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Research

May 15, 2020: A Randomized, Open-Label Study of the Vascular and Microbiologic Efficacy of Dipyridamole Plus Standard Care vs. Standard Care in Hospitalized COVID-19 Patients

Contributor: Kevin Dieckhaus, MD
Principal Investigator: Bruce Liang, MD

Dipyridamole (DIP) is an FDA-approved drug which inhibits adenosine uptake that leads to increased extracellular adenosine which in turn stimulates adenosine receptors-mediated vasodilator, anti-platelet and anti-inflammatory effects. DIP’s effects are augmented by DIP’s inhibition of phosphodiesterase.

DIP appears to bind to the SARS-CoV-2 3c-like protease enzyme (nsp5 or Mpro) and also suppresses SARS-CoV-2 proliferation in Vero E6 cells with an IC50 ≤100 nM. This is an achievable serum concentration by standard dosing with 100 mg 3 times daily. A background study showed DIP increased platelets and lymphocyte counts and reduce d-dimer levels in patients with COVID, with a hint of possible clinical benefit but was significantly under powered.

The study intervention: DIP 100 mg 3 times daily x7 days vs. Standard of Care

Outcomes

  • Primary: Effect d-dimer and platelet counts
  • Secondary: Rate of positive PCR's by nasopharyngeal swab at days 3,6,9
  • Exploratory outcomes: Multiple clinical parameters, and lab parameters including CRP, lymphocyte count, PT, PTT, fibrinogen, and ferritin levels

Inclusion criteria: Age greater than 18, diagnosis of COVID, and written consent

  • (Unable to consent patients on ventilator)

Exclusion criteria include inability to take oral medication, pregnancy, allergy, secondary bacterial infections, bleeding disorders, severe underlying medical illnesses, certain medications or enrolled in another clinical trial.

  • Medications as exclusions: treatment-dose heparin, factor 10 inhibitors (such as warfarin), antibiotics for bacterial pneumonia (excluding Azi when given with HCQ for COVID)
  • Treatment trial exclusion: receiving convalescent plasma

Next modification (pending) will remove antibiotics and warfarin use from the exclusion criteria.

Treatment flow diagram:

Treatment flow diagram

Additional outcomes on day 3, 6, and 9 include the following: 10 cc blood draw added to current labs for metabolomics and immunologic studies (PBMCs), stool collection for microbiology analysis, nasopharyngeal swab for PCR.

Some practical issues for the medical teams taking care of patients:

Consenting: Study staff will identify appropriate patients and communicate this to the floors. The medical team or nursing staff will need to give the informed consent documents to the patient and introduced the study. Consent will occur by telephone into the room, with the signed consent document being sent to the coordinators using the "dirty "fax on the unit.

On day 3, 6, and 9, the blood work will be added to standard ordered labs. Stool collection will be requested of the nursing staff, and a nasopharyngeal sample will need to be requested of the treating physician team.

April 30, 2020: Covid and Anosmia – Update

Contributor: Denis Lafreniere, MD

Giacomelli et al. reported that 20 (33.9 %) of 88 inpatients in Milan Italy with confirmed COVID-19 infections reported at least one taste or olfactory disorder. Twelve had symptoms prior to admission and 3 developed symptoms in the hospital. Younger patients tended to have more taste and smell complaints.

Yan et al. (Accepted article in Int Forum of All. and Rhin) describe 1,480 patients with influenza like symptoms who underwent Covid testing. Their study looked at 59 of 102 covid positive patients and 203 of 1378 covid negative patients. Smell and taste loss were reported in about 70% of the Covid positive patients compared to 16% of the covid negative patients. Sore throat was associated with COVID-19 negativity. Patient’s with acute anosmia may be otherwise asymptomatic carriers of infection. Twenty-two percent reported anosmia as a presenting symptom. Patterns of anosmia revealed profound to complete anosmia with a significant majority achieving spontaneous improvement with in a 4 week period (72.5%). The majority of covid positive patients had improvement of olfaction that temporally correlated with clinical resolution of illness. In 10% patients reported an early resolution in symptoms without return in olfaction (at 2 weeks). Most patients did not require hospitalization and none required intubation. Do ambulatory covid patients follow a fundamentally different course?

Other viruses can cause smell loss and have been found in the olfactory epithelium. Butowt and Bilinska suggest that the olfactory epithelium express ACE2 and TMPRSS2 required for host cell entry. They believe olfactory mucosa may be a better locale to test compared to the NP. They speculate that the sudden anosmia may be due to a process that leads to direct damage to the olfactory receptor neurons. This can provide a pathway for direct CNS access. More importantly they have shown in some fish studies that Olfactory receptor neurons initiate an ultra-rapid immune response after binding rhabdovirus surface glycoproteins. This virus binding results in neuronal activation and pro-inflammatory effects in Olfactory epithelium but inhibits inflammation in the brain. These cells undergo apoptosis and result in smell loss. If this translates to humans it could mean that The Olfactory receptor neurons may act as a first line viral sensors and initiators of antiviral immune response. SARS CoV2 binding to the ORNs may initiate a rapid immune response. Infected individuals who show signs of Olfactory dysfunction may actually represent those individuals with faster and stronger immune response and  better body mobilization against the SARS coV2 infection. It appears that patients that present with anosmia tend to have a  milder course with COVID-19 infections. Most older men in particular tend to have diminished sense of smell which may imply a weaker ORN immune response?

We have submitted an IRB  to look at our covid positive population to see if they complained of smell loss and to see if the course of the disease was any milder in this group. If the preliminary data is of interest we can try to contact the Hartford call center to see if we can extend the study.

References

  1. Giacomelli A, et al. CID. 2020 - epublished.
  2. Butowt R, et al. ACS Chem Neuroscien. 2020 - epublished.
  3. Yan CH, et al. Int Forum Allergy Rhinol. 2020 - epublished.