Monday, February 3, 2020

Adventures In Vaccine Reactions



This area of erythema appeared on day 3 - only on the arm where the Pneumovax was placed




This post is about vaccinations for old people.  It is a mix of science and anecdotes because that is all there is out there right now. A lot of the information I elicited by posting my experience getting the Shingrix Zoster Vaccine and the Pneumovax 23 Vaccine. It illustrates the concept of biological heterogeneity that I post about on this blog. Many people can seem confused about that, particularly the idea that practically every biological system in the human body has significant heterogeneity and the immune system is no exception.

I don’t work on Fridays anymore so last Friday afternoon I headed down to a primary care clinic to get some problems checked out. The primary care doctor was clearly knowledgeable, reassured me that I had no major problems, and asked me if there is anything else that he could do for me. At that point the conversation went something like this:

Me:  “Well I keep being told every other visit that I need a second Pneumovax vaccination and I need the second Shingrix vaccination. Is it possible get those today?”

MD:  “That should not be a problem”

Me:  “Is there any problem with getting them on the same day?”

MD:  “No you can get them both on the same day.”

At that point he pulled up the EHR and verified that I had a Pneumococcal Conjugate Vaccine (PCV13) on 1/11/2016 and a Pneumococcal polysaccharide vaccine (PPSV23) on 9/8/2010 and a previous Shingrix vaccine on 10/30/2019. He explained the rationale for the second PPSV23 vaccination.

MD: “Did you have any reactions to the first vaccinations?”

Me:  “Just a little pain at the injection site but nothing major.”

The nurse came in the room and asked me if I wanted the shots in the same arm or different arms.  She gave me the Shingrix injection in the left arm and the PPSV23 injection the right arm. I noted the time was 2 PM.  I have a history of anaphylactic reactions and an anaphylactic reaction to a second dose of anti-rabies duck embryo vaccine when I was in the Peace Corps. I forgot to bring an EpiPen, but there is a coffee shop just down the street. I spent an uneventful 40 minutes there (to get through that window) and then headed home.

About six hours later I started to get more intense muscle pain in both arms that eventually extended into the back and down the back. A short time later I started to get a headache. By 9 o’clock that night I was taking acetaminophen for those symptoms. I also noted that I was feeling physically ill and fatigued. The next morning I did not feel any better and continued to take the acetaminophen and added naproxen.  By 1 o’clock the next day - nearly 24 hours after the injection I started to get intense chills. It took my temperature and it was normal. I had put on outdoor clothing and sat next to the fireplace. I was shaking. It reminded me of when I had malaria back in 1975. In those days I had a cheap sleeping bag and crawled into that but eventually crawled across the floor into a tub of hot - water dragging the sleeping bag with me.  I had better resources now. I developed some tachycardia and felt very physically ill until about the 60 hour mark. At that point the chills stopped and the tachycardia resolved.

In the meantime I had solicited a number of medical and nonmedical opinions. One of the best internists I know told me that he advises patients take Shingrix vaccination but that they should plan on being out of commission for 2 to 3 days. He also does not recommend any other vaccinations with it because of the severity of the reaction. Several other primary care physicians have given me similar advice. I posted my experience on a listserv for psychiatrists and my Facebook site and several people had similar experiences. The physical illness caused by the immunizations was intense enough to take sick leave from work.

When I left the doctor’s office I was given “Vaccine Information Statements” that were both CDC documents.  One was entitled “Pneumococcal PolysaccharideVaccine - What You Need to Know” and the other was “Recombinant Zoster (Shingles)Vaccine: What You Need to Know”.  For the shingles vaccine the risk of reaction to the vaccine was listed as mild to moderate arm pain in 80% of people and side effects that prevented 1 of 6 people from doing regular activities that included fatigue, muscle pain, headache, shivering, fever, stomach pain, and nausea. The side effects were supposed to resolve in 2 or 3 days. By comparison the pneumococcal vaccine states that “less than 1/100 people develop a fever, muscle aches, or more severe local reactions”.

At a theoretical level it is interesting to consider the differences between both vaccines. In order to generate an immunological response, vaccinations need to create inflammation at the injection site. That typically requires an adjuvant. Adjuvants like aluminum compounds result in local cell death that leads to release of IL-1 family cytokines and danger-/damage associated molecular patterns (DAMPS). That in turn leads to T cell response and immunity (3). 

The adjuvants for these vaccines are significantly different.  The PPSV23 adjuvant is a standard alum based.  The Shingrix adjuvant is an ASO1B that is described as “ f 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota and QS-21, a saponin purified from plant extract Quillaja saponaria Molina, combined in a liposomal formulation. The liposomes are composed of dioleoyl phosphatidylcholine (DOPC) and cholesterol in phosphate-buffered saline solution containing disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, and water for injection.” By comparison Zostavax the original shingles vaccine was live attenuated varicella-zoster virus without an adjuvant.  The Zostavax vaccination is much less effective, leading the CDC to recommend both doses of Shingrix, even if there is a significant non-allergic reaction to the first injection. 
Flu-like symptoms are an area great interest to me into a large extent they are cytokine mediated.  The top flow sheet at this post gives common cytokines that can cause flu like illness.  Given the complexity and sheer number of cytokines the scope of inflammatory cytokines triggering these reactions is not known.  Of the known cytokines from the Shingrix inflammatory reaction (4) it is likely that IFN- γ is a cause. The other interesting aspect of this response is that it is hypothalamically mediated.  The preoptic anterior hypothalamic area (POAH) has networks for heat production (shivering) and dissipation (vasodilation) (5) and both were affected in my situation. This area is described as being sensitive to a number of compounds including cytokines.  Other  cytokines may explain the associated flushing and sweating.

At the time this was posted I have been seen in the Urgency Room last night because my health plan was concerned about tachycardia and flushing.  The ED doc thought it was all a post vaccine reaction and did not do any further testing.  He said to come back if I got a rash, bloody urine, or a temp of 100.5.  I had the chills for about 8 hours at that point. I went to bed at midnight and woke up at 3AM sweating.  By 7AM, the tachycardia and flushed sensation and appearance were gone. Things were going well until this afternoon when I noticed the redness on the arm where I had received the Pneumovax (see photo).  I was seen in Urgent Care this time.  They had an alternate explanation for the inflammatory response, if the needle is withdrawn too quickly some of the vaccine and adjuvant gets deposited in subcutaneous tissue and leads to a broad inflammatory response.  They recommended an antibiotic (cephalexin) and prednisone just in case. I declined the prednisone and could not get the antibiotic filled anyway.  The pharmacy I use closes at 7PM and I got out of Urgent Care at 7:07.

What are the lessons from this adventure in vaccinations?  First off, as I have said repeatedly on this blog there are no guarantees in medicine. Everything is a probability statement.  In the case of Shingrix, I am taking a vaccination that may be 90% effective in preventing shingles but the trade off is that in clinical trials as many as 1 person out of 6 gets disabling side effects for at least 2-3 days. I have heard from some people where it lasts for 10 days.  Second, even though those are significant side effects shingles is potentially far, far worse. In the people I have treated, that includes months of disabling neuropathic pain, eye complications, facial nerve complications, and in some cases extensive testing just to find out what the problem was.  As an example, a 79 year old man had extensive testing for severe abdominal pain that was thought to be a malignancy that was ultimately diagnosed as shingles.  In the case of Pneumovax it is pneumonia, meningitis, sepsis and death. Case closed.  My memorable case there was an eldelry patient who presented to the emergency department with "agitation".  As the intern on Neurology I was called to see her.  By the time I arrived she was unresponsive.  Upon examination she had pus running out of her ear and nuchal rigidity. A lumbar puncture showed pneumococcal meningitis.  She survived a complicated course including acute respiratory distress syndrome (ARDS) but became completely deaf from the meningitis. Third, it is probably reasonable to not get both vaccinations at once. The physicians writing to me at this point have all been affected by complications they have seen in their patients who got Shingrix and they have seen it as a vaccine that has more than the ordinary amount of adverse effects compared with typical adult vaccinations.  Finally, what about the issue of repeat Pneumovax vaccinations?  It only comes up in cases where a person has COPD or asthma (me) and gets a vaccination before the age of 65 on that basis. Clearly, the arm rash here seems to indicate more of an inflammatory response on the Pneumovax side than the Shingrix in my case. Was it because of a robust antibody response after the initial vaccination?  I don’t have the answer to that question but if there are any immunologists reading this post – I would be very interested in your comments.

That is it for now.  Hopefully I am heading into work tomorrow morning.


George Dawson, MD, DFAPA




References:

1.  SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted), suspension for intramuscular injection.  FDA Package Insert   https://www.fda.gov/media/108597/download

2.  PNEUMOVAX® 23 (pneumococcal vaccine polyvalent) Sterile, Liquid Vaccine for Intramuscular or Subcutaneous Injection.  FDA Package Insert  https://www.fda.gov/media/80547/download

3.  Muñoz-Wolf N, Lavelle EC. A Guide to IL-1 family cytokines in adjuvanticity. FEBS J. 2018 Jul;285(13):2377-2401. doi: 10.1111/febs.14467. Epub 2018 May 3. Review. PubMed PMID: 29656546.



4. Cunningham AL, Heineman TC, Lal H, Godeaux O, Chlibek R, Hwang SJ, McElhaney
JE, Vesikari T, Andrews C, Choi WS, Esen M, Ikematsu H, Choma MK, Pauksens K, Ravault S, Salaun B, Schwarz TF, Smetana J, Abeele CV, Van den Steen P, Vastiau I, Weckx LY, Levin MJ; ZOE-50/70 Study Group. Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older. J Infect Dis. 2018 May 5;217(11):1750-1760. doi: 10.1093/infdis/jiy095. PubMed PMID:29529222.


5. Swaab DF. Autonomic Disorders in Handbook of Clinical Neurology, Vol. 80
(3rd Series Vol. 2) The Human Hypothalamus: Basic and Clinical Aspects, Part II,
2004, Elsevier, Amsterdam, pp351-370.




Supplementary 1:

Did not make it into work as expected on February 4. Went to see my primary care MD instead.  The erythema (redness) had not gone down and actually extended farther down the arm (I drew a line around it the night before).  No systemic symptoms but more redness.  Needed to know if the antibiotic needed to be changed and if prednisone was a good idea.

His conclusion - not an infection but inflammation from a reaction to the vaccine.  He has only seen a couple of reactions like this with Pneumovax and pointed out that it is given to immunocompromised people every ten years starting at a younger age.  He said to keep taking the cephalexin for a week but no prednisone: "I give prednisone to people with life threatening problems - not a red arm.  More medicine is not necessarily good medicine."

Work tomorrow. 

Supplementary 2:

New CDC Guidelines on Pneumococcal Vaccinations:



New Pneumococcal Vaccine Recommendations for Adults Aged ≥65 Years Old

PCV13. PCV13 vaccination is no longer routinely recommended for all adults aged ≥65 years.
Instead, shared clinical decision-making for PCV13 use is recommended for persons aged ≥65 years
who do not have an immunocompromising condition, CSF leak, or cochlear implant and who have
not previously received PCV13 (Table 1).

CDC guidance for shared clinical decision-making. When patients and vaccine providers engage
in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for the specific individual aged ≥65 years, considerations may include the individual patient’s risk for exposure to PCV13 serotypes and the risk for pneumococcal disease for that person as a result of underlying medical conditions (Box).

If a decision to administer PCV13 is made, it should be administered before PPSV23 (5).
The recommended intervals between pneumococcal vaccines remain unchanged for adults without
an immunocompromising condition, CSF leak, or cochlear implant (≥1 year between
pneumococcal vaccines, regardless of the order in which they were received) (5). PCV13 and PPSV23 should not be coadministered.

ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years
(including those aged ≥65 years) with immunocompromising conditions, CSF leaks, or
cochlear implants (Table 1) (2).

PPSV23 for adults aged ≥65 years. ACIP continues to recommend that all adults aged ≥65 years
receive 1 dose of PPSV23. A single dose of PPSV23 is recommended for routine use among all adults aged ≥65 years (1). PPSV23 contains 12 serotypes in common with PCV13 and an additional
1 serotypes for which there are no indirect effects from PCV13 use in children. The additional
11 serotypes account for 32%–37% of IPD among adults aged ≥65 years (22). Adults aged ≥65 years
who received ≥1 dose of PPSV23 before age 65 years should receive 1 additional dose of PPSV23 at
age ≥65 years (2), at least 5 years after the previous PPSV23 dose (Table 1) (5).


Note:  In the above case of the vaccine reaction I received 1 dose of PPSV23 before the PCV13 and one dose after by a period of 4 years.  That is not consistent with the guideline but they  were no coadministered and there was a period of at least one year between injections (PPSV23 in 2010, PCV13 in 2016, and PPSV23 in 2020). 




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