharge | Worst score (lowest) recorded each day
Statistical analysis
400 patients (200 in each group)
>85% power to detect an odds ratio (OR) for improvement of 1.75
Two-sided significance level of 0.05
RESULTS:
397 patients began treatment
5-day group: 200 patients
Median duration of treatment: 5 days
10-day group: 197 patients
Median duration of treatment: 9 days
10-day group had significantly worse clinical status at baseline but otherwise 2 groups were demographically balanced
Primary outcome
There was no statistical difference in clinical improvement between groups at 14 days once adjusting for baseline clinical status (P=0.14)
Nor were there any differences in secondary outcomes including
Time to recovery
Proportion of patients who recovered by days 5, 7, 11 and 14
Death from any cause
The most common adverse effects (5-day vs 10-day)
Nausea: 10% vs 9%
Acute respiratory failure: 6% vs. 11%
Increased ALT: 6% vs 8%
Constipation: 7% in both groups
Discontinuation of treatment due to adverse events
4% in the 5-day group vs 10% in the 10-day group
Post hoc analysis was performed to determine if there was benefit for any subgroups
Patients who progressed to mechanical ventilation: Death by day 14
5-day group: 40%
10-day group: 17%
CONCLUSION:
There was no significant difference in patient outcomes with a 5- or 10-day course of remdesivir in patients with severe COVID-19
These results can not be extended to patients who are ventilated as most patients were not receiving respiratory support prior to receiving remdesivir
The authors note that there was no placebo arm and therefore this study could not determine the efficacy of remdesivir
The authors state
Our trial suggests that if remdesivir truly is an active agent, supplies that are likely to be limited can be conserved with shorter durations of therapy
RCT Results: Does Hydroxychloroquine Work for COVID-19 Postexposure Prophylaxis?
PURPOSE:
Boulware et al. (NEJM, 2020) sought to determine if hydroxychloroquine can be used to prevent COVID-19 in individuals who have been exposed to SARS-CoV-2
Side effects where higher in the hydroxychloroquine group, although no severe side effects were reported
Hydroxychloroquine: 40.1%
Placebo: 16.8%
CONCLUSION:
The trial was stopped during interim analysis due to futility, with no significant difference between groups
The authors concluded
High doses of hydroxychloroquine did not prevent illness compatible with Covid-19 when initiated within 4 days after a high-risk or moderate-risk exposure
Is Blood Viscosity Greater in Patients with Severe COVID-19?
PURPOSE:
Coagulation disorders and thrombosis are recognized COVID-19 complications, particularly for patients with severe disease
Maier et al. (Lancet, 2020) found evidence for multiple anticoagulation failures at their institution among patients with severe COVID-19
Therefore, the authors sought to identify other mechanisms to explain ‘refractory hypercoagulability’ (i.e. when prophylactic/ therapeutic dosing of medications such as heparin do not prevent significant VTE)
METHODS:
Case series
Participants
COVID-19 pneumonia, critically ill and admitted to the ICU
Testing
Capillary viscometry which tests for plasma viscosity
RESULTS:
15 patients included
Intubation for ARDS: 14 patients
Shock requiring vasopressors: 12 patients
Renal failure (on renal replacement therapy): 11 patients
Anticoagulation
D-dimer ≥3 μg/mL
Clinical concern for thrombotic event: 5 patients received therapeutic anticoagulation | 2 patients received IV heparin and 3 patients received direct thrombin inhibitor (argatroban or bivalirudin)
No clinical concern for thrombotic event: 6 patients received intermediate dosing (subtherapeutic) of LMWH or IV heparin
D-dimer <3 μg/mL: 4 patients received low dose thromboprophylaxis with LMWH or subcutaneous heparin
Viscosity Testing Results
All patients had plasma viscosity measurements >95% normal
1.9 to 4.2 centipoise | Normal range 1.4 to 1.8
4 patients >3.5 centipoise had thrombotic events
PE | limb ischemia and PE | Renal treatment related clotting (2 patients)
Centipoise levels were highly correlated with disease severity (p<0.001)
Fibrinogen Levels
Fibrinogen results significantly elevated
Median fibrinogen: 708 mg/dL (range 459 to 1188) | Normal reference range 200 to 393
CONCLUSION:
Hyperviscous plasma can damage endothelium and lead to thrombosis
Patients with severe COVID-19 had significantly increased plasma viscosity compared to normal range
Plasma viscosity was highly correlated with disease severity
Cellular components associated with inflammation (e.g. fibrinogen or immunoglobulin) can lead to increased viscosity
The authors conclude that
Our novel observation might provide an important link between inflammation and coagulopathy in critically ill patients with COVID-19
We are actively exploring any beneficial role of therapeutic plasma exchange, a highly effective treatment for symptomatic hyperviscosity in other conditions such as hypergammaglobulinaemia, in the clinical management of these patients
Shanes et al. (American Journal of Clinical Pathology) sought to identify placental pathology associated with COVID-19 infection
METHODS:
Case control study
Histologic evaluation of the placenta was performed
Cases: Placentas from pregnant women with confirmed SARS-CoV-2 infection who delivered between March 18, 2020 and May 5, 2020
Historical controls
Placental samples derived from women who had placental evaluation for maternal/fetal indications (e.g, FGR, chorioamnionitis)
History of melanoma | Considered a superior control because evaluation would be performed for potential metastases rather than possible confounding indication (e.g. SGA)
Prior to April 7, only patients with moderate to severe disease were tested | Following this date, all women admitted to labor and delivery underwent testing
RESULTS:
16 placentas from women with COVID-19 were evaluated
Gestational Age at delivery
Term deliveries (37 to 40 weeks): 14
34 week delivery: 1
16 week IUFD: 1
Placental size
SGA: 5
LGA: 1
Indication for placental exam
SARS-CoV-2: 13
Cholestasis in pregnancy and GDM: 1
Pregnancy-induced hypertension: 1
IUFD (above): 1
Timing of COVID-19 diagnosis
Remote from delivery (25 to 34 weeks): 4
6 to 7 days prior to delivery: 2
At time of admission for delivery: 10
Clinical COVID-19 course
Symptomatic: 10 patients
Oxygen requirement: 2
Maternal deaths or requiring intubation: 0
All infants had normal Apgar scores and discharged home except for 34 week delivery who was still in NICU
16 week IUFD: Retroplacental hematoma | Removed from analysis of placental findings because controls were all from 3rd trimester deliveries
Placental Findings
Placentas from COVID-19 pregnancies were more likely to have ≥1 feature of maternal vascular malperfusion (MVM) compared to
Melanoma controls: Odds ratio (OR) 7.3 (P = .001)
Other historical controls: OR 3.4 ( P = .046)
Individual MVM features were more likely be found in COVID-19 pregnancies
Decidual arteriopathy vs both control groups
Atherosis and fibrinoid necrosis vs both groups
Peripheral villous infarction vs melanoma group
Features of fetal malperfusion (FVM) were also more common in the COVID-19 placentas vs both control groups such as delayed villous maturation
Findings associated with acute and chronic inflammation were not increased
CONCLUSION:
MVM reflects abnormalities in oxygenation within the intervillous space and is associated with adverse perinatal outcomes, including hypertensive disorders and preeclampsia
Despite MVM findings, only 1 patient with COVID-19 had hypertension
The authors conclude that the changes found in the placentas from pregnant women with COVID-19
…may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology
…these findings suggest that increased antenatal surveillance for women diagnosed with SARS-CoV-2 may be warranted
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