D.R.E.S.S. and COVID-19

COVID-19 cases, hospitalizations, and deaths are rising again, and the stronger, more contagious Delta variant is highly responsible for this increase.  Understandably, DRESS patients and survivors, more than ever, are anxious about getting vaccinated and the safety of SARS-CoV-2-Vaccines. We are here to help bring you scientific, evidence-based information to make the best decisions for yourselves and loved-one. Fortunately, we have guidance from DRESS Syndrome expert Dr. Elizabeth J. Phillips, our lead scientific advisor at the DRESS Syndrome Foundation. Dr. Phillips heads the Center for Drug Safety and Immunology at Vanderbilt University Medical Center and has shared the following information on vaccines for our DRESS community.  This is updated regularly. We hope it helps.

In addition, we continue to gather feedback from DRESS patients who've received the vaccine. You can find a summary of the current survey results here.

Quotes from DRESS patients who've received the vaccine: 

 

I received both doses of Pfizer and had mild vaccine side effect after the 2nd dose, but no DRESS reaction. I would rather get the shots than get Covid and potentially be on the medications prescribed for complications from the virus.

My doctor recommended that I get vaccinated and I've not had any issues.

I had dress syndrome last year & was vaccinated with AstraZeneca early this year. Apart from a few hives on the first one, I was fine.

 

My hands and feet had a maculopapular rash, and I had mildly elevated transaminases (liver enzymes) on the third day after the second vaccination. This resolved in 5 days without any therapy needed.

 

My daughter had DRESS and was hospitalized almost three years ago. After a lengthy conversation with her doctor, and her college making it mandatory, we decided to do it. The 2nd shot of Pfizer was on the 28th. It was a difficult decision, but she didn't have a reaction to either doses.  

  

I have experienced heavy head and headache with both vaccines. I have had fainting episodes for the past number of months…so not sure if it's the vaccine that actually caused the pre-syncope /fainting episode.

  

I had the worst headache I’ve ever had. My fever went up to 102.5. I had very bad GERD symptoms and stomach pain. I couldn’t eat for 30 hours and slept most of the time. After three days I feel fine. I have a very itchy and red rash on my upper arm where I had my injection. It started before my second dose, so it seems like it’s a delayed reaction from the first injection. My 2nd dose was five days ago.

 

I had the Astra Zeneca with no real side effects. I had DRESS 3 years ago.

 

I had mild symptoms with the Moderna vaccine. Mild headache and sore arm.

If you are a DRESS patient and have already had one or both doses of a COVID-19 vaccine, please share your experience with us here: Vaccine Survey

  

COVID-19 Vaccination Information for Survivors and Families of 

Drug Reaction with Eosinophilia and Systems Symptoms (DRESS)

SOME COMMON QUESTIONS AND ANSWERS ABOUT DRESS, COVID-19, and VACCINES

 

1.     I have had DRESS related to a drug and have avoided all drugs and vaccines since then. What are my chances of getting DRESS again?

 

Fortunately, it is highly uncommon to get DRESS a second time if you avoid the original drug you took and all structurally related drugs. There are many challenges with DRESS, however, that could impact the success of COVID-19 vaccinations:

 

•    DRESS relapse may occur in 20% of those with DRESS, requiring patients to stay on steroids or other immunosuppressants longer. In addition, steroids and immunosuppressants could impact your ability to respond to the COVID-19 vaccines.

•    Symptoms associated with the acute phase of DRESS - the period following DRESS, the hyperinflammatory period, and DRESS relapse, could be confused with a reaction to the vaccine.

•    Currently, it is unknown how COVID-19 natural infection may impact how long DRESS lasts, the risk of DRESS relapse, or the autoimmune conditions that may follow DRESS.

 

Given these uncertainties, it's prudent for DRESS patients to wait three months after natural infection of COVID-19 until there is no evidence of active DRESS diseases before getting the vaccine.

 

 -It's essential to be followed by a physician who has experience recognizing and treating DRESS relapse.

 -It makes sense to wait to get vaccinated once steroids have been weaned to less than 20 mg/day and until other    immunosuppressants such as cyclosporine or mycophenolate have been stopped.

 

2.     Are there components in the COVID-19 vaccines that could cause DRESS?

 

The inactive components of the vaccines, such as polyethylene glycol (PEG), have NOT been associated with DRESS.  Occasionally molecular mimicry can occur between a protein (antigen) seen in the vaccine and a previous immune response.  This mimicry can produce an immune reaction called a "heterologous response."  SARS-CoV-2 is a new virus in the community.  The Adenoviral vectors chosen for the Janssen and Astra Zeneca virus vaccines were explicitly designed to be different than viruses we had seen in the past.  Therefore, there is low risk of a response to the active vaccine component or another inactive viral vector component of the vaccines.  However, reactions such as erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been seen with the mRNA and viral vector vaccine, respectively.  These have been self-limited, and with mRNA vaccines, they occurred on the second dose in under 50% of cases.

 

3.     How much experience is there with the COVID-19 vaccines.  It seems like they were developed very quickly. Is this a risk for me and others?

 

Worldwide more than 4.1 billion people, as of August 1, 2021, have received at least one shot of a COVID-19 vaccine.  This is an unprecedented effort and represents almost 50% of the world's population.  Although mRNA vaccines (like Moderna and Pfizer) and adenoviral vector vaccines (like Johnson and Johnson and AstraZeneca) have never been used in the routine vaccine setting, more than two decades have gone into making these vaccine constructs.  They are not new. An astonishing amount of research had already gone into their development well before COVID-19.  These vaccines were developed over many years and were tested in animals before they underwent early trials in humans for viruses of global importance, such as Ebola.  We reaped an enormous benefit from these arduous efforts during the pandemic, which allowed the COVID-19 vaccine effort to be rolled out very quickly.

4.     How have the COVID vaccines been made?

 

The SARS-CoV-2 virus, like other closely related coronaviruses (SARS-CoV and MERS), has a large spike protein that extends out from the surface of the virus. This spike protein is the primary mechanism by which the viruses attach to and enter human cells. In addition, it's the primary target or construct from which vaccines were designed. Antibodies induced against the spike protein can prevent  SARS-CoV-2 from attaching to and infecting human cells.  However, there are a number different technologies involved in making vaccines designed against the spike protein.

 

The current vaccines in the US, such as the mRNA vaccines and viral vector vaccines, are remarkable for how easily they can be modified to be more active against viral variants.

 

Currently, more than 40 vaccines are being studied to prevent SARS-CoV-2 infection.  You can find an updated list of vaccine candidates at the World Health Organization (WHO) website Here.   

5.    When will the current COVID -19 vaccines receive a full license, and what purpose is an emergency use authorization?

 

During emergencies like the current COVID-19 pandemic, the FDA can approve the use of tests, treatments, and vaccines under an emergency use authorization (EUA).  The FDA will only issue an EUA if there is evidence of vaccine safety and effectiveness. This includes at least two months of follow-up data on 50% of the vaccine recipients.

 

Currently, three vaccines are approved for EUA in the United States. The companies who make these approved vaccines are Pfizer, Moderna, and Janssen.  Before vaccines can be issued EUA, they must be thoroughly reviewed by an advisory committee to FDA for efficacy and safety. This advisory committee is called the Vaccine and Related Biologic Products Advisory Committee (VRBPAC). However, the ultimate decision on whether to extend a EUA is determined by The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). The ACIP comprises medical and public health experts who make ultimate recommendations on vaccines in the United States. Their recommendations include vaccine schedules and which groups will be prioritized for SARS-CoV-2 vaccinations. 

 

Both the Moderna and Pfizer companies have now filed for full FDA approval. As of July 16, the FDA had accepted and granted priority review of the Biologics License Application (BLA) from Pfizer-BioNTech to provide vaccines for people 16 years and older.  Thus, as early as the Fall of 2021, at least one mRNA COVID-19 vaccine could be licensed with full FDA approval.  This license would broaden the scope of who can distribute the vaccines in the United States.  The difference between "EUA" and "full approval" is that "full approval" companies will have submitted longer-term data on vaccine safety.  Currently, studies have been completed on over six months of follow-up.  

6.    Why are vaccines important in helping to control and end the COVID-19 pandemic?

 

Although many tools are necessary to stop a pandemic, vaccines are vital in reducing related illnesses and deaths. Vaccines help even when viral variants, like the Delta variant, emerge in the community. Although current vaccines may be less active against these specific variants, they still help protect individuals and society.  This is because vaccines protect against becoming infected and also the replication of the virus. And, just as important, they protect against the severity of infection.  In the month of June alone, over 99% of those hospitalized for COVID-19 were unvaccinated.  As time elapses and new variants emerge in the community, individuals are indeed more likely to get infected with COVID-19. However, those infected will most likely have mild illness with a significantly shortened time of being infectious.  This means that vaccinations limit morbidity and mortality and slow viral spread in the population.  Curtailing replication and spread of COVID-19 is the key to preventing more variants from developing - to which vaccines may not work as well.

7.     What side effects and toxicities are associated with the COVID-19 vaccines?

 

Common, Mild to Moderate Symptoms

SARS-Cov-2 vaccines have been associated with mild to moderate but short-lived symptoms that occur within 24-48  hours after vaccination.   These symptoms include fever, chills, headache, muscle and joint pain, and short-term fatigue. Up to 50% of those receiving vaccination may experience some of these symptoms to varying extents. These symptoms appear to be worse after the second injection in those who have not previously had natural infection with COVID.  Injection site reactions are common with both vaccines. However, they appear to be slightly more enhanced with the Moderna vaccine and worse after the second dose.  Anaphylaxis (an immediate allergic reaction not related to DRESS) has been described to occur in approximately 4.7 per million doses of the Pfizer vaccines and 2.5 per million doses of the Moderna vaccines.  Rare cases of anaphylaxis have been reported with the Janssen and Astra Zeneca vaccines.  None of the vaccines have been directly associated with causing DRESS.  

Less Common Symptoms: Rashes & Skin Eruptions

Many types of delayed rashes (nonspecific) have occurred in up to one in five people who receive a COVID-19 vaccine. However, these recur in less than 50% of those who get a second dose. One specific type of rash-related illness, Erythema multiforme (EM), can occur in those who actually have infection with COVID-19, but it can also occur, less frequently, in those who receive the COVID-19 mRNA vaccines. Erythema multiforme (EM) is associated with viral illnesses and can mimic the severe cutaneous adverse drug reaction known as Steven's Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) - more so than it mimics DRESS. Of those who do get EM after dose 1 of the mRNA vaccines, under 50% have experienced a repeat episode after dose 2.

 

Another type of rash-related illness that has been seen with the Astra Zeneca and Johnson & Johnson viral vector vaccines is Acute generalized exanthematous pustulosis (AGEP). This is a cutaneous (skin) eruption associated with drugs, vaccines, and viruses. However, none of the associated mortality or long-term morbidity has been connected with the Astra Zeneca and Johnson & Johnson viral vector vaccines.  

 

Less Common Symptoms from Viral Vector Vaccines: TTS

The Janssen single-dose vaccine and the Astra Zeneca vaccine (not available in the US) are viral vector vaccines.  As of July 25, 2021, over 13 million doses of the Janssen vaccine had been administered in the US.   The Astra Zeneca vaccine and Janssen vaccines (J&J) are currently being investigated further for clotting events (see thrombosis with thrombocytopenia – TTS below). TTS is thought to rarely occur with these viral vector vaccines. After a ten-day pause on vaccinations was initiated to investigate clotting events, the Janssen vaccine was reinstituted. Thrombosis (clotting) with thrombocytopenia (low platelets), also known as TTS, have occurred within 4-30 days following vaccination with a viral vector vaccination.  All cases have occurred in those under 65.  The risk to women aged 18-49 is approximate 7 TTS cases per million doses.  It is much lower for men and women outside this age group and estimated to be under 1 per million. There is insufficient data in those 18 years old and under for whom the vaccine is currently not approved.  The pause on the Janssen (J&J) vaccine was released after review by the CDC and FDA, and the Janssen (J&J) vaccine is currently given emergency use access for those over 18.  Warning language included with the Janssen vaccine states that it has caused TTS in women under 50 in rare instances.  There is no association between these clotting events and DRESS or other types of drug hypersensitivity. Find additional information at:  https://hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia.

Rare Symptom: Myocarditis

Myocarditis (inflammation around the heart) is a prominent type of organ dysfunction associated with COVID-19 natural infection. It has been noted that myocarditis can rarely occur after COVID-19 mRNA vaccination. It's thought to occur after the second dose of the Pfizer-BioNTech and Moderna vaccines, and more commonly in males under 30. These cases have been mild and, in most cases, have responded to anti-inflammatory medications such as non-steroidal anti-inflammatory drugs (NSAIDS).

 

Click Here for more information on common side effects associated with the COVID-19 vaccines and some helpful tips.

 

8.     Is there a cost associated with the COVID-19 vaccines?

 

The SARS-CoV-2  vaccines will be offered free of charge to all insured and uninsured individuals based on ACIP recommendations.

 

9.     How will the ongoing safety and efficacy of the COVID-19 vaccines be monitored?

 

The EUA is issued based on phase III clinical trial data. Still, the FDA will mandate careful studies after the EUA is issued.  In addition, since it is unknown how long protection from the SARS-CoV-2 vaccine will last, whether it will prevent transmission in the community, and how well it works in populations that have not been studied - monitoring of post-EUA will continue. The safety and effectiveness of the SARS-CoV-2 vaccine will be monitored through individual pharmaceutical companies and the CDC.

 

10.    Does Rash Occur in Association with COVID-19 Illness, and Can this be Confused with DRESS?

 

Approximately one in five people will develop a skin rash in association with COVID-19 illness.  These rashes are generally either hives, measles-like (erythematous rash), or COVID fingers or toes (chilblains) that presents with reddish purplish bumps on the fingers and toes. The latter appears more common in children and young adults and appears to be related to damage of the lining of vessels. Erythema multiforme (EM) is typically triggered by viral infection (most commonly Herpes simplex virus I). EM can be difficult to differentiate from DRESS, but it is characterized by a more typical rash with target lesions (resembling a bullseye) and rash that appears mainly on the extremities versus the truncal distribution characteristic of early DRESS.  In EM, there is often mucosal involvement (and with DRESS, there is typically swelling and ulcerations outside of the mouth). EM also has less common presenting features such as fever and lymphadenopathy that are usually early symptoms of  DRESS.  There have been case reports of EM in association with COVID-19 illness. 

 

Drug-induced DRESS has increasingly been found to be related to a distinct genetic predisposition. Therefore, it would be unexpected that DRESS would predispose one to COVID-19 related drug rashes or other rashes.  Understandably, COIVD-19 related drug rashes could be confused with DRESS, as viral drug interactions can cause rashes that may be identical to DRESS. However, symptoms such as lymphadenopathy, eosinophilia, and organ involvement are what help to differentiate and make the diagnosis of DRESS. 

 

11.    Are there any reasons why a person who has recently experienced DRESS or is a survivor of DRESS should be concerned about receiving a COVID-19 vaccine?

 

The SARS-CoV-2 vaccines to date have been safe and effective in the populations that they have been studied, which include adults >65 years of age. The vaccine prompts a predictable immune response against the SARS-CoV-2 spike protein that does not lead to the hyperinflammatory environment seen in some patients with acute COVID-19 disease.  It would thus be predicted that getting the SARS-CoV-2 vaccines would be safer for current or past DRESS patients than going through acute SARS-CoV-2 clinical illness. Moderate to severe COVID-19 disease is associated with activation of the immune system and the release of cytokines that lead to a proinflammatory and hypercoagulable state.  In addition to the inflammation associated with acute COVID-19 illness, rarely a multi-inflammatory syndrome has been seen. This syndrome happens more commonly in children (MIS-C) than adults (MIS-A), and it tends to occur 2-4 weeks following acute COVID-19 illness.  This multi-inflammatory syndrome response has not been described following the COVID-19 vaccination.  

 

It is also much easier to treat mild to moderate vaccine-related side-effects than it is to treat moderate to severe COVID-19.   

 

The immune response to the SARS-CoV-2 vaccine has not been studied in immunocompromised patients or those on high-dose steroids. This will need to be evaluated further.  However, many studies of other vaccines in this population show that immune responses have not been significantly impacted. 

 

It is recommended that the administration of live-attenuated vaccines be deferred in patients on steroids over 10 mg prednisone equivalent for greater than two weeks and until three months following steroid discontinuation (e.g., measles/mumps/rubella(MMR) or chickenpox (Varicella) vaccines).  However, please know the current SARS-CoV-2 vaccines in late-stage studies likely to receive EUA in the near future do not contain live virus products.  

 

Given the randomness and severity of the disease, it is understandable that survivors of DRESS  would be hesitant to take any drug or vaccine. It can be uncomfortable to consider taking medications even if they are structurally unrelated to the original drug that caused their DRESS.  However, those who have recently experienced DRESS  and survivors of DRESS can be reassured that receiving the SARS-CoV-2 vaccine is a safer option than natural infection. 

 

12.  If I have had DRESS, am I at risk for Anaphylaxis?

 

Reports of Anaphylaxis occurred shortly after the rollout of the Pfizer-BioNTech mRNA vaccine in healthcare workers and on the first dose of the vaccine.  This caused concern that a specific allergic reaction could be occurring to the PEG component of the mRNA vaccines. However, over the last few months, many who had immediate reactions to the first dose have tolerated the second dose with recommendations and expert guidance.  Although there is not a clear mechanism associated with Anaphylaxis with the mRNA vaccines, it appears that these are uncommonly IgE-mediated reactions that would put individuals at risk of having a worse and life-threatening response with each and subsequent doses of vaccine.  In fact, many such patients have tolerated the second dose of mRNA COVID-19 vaccines without any symptoms.  Ongoing studies in the United States are looking at the risk and mechanisms of Anaphylaxis related to the mRNA vaccines. There is no association between anaphylaxis, an immediate reaction occurring within 30 minutes of dosing, and DRESS as they are mechanically different reactions.   Anaphylaxis associated with mRNA vaccines appeared to occur at a rate of 2.5 per million doses for the Moderna vaccine and 4.7 per million for Pfizer. 

 

 Although rare immunological events may be reported in the future under the scrutiny of post-licensure vaccine safety programs, there is no reason to believe that patients who have experienced DRESS would be at higher risk for these events. In addition, the genetic factors predisposing someone to DRESS are specific for a specific drug or chemically related drugs. Therefore, there is no reason to believe these predisposing factors would increase the risk of an adverse reaction to a SARS-CoV-2 vaccine.

 

13.     If I have a safety reason that prevents me from getting a COVID-19 mRNA vaccine, is it safe for me to get the Janssen (Johnson & Johnson) vaccine?

The J&J vaccine is a single-dose viral vector vaccine based on the spike protein construct.  The J&J vaccine does not contain PEG but does contain polysorbate, which is closely related to PEG.  Suppose you have had previous Anaphylaxis associated with a vaccine or injectable drug or have had Anaphylaxis to a PEG product. In that case, you should talk with your doctor. They may refer you to a specialist to determine if it is safe for you to get the J&J vaccine.

 

14.    What are the implications for DRESS if I get COVID-19 Infection?

 

Generally, you can expect the course of COVID disease to run as usual. However, if you have had recent or acute DRESS  and have been on high-dose steroids and/or other immunosuppressants, you may be at higher risk with COVID-19 infection or at risk for having a delayed protective immune response.  Currently, a cocktail of monoclonal antibodies to COVID-19 is being offered to individuals who are on immunosuppressants when they develop an infection with COVID-19, and you should discuss this with your provider. COVID-19 monoclonal antibodies, if given to higher risk individuals early in the disease, may show benefit for recovery.  

15.       I have taken and tolerated the COVID-19 vaccine primary series – is it time for a booster shot?

The FDA has modified the emergency use authorization for both the Pfizer-BioNTech and Moderna vaccines for the use of booster shots (third doses) in individuals who meet specific criteria of having an immunosuppressive state. The third dose only applies to those that have received two doses of an mRNA vaccine, such as the Moderna or Pfizer-BioNTech vaccines. There is currently no recommendation from the FDA or CDC to boost with a second dose of either the same vaccine or an mRNA vaccine following the Janssen (Johnson &Johnson vaccine). The recommendations below are predicated on the patient having an immunosuppressive state. There are no recommendations to minister a booster shot based on age criteria alone, and studies are now being conducted to determine what other conditions might be prioritized for booster.

 

SARS-CoV-2 antibody tests should NOT be the basis for a third dose determination. Antibody tests do not help define who is eligible for the third dose of a COVID-19 mRNA vaccine. 

The indication for the third dose of an mRNA COVID-19 vaccine includes patients with moderate or severe immunocompromised state who have already received two doses of a mRNA COVID-19 vaccine (e.g., Pfizer-BioNTech or Moderna) with the 2nd dose at least 28 days ago AND immunosuppressive state such as:

 

  • Underactive treatment for cancer

  • Transplant patients on drugs that dampen the immune system to prevent organ rejection. 

  • Bone marrow transplant in last two years

  • Receipt of CART-cell therapy in last two years

  • Primary immunodeficiency syndrome (Common Variable Immune Deficiency, DiGeorge Syndrome, Wiskott-Aldrich syndrome)

  • Advanced (CD4<200) or untreated HIV infection

  • Active treatment in the last month with a drug that dampens the immune system (this could be relevant to SJS/TEN or DRESS patients who have been recently treated or hospitalized)

  • High dose corticosteroids (≥20mg prednisone or equivalent per day for ≥14 days) 

  • Specific chemotherapeutic agents that dampen the immune system (if in doubt, ask your doctor) (ex: cyclophosphamide, temozolomide, chlorambucil, carboplatin, cisplatin. methotrexate, hydroxyurea, gemcitabine, fludarabine)

  • Other drugs are sometimes used to treat SJS/TEN and other autoimmune diseases, inflammatory bowel disease, rheumatoid arthritis, etc. e.g., TNF alpha inhibitors (ex: adalimumab, etanercept, infliximab) or rituximab, anakinra, golimumab, natalizumab) 

  • If in doubt about a monoclonal antibody and whether it dampens your immune system, ask your doctor

  • Select patients with other diseases that cause immunocompromise (e.g., end-stage kidney disease on dialysis)

 

Some important points:

 

•    If you have had recent monoclonal antibody therapy for COVID-19 (products by Regeneron and Lilly), you should also wait 90 days before getting vaccinated.  

 

•    If a DRESS patient got sick with COVID-19, there is no contraindication to giving anti-viral therapy such as remdesivir or steroids such as dexamethasone.

 

•    It is important to be clear about what drugs were associated with your DRESS in the case that you need to be treated for bacterial pneumonia or any other complications that could occur due to COVID-19 infection.  You need to know what antibiotics are safe for you to take.  If any doubt, please email:  drugsafetyresearch@vumc.org for more information.

 

References:

Castells MC, Phillips EJ.  Maintaining safety with SARS-CoV-2 vaccines. N Eng J Med 2020 Dec 30: NEJMra20335343.  Click here for a link to article.

 

CDC:  Vaccines for COVID-19 (https://cdc.gov/coronavirus/2019-ncov/vaccines/index.html)

 

In the event you have experience what you think is an adverse event from the vaccine please talk to your physician about reporting this to the Vaccine Adverse Event Reporting System (VAERS) (https://vaers.hhs.gov)

 

 Regardless of which COVID-19 vaccine you receive please also sign up for V-safe which is a smartphone application designed to remind you to get your second dose and track potential vaccine related side effects (https://cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html)