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
Respiratory Support of Pregnant Women with COVID-19 Including Fetal Assessment Recommendations
SUMMARY:
Although overall respiratory management is similar for pregnant women with COVID-19 compared to the general population, there are certain issues that are unique to this group. In addition, fetal wellbeing needs to be taken into consideration. This expert review by Pacheco et al. (Green Journal, 2020) provides key management points for treating patients with COVID-19 related respiratory compromise during pregnancy.
Management Algorithm
Pregnant Patient with Confirmed or Suspected COVID-19 and SpO2 <94%
Initial management
Conventional O2 therapy*: Target range 94% to 96%
Consider self-awake prone position
Limit fluids
Ensure airway expert is aware of patient
If patient not improving using conventional oxygen delivery methods
Reduce flow 5 to 10 L/min every 4 to 6 hours when an FiO2 of 0.4 to 0.5 is reached
Target SpO2 level >94%
If patient still does not improve
Consider intubation and invasive mechanical ventilation
*Conventional Oxygen Delivery Methods
Conventional Nasal Cannula
O2 flow: 1 to 6 L/min
O2 concentration: 24% to 40%
Conventional face mask
O2 flow: Set between 5 and 10 L/min
O2 concentration: Typically 40%
Venturi mask
Same as conventional face mask, but operator has more control over FiO2
Partial rebreather mask
Set O2 flow ≥10 L/min
O2 concentration: 60% to 70%
Nonrebreather mask
Set O2 flow ≥10 L/min
O2 concentration: 80%
**Requirements for high-flow nasal cannula
Ensure patient is
Hemodynamically stable with normal mental status
Can protect her own airway: Clear own secretions and good cough reflex
KEY POINTS:
Fetal Assessment for Patients with COVID-19 Respiratory Failure
<23 to 24 weeks
Fetal monitoring is not recommended
Stable and on conventional oxygen delivery system or high-flow nasal cannula
>24 weeks: Daily NST
Mechanical ventilatory support
24 to 28 weeks: Individualize based on multiple clinical factors including EFW, NICU support, maternal body habitus and availability of PPE
>28 weeks: Continuous monitoring
If patient’s respiratory status is deteriorating
Especially >28 weeks, the authors recommend:
…proceeding with a controlled delivery (likely cesarean) instead of awaiting fetal distress from refractory hypoxemia and needing an emergent delivery in the intensive care unit
Note: Authors caution that it is still important to weigh risks and benefits of fetal monitoring due to the significant risks associated with emergency cesarean delivery in patients with impaired respiratory function | Delivery “does not improve respiratory status of patients with acute respiratory failure” although authors acknowledge that this statement is based on limited evidence
NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date. This entry has been updated with additional information on counseling patients working in a non-healthcare setting.
SUMMARY:
ACOG has released FAQs that address common questions faced by obstetrical care professionals. The recommendations in this document reinforce CDC guidance and clarify some issues specific to obstetrics. Below are highlighted FAQs from the document (please see ‘Learn More – Primary Sources’ below for link to complete document)
Wear a mask or cloth face covering in public and when around people outside of the household
ACOG recommends the above particularly when social distancing may not be doable
Fully vaccinated
Follow CDC guidance | However, some pregnant women may wish to continue using masks and should be supported
Healthcare settings, schools, public transport
Regardless of vaccine status, precautions including mask or cloth face covering should be used
CDC specifies cloth vs surgical masks or respirators, which should be reserved for healthcare personnel
Health Care Professionals (CDC Guidance)
Source control options (prevent spread of respiratory secretions when breathing, talking, sneezing or coughing) for HCP include
NIOSH-approved N95 or equivalent or higher-level respirator or
A respirator approved under standards used in other countries that are similar to NIOSH-approved N95 filtering facepiece respirators (note: these should not be used instead of a NIOSH-approved respirator when respiratory protection is indicated) or
A well-fitting facemask
When used solely for source control, any of the options listed above could be used for an entire shift unless they become soiled, damaged, or hard to breathe through
If masks used for protective equipment (PPE) (e.g., NIOSH-approved N95 or equivalent or higher-level respirator during the care of a patient with SARS-CoV-2 infection, facemask during a surgical procedure or during care of a patient on Droplet Precautions) then discard after the patient care encounter
Healthcare providers should use PPE, including respirators or face masks, goggles, gowns and gloves | N95 respirators should be used for aerosol-generating procedures
ACOG states that “COVID-19 infection is highly contagious, and this must be taken into consideration when planning intrapartum care”
KEY POINTS:
Clinical Guidelines that Remain Unchanged
Continue to Manage According to Current Clinical Guidance
Timing of delivery
COVID-19 should generally not impact timing of delivery
Exception: If a woman is infected in the third trimester and there are no medical indications to the contrary, “it is reasonable” to try and postpone delivery until there is a negative test result or quarantine lifted
Induction of labor
Operative delivery
Mode of delivery
Delayed cord clamping
Antenatal fetal testing
Antenatal fetal surveillance
Detailed mid-trimester anatomy scan “may be considered” after pre-pregnancy or first-trimester maternal infection
Interval growth assessments “could be considered depending on the timing and severity of infection”
Timing and frequency of ultrasound should take in to account clinical setting and additional maternal risk factors
Detailed mid-trimester anatomy scan “may be considered” after pre-pregnancy or first-trimester maternal infection
Interval growth assessments “could be considered depending on the timing and severity of infection”
Timing and frequency of ultrasound should take in to account clinical setting and additional maternal risk factors
Anti-SARS-CoV-2 Monoclonal Antibodies
Monoclonal antibodies are recommended by the NIH for use in the following clinical scenarios (see ‘Related ObG Topics’ below for NIH COVID Treatment Guidelines)
For patients with mild to moderate COVID-19 who are at high risk of clinical progression
Start treatment as soon as possible after positive SARS-CoV-2 antigen or NAAT report becomes available and within 10 days of symptom onset
Post-exposure prophylaxis (PEP) should be considered for inadequately vaccinated individuals who have been exposed to SARS-CoV-2
These individuals include those who have had a recent exposure to an individual with SARS-CoV-2 for a cumulative total of ≥15 minutes over a 24-hour period or
There is a recent occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting AND are 1) not fully vaccinated or 2) fully vaccinated but may not mount an adequate immune response
The NIH specifically addresses use of PEP in pregnancy and states
PEP should not be withheld from pregnant or lactating individuals who have been exposed to SARS-CoV-2, especially those with additional conditions that increase their risk of progressing to severe disease
Pregnant or lactating patients and their providers should determine whether the potential benefits of the drugs outweigh the potential risks
ACOG supports the use of monoclonal antibodies in both clinical scenarios (risk for progression or PEP) and states the following
Pregnancy is included among the conditions that put individuals at high risk for clinical progression
This makes patients with pregnancy as their only risk factor eligible to receive outpatient monoclonal antibodies, according to the EUA (NIH)
Obstetric care clinicians may consider the use of monoclonal antibodies for the treatment of non-hospitalized COVID-19 positive pregnant individuals with mild to moderate symptoms, particularly if one or more additional risk factors are present (eg BMI >25, chronic kidney disease, diabetes mellitus, cardiovascular disease)
Lactation is not a contraindication for the use of monoclonal antibodies
Note: Some monoclonal antibodies that were effective against previous variants have limited effectiveness against Omicron variant and therefore ACOG recommends “physicians should consult their facilities as to which monoclonal antibody therapies against SARS-CoV-2 infection are available for treatment options”
SARS-CoV-2 Protease Inhibitors in Pregnancy
PAXLOVID
Oral medication
Includes nirmatrelvir (SARS-CoV-2 main protease inhibitor) and ritonavir (HIV-1 protease inhibitor and CYP3A inhibitor)
Available only under emergency use authorization (EUA)
Recommended for the treatment of outpatients with mild to moderate COVID-19 infection who
Have a positive SARS-CoV-2 viral test
Are at higher risk of clinical progression
Pregnancy
Pregnancy is a risk factor for clinical progression and therefore meets criteria for use of medication use, particularly if other high risk factors are pregnant (e.g., diabetes)
Lactation
Breastfeeding is not a contraindication to use and can be used as indicated in this population
Dosage
Start as soon as possible following diagnosis and within 5 days of symptoms
The dose for patients with normal renal function is nirmatrelvir 300 mg (two 150 mg tablets) plus ritonavir 100 mg (one 100 mg tablet) orally twice daily for 5 days
Note: There is risk for drug interactions including mediations used in pregnancy (e.g., nifedipine) | ACOG recommends that “Prescribing clinicians should consult the full prescribing information prior to and during treatment for potential drug interactions”
Fetal Risks
Nirmatrelvir
Human study data
None available but observational data has not demonstrated increased risk for birth defects
Animal studies
Reduced fetal body weights noted among pregnant rabbits at doses 10 times higher than comparable typical human exposure
Ritonavir
Used commonly for management of HIV during pregnancy, suggesting acceptable safety profile
Note: ACOG states that “short-term exposure to these medications must be balanced against the maternal and fetal risks associated with untreated COVID-19 in pregnancy”
PPH: Use of TXA and Hemabate
TXA
COVID-19 appears to be a hypercoagulable state
TXA can be considered for the treatment of PPH in keeping with guidance for non-COVID-19 patients
However, the document states
Because of the possible additive effect of the increased risk of thrombosis from COVID-19 infection and the hypercoagulative state of pregnancy, it may be prudent to consider this increased likelihood of clotting before adminisitering TXA for postpartum hemorrhage
Hemabate
While Hemabate is not used in asthma due to risk for bronchospasm, patients with COVID-19 have respiratory symptoms consistent with viral pneumonia
While there is no data specific to COVID-19 and this medication, “Hemabate is not generally withheld” in patients with viral pneumonia
Visitation Policies During COVID-19
Visitation policy decisions are ultimately guided by
Local facilities and capabilities (e.g., physical space, equipment)
Community spread and prevalence
Governmental regulations and recommendations at multiple levels
ACOG recommends that for both inpatient and outpatient
Reduce number of visitors to minimum necessary
Limit to those individuals “essential for the pregnant individual’s well-being (emotional support persons)”
Screen all visitors for symptoms of respiratory illness
Patient should be attended to by an asymptomatic visitor
A visitor with fever or respiratory symptoms should not accompany the patient
Additional support persons
Encourage the use of alternative forms of interaction (e.g., video-call apps)
Counseling patients and families regarding restrictive visitation policies
Acknowledge value of support persons
Explain the temporary nature of the policies and that they are in place to protect everyone’s safety, including the patient, baby and community at large
Special considerations for underserved communities
Support systems including support persons are especially important throughout the delivery journey, including postpartum care
ACOG states that
…institutions should be mindful of how restrictions might differentially and negatively affect these communities, which in many areas are also disproportionately affected by COVID-19
NOTE:Guidance has been updated to include the latest ACOG statement regarding gyn patient prioritization. Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date.
SUMMARY:
ACOG has released FAQs that address common questions faced by those healthcare professionals providing gynecologic care. The recommendations in this document reinforce CDC guidance and clarify some issues specific to gynecology. Below are highlighted FAQs from the document (please see ‘Learn More – Primary Sources’ below for link to complete document). ACOG states that
Determining how best to care for patients given the COVID-19 pandemic depends on the patient’s signs and symptoms, the patient’s comorbidities and underlying medical condition, the acuity of the presentation (eg, acute versus chronic condition), available health resources, and other factors
Change in practice prioritization is based on resource reduction resulting from the current COVID-19 pandemic
ACOG provides examples (“list is not meant to be exhaustive”)
In-person appointment
Fever risk for gyn infection
Ectopic
Post-op complications not suitable for phone
Heavy vaginal bleeding with signs/symptoms suggestive of anemia
By telehealth (includes virtual visit or phone)
Contraceptive management
Asymptomatic ovarian cyst
Menopause management
Routine gyn or post-op care
Routine medication abortion care
Mental or behavioral health screening
“May potentially” defer till after COVID-19
Preventive visits
Routine screenings for average-risk patients
Patient Prioritization: GYN Surgeries
ACOG emphasizes that decisions related to surgical triage should be based on disease severity, not necessarily a particular surgical procedure
ACOG along with multiple other gynecology societies, released a joint statement on the suspension of elective surgeries during the COVID-19 pandemic
The joint statement supports the Surgeon General’s statement to modify surgical scheduling if the patient will not be harmed by delay
If a delay will impact patient health and cause harm, the surgery should be performed as scheduled
SGO recommendations
Examples of surgeries that could be potentially delayed include
Benign-appearing ovarian cysts | Hysterectomy for menorrhagia without evidence of anemia
Surgeries for precancerous lesions or low risk for endometrial cancer (especially in healthy patients)
Examples of surgeries that should not be delayed
Most cancer surgeries
Resections of masses that will cause end-organ damage or impair quality of life
KEY POINTS:
Abortion Services
Due to its time-sensitive nature, ACOG states that “Abortion is an essential component of comprehensive health care”
Furthermore, ACOG and other gynecology societies released a joint statement supporting access to abortion services during the COVID-19 pandemic
To decrease risk of exposure and transmission, strategies include
Counsel remotely (video or phone)
Offer timely referral if practice does not provide service
If no risk factors for ectopic pregnancy and patient has regular menses with a known LMP
Assess gestational age remotely | Ultrasound not required
If uncomplicated, pre-op visit and consent can be done remotely (video or phone)
“Routine in-person or video or telephone visits are not necessary after an uncomplicated abortion procedure”
Medical abortion
Assessment, counseling, and consent can be done remotely (by video or telephone)
Mifepristone and misoprostol can be self-administered at home
Follow-up after an uncomplicated medication abortion can be done remotely (video or telephone) | In-person visit not required
Note: ACOG states “The FDA has lifted additional burdens on patients seeking access to and clinicians prescribing mifepristone for pregnancy termination and miscarriage during the COVID-19 public health emergency. As you consider changes to your clinical practice, however, please take several important factors into account. Whether you now have authority to mail mifepristone is a fact-specific, state-specific legal question. We strongly encourage any clinician seeking this relief to consult with a lawyer before making any changes to your clinical practice.”
Rh testing and RhD immunoglobulin administration
Should not be a barrier to the provision of medication abortion
Low risk of sensitization
NSAIDS
No evidence of association between NSAIDs, such as ibuprofen, and COVID-19 exacerbation | Situation may change in the future with further information
Continue to offer low-dose aspirin and other NSAIDs as medically indicated
Antibody Testing
Some institutions are testing all patients prior to procedures
Antigen testing
Remains the test of choice for diagnosis
Antibody (serologic) testing
Not diagnostic
Can be used to obtain information that may indicate prior exposure
At present, it is unclear if antibodies confer immunity
The document states that antibody testing
…should not be used as the sole basis to diagnose COVID-19, to determine staffing decisions or decisions regarding the need for personal protective equipment (PPE), or to determine if a person has immunity to COVID-19
Breast Imaging and Post-Vaccine Lymphadenopathy
COVID-19 vaccination may be associated with temporary contralateral or ipsilateral lymphadenopathy
A Radiology Scientific Expert Panel has addressed this issue, as the nodal enlargement identified on breast imaging may be difficult to distinguish from lymph node enlargement seen with malignancy
Vaccination should not be delayed due to imaging needs, including indications related to cancer or screening
“The estimated infection fatality risk of COVID-19 is orders of magnitude higher than the estimated mortality reduction achieved through effective cancer screening programs in the general population”
If possible, mammograms should be conducted prior to COVID-19 vaccination
Following vaccination and to avoid complicating interpretation of imaging results
Urgent cancer-related clinical indications (e.g., acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications): Do not delay breast imaging
All other indications (routine surveillance, screening, staging): Consider postponing imaging for ≥6 weeks after completion of recommended vaccinations
Note: The Society of Breast Imaging recommends delay of 4 to 6 weeks
Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19
SUMMARY:
While most children will be asymptomatic or exhibit mild symptoms, SARS-CoV-2 infection has been temporally associated with a syndrome now labeled by the CDC as Multisystem Inflammatory Syndrome in Children (MIS-C). It was first identified in the UK. The underlying mechanism for this severe inflammatory syndrome is not yet understood, but some speculate that the antibody following illness may be generating an overly vigorous immune response in these children and teens. MIS-C can appear weeks after initial infection. According to the CDC, “there have been very few cases of death reported in hospitalized patients”.
Key Features
Presentation is that of an inflammatory syndrome and appears to overlap with Kawasaki Disease, Toxic Shock Syndrome, bacterial sepsis and macrophage activation syndromes
Kawasaki Disease
Inflammation of blood vessels in children (including coronary arteries)
Findings include rash, conjunctivitis, and swollen hands or feet which can also be seen in Pediatric Multi-System Inflammatory Syndrome | However cardiac inflammation is greater in Pediatric Multi-System Inflammatory Syndrome and can affect teens, while Kawasaki disease is usually seen in younger children
Findings in Pediatric Multi-System Inflammatory Syndrome include
Inflammatory markers: Abnormal Fibrinogen | High CRP | High D-Dimers | High ferritin | Hypoalbuminaemia | Lymphopenia | Neutrophilia in most – normal neutrophils in some
Fever: Persistent >38.5°C
Additional presenting signs and symptoms may include
Abdominal symptoms
Rash
Myocarditis (and other cardiovascular changes)
Some children will develop cardiogenic or vasogenic shock with evidence of single or multi-organ failure
Cardiac, respiratory, renal, gastrointestinal or neurological system failure
CDC Recommendations
Case Definition for MIS-C
An individual aged <21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological) and
No alternative plausible diagnoses and
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms
Notes
*Fever: >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
**Evidence of inflammation: Including, but not limited to, one or more of the following
Elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6) | Elevated neutrophils | Reduced lymphocytes and low albumin
Even if patients fulfill full or partial criteria for Kawasaki disease, the case should still be reported if they meet the case definition for MIS-C
Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection
Evaluation
Laboratory Testing
Test for evidence of inflammation as listed above
SARS-CoV-2: RT-PCR or antigen test
Antibody testing (where feasible) | Test prior to IVIG or other antibody treatment
Baseline cardiac tests including but not limited to
Echocardiogram
Electrocardiogram
Cardiac enzyme or troponin testing (per the center’s testing standards)
B-type natriuretic peptide (BNP) or NT-proBNP
Additional testing should be guided by patient’s clinical findings
Work Up
Obtain history of any past COVID-19 like symptoms or close contact with someone who may have COVID-19
Rule out microbial cause, including
Bacterial sepsis | Staphylococcal or streptococcal shock syndromes | Infections associated with myocarditis such as enterovirus
Note: Do “not delay seeking expert advice while waiting for results of these investigations”
Requires quick recognition and referral to in-patient specialist as patient may require further intensive/critical care
Additional specialists may include those with expertise in pediatric infectious diseases, cardiology, and rheumatology
KEY POINTS:
Treatment
Treat all children with this presentation as suspected COVID-19
Blood cultures and empiric antibiotics should be started as per local sepsis protocols
No current data available for efficacy of various treatments | However, information is available in the literature based on experience of various institutions
Supportive care
Fluid resuscitation
Inotropic support
Respiratory support
ECMO (rarely)
Anti-inflammatory measures
Intravenous immunoglobulin (IVIG)
Steroids
Aspirin: Frequently used due to concern for coronary involvement | Aspirin is a mainstay for the treatment of Kawasaki Disease
Antibiotics: Routinely used to treat potential sepsis while awaiting bacterial culture
Prognosis
The RCPCH expert panel add that
Most of the children were very ill but recovered
It is a syndrome where there is a pattern to the features that leads physicians to suspect the diagnosis
Dr Sanjay Patel, consultant in pediatric infectious diseases at Southampton Children’s Hospital, recommends that if there is concern, recommendations remain to get medical help, alert the child’s physician and if necessary obtain emergency services | In addition, Dr. Patel states
It’s very important to keep this in perspective. It’s a very rare condition and because of that parents shouldn’t be alarmed. We’re talking about a really small number of cases, each of which was picked up and treated by experts in our health system. It remains extremely unlikely that a child will become unwell with COVID-19, and it’s even more unlikely that a child will become unwell with this condition.
Remdesivir Emergency Authorization: FDA Update and Summary of Preliminary NIH Study Data
NOTE:Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date
SUMMARY:
The FDA has issued an emergency use authorization (EUA) for the investigational antiviral drug remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. The approval is based on the NIH’s clinical trial showing “promising results.”
An EUA is different than a full FDA approval
An EUA is based on an FDA evaluation of evidence and risks vs potential or known benefits of of “unproven” products during an emergency
The FDA states
The emergency use authorization allows for remdesivir to be distributed in the U.S. and administered intravenously by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease
Severe disease is defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator
It was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use
KEY POINTS:
NIH Remdesivir Trial
RCT involving 1063 patients:
Adaptive COVID-19 Treatment Trial (ACTT)
Sponsored by the National Institute of Allergy and Infectious Diseases (NIAID)
Multicentered (including US, UK, and Singapore)
Started in February 2020
Current primary endpoint: Being well enough for hospital discharge or returning to normal activity level
Preliminary Data
Time to recovery
Median time to recovery: 11 days for remdesivir group vs 15 days for placebo group
31% faster time to recovery in remdesivir group vs placebo (p<0.001)
Mortality Rate
8.0% in remdesivir group vs 11.6% for the placebo group (p=0.059)
“Suggests benefit” but not statistically significant
Second (next) stage of trial
Remdesivir in combination with another agent | Likely to be a janus kinase inhibitor
One of the investigators (UK team) stated (April 30, 2020)
As far as the results are concerned, it’s cautious optimism
There is some effect but it is not a wonder effect
We have to find out when is the best time to give this drug, who benefits more
There is still a lot of data to come out of this trial
AAP Recommendations: L&D Guidance and Management of Infants Born to COVID-19 Positive Mothers
NOTE:Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date
SUMMARY:
The AAP provides guidance on clinical issues related to the newborn when a mother has confirmed or suspected COVID-19. Neonates born to women with confirmed or pending COVID-19 results at delivery should be considered as persons under investigation (PUIs) for infection. The guideline also addresses particular areas of concern to healthcare professionals, such as PPE requirements for delivery
AAP specifically addresses the aerosolization of SARS-CoV-2 viral particles during delivery and states that, in addition to gown and gloves, N95 respiratory masks or air-purifying respirators that provide eye protection should be used
Rooming-In vs Separation
Mother with confirmed or suspected COVID-19 and well newborns can room-in
Risk of newborn infection is low if proper precautions are taken
A mother who is accutely ill may not be able to care for her infant
May be appropriate to temporarily separate mother and newborn or have the newborn cared for by non-infected caregivers in mother’s room
NICU Care of Exposed Infant
Admit to single-patient room
Ideal: Potential for negative pressure or air filtration system
If negative pressure unavailable or if individual space unavailable: Space by ≥6 feet and/or use air temperature-controlled isolettes
Intubation is an aerosol-generating procedure and therefore use either an N95 respiratory mask and eye protection goggles or an air-purifying respirator that provides eye protection
Mothers and Partners Visiting the NICU
If fully vaccinated who have then had an exposure
Do not exclude unless they develop symptoms consistent with SARS-CoV-2 infection
Confirmed COVID-19
Should not visit NICU infants while able to transmit SARS-CoV-2
Immunocompetent persons may be considered non-infectious if
Afebrile for 24 hours without use of antipyretics
At least 10 days have passed since symptoms first appeared (or, in the case of asymptomatic women identified only by obstetric screening tests, at least 10 days have passed since the positive test)
Symptoms have improved
Persons who are severely or critically ill with COVID-19
Should not enter the NICU until at least 20 days have passed since symptoms first appeared or first positive test
Severely immunocompromised and infected with SARS-CoV-2
Recommend consultation with your local infectious disease specialists for specific case management
Testing Newborns Prior to Discharge
Bathe newborns after birth to remove virus that may be on skin
Timing of testing for healthy newborns: At least once before discharge
24 hours of age
Repeat at 48 hours
Procedure
Use one swab: Swab throat and then nasopharynx
If infant is positive
Test using combined throat/nasopharynx specimens every 48 to 72 hour intervals until there are 2 consecutive negative tests
KEY POINTS:
Hospital Discharge
Base discharge on a center’s normal criteria
Discharge Planning Based on Newborn Test Results
If infant can’t be tested
Treat as if positive for the virus for the 14-day observation period
Mother should maintain precautions until she meets the criteria for non-infectivity (see ‘Related ObG Topics’ below)
Positive test results
No symptoms: Plan for frequent outpatient follow-up (phone, telemedicine or in-office) through 14 days after birth
Follow CDC precautions to prevent household spread from infant to caregivers (see ‘Primary Sources – Learn More’ below)
Negative test results
Ideally, discharge to designated healthy caregiver
Mother should
Maintain ≥6 foot distance when possible
Use a mask and hand hygiene when directly caring for the infant
The above transmission precautions should be used until
she has been afebrile for 24 hours without use of antipyretics
at least 10 days have passed since her symptoms first appeared (or, in the case of asymptomatic women identified only by obstetric screening tests, at least 10 days have passed since the positive test), and
symptoms have improved.
Other caregivers in the home who are have confirmed or suspected COVID-19
Should use standard procedural masks and hand hygiene when within 6 feet of the newborn until their own status is resolved
COVID-19, ACE Inhibitors and ARBs: Professional Guidance and Evidence Update
NOTE:Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date
SUMMARY:
Coronavirus disease 2019 (COVID-19) is an infection caused by the SARS-CoV-2 virus. The virus is known to target the angiotensin converting enzyme 2 (ACE-2) co-receptor. Therefore, concern has been raised whether the use of common medications that impact ACE and the renin angiotensin system may also result in increased COVID-19 infection risk. Papers have been now been published demonstrating no increased risk with use of ACE inhibitors or angiotensin receptor blockers (ARBs).
Patients at higher risk for significant morbidity and mortality from COVID-19 infection include older patients, especially those with chronic medical conditions such as the following
Pulmonary disease
Cardiac disease
Kidney disease
Diabetes
Hypertension
It is unclear whether the above associations are independently related to pathogenesis, other associated comorbidities, or even treatment
These disorders themselves are not necessarily independent and often appear together in patients, particularly in the context of the metabolic syndrome
ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19
Angiotensin Converting Enzymes
ACE-1 and ACE-2 are two major enzymes found in the renin-angiotensin system
ACE enzymes play a critical role in the balance of peptides in the angiotensin family
ACE-2 is found on
Epithelial cells in both respiratory and GI tracts
Cardiac and kidney cells
ACE Inhibitors and ARBs
ACE inhibitors and ARBs
Strongly influence angiotensin peptides
Increase ACE-2 activity in cardiac tissue
What We Currently Know about SARS-CoV-2 Infectivity
SARS-CoV-2 is covered with crown-like glycoprotein spikes (hence ‘corona’) comprised of 2 subunits
Subunit S1: Binds to ACE-2 on the cell surface
Subunit S2: Fuses with the cell membrane
TMPRSS2 (host enzyme): Promotes cellular entry of the virus
Do ACE Inhibitors and ARBs Increase Risk for COVID-19?
ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19
Theoretical risk raised
Because ACE inhibitors and ARBs ‘may’ increase expression of ACE-2 leading to greater risk for virus to enter and infect cells, could these medication lead to increased risk for COVID-19 morbidity and/or mortality?
Possible benefit
Study from China showed that while hypertension is a risk factor for COVID-19 mortality, patients on ACE inhibitors and ARBs did better (see review in ‘Learn More – Primary Sources’ below)
Underlying mechanism is unclear, but there may be a biphasic pattern: (1) In phase 1, these medications could increase infectivity (2) In phase 2, ACE-2 downregulation by the virus may be the “hallmark” of COVID-19 progression and therefore medications that upregulate in the second phase may be of benefit
In addition, there is a hypothesis that ACE-2 also stimulates one of the angiotensin peptides (angiotensin-(1-7)) that has positive anti-inflammatory effects | Therefore, medications that stimulate ACE-2 could have a beneficial effect
Current Evidence
Zhang et al. (Circ Res, 2020)
Retrospective, multi-centered study | 1128 hospitalized patients with COVID-19 | ACE Inhibitors/ARB group: 188
After adjustment, detected risk for all-cause mortality was lower in the ACE Inhibitors/ARB group compared to the non-ACE Inhibitors/ARB group
Adjusted hazard ratio: 0.42 (95% CI, 0.19 to 0.92; p = 0.03)
These medications may be associated with a lower risk of all-cause mortality in the setting of COVID-19 compared to non-users
Reynolds et al. (NEJM, 2020)
12,594 tested | 5894 patients positive for COVID-19 | Severe in 17%
Hypertension history: 34.6% of tested patients | 59.1% were COVID-19 positive had a positive test | Severe in 24.6%
Authors conclude that there was no association with likelihood of a positive test or severity of illness
Mancia et al. (NEJM, 2020)
Population-based case–control study | 6272 patients with confirmed SARS-CoV-2 infection
Use of ARBs or ACE inhibitors did not show any association with Covid-19 overall or those with severe or fatal disease
Editorial (Jarcho et al. NEJM, 2020)
The accompanying editorial recognizes limitations inherent in observational data
However, these studies support professional guidance that recommend against altering these medications when indicated
Furthermore, the editorial authors state
Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test.
KEY POINTS:
Recommendations
Guidance is based on the current lack of evidence that ACE inhibitors or ARBs increase risk of infection or result in a more severe course of COVID-19 disease
It is acknowledged that new data may result in a future update to these guidelines
Professional recommendations do not support stopping or changing medications for patients who are currently being treated with ACE inhibitors or ARBs
In addition, cessation is associated potential for significant harms including
Medical risk: Exacerbation of underlying medical conditions
Infection risk: Due to increased pharmacy encounters, visits for blood work etc.
The HFSA/ACC/AHA recommends
…continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease
In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation
Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice
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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
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presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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