Euro2021….The problem for CD20.

E

The UK has been deluding itself and its citizens (So what’s new there?) The French and Italian Data show worse signs with anti-CD20 treatment, Swiss data show poor vaccine response in both T and B cells after CD20 depletion and the Dutch support the Italians on delaying tactics.

It seems that the UK government (public health) is coming under fire for suggesting everything is fine with the double jab for clinical risk groups. However, if you have been reading my posts you know this is not the case notably for people with blood cancers, arthritis and MS. The people writing the Green book (UK advice for vaccinations) have been deluding themselves since they wrote chapter 14 in Novemebr 2020, where they implied ebola vaccine studies were in people infected with HIV (read the paper and this was 5% of the trial cohort and none had AIDS. Even in the most recent COVID-19 in people with HIV the level fo CD4 was less than in most people treated with MS drugs).

We know that CD20-depleting antibodies can be associated with worse course. This is re-affirmed with the combined Italian (Reported a problem before) and French (Didn’t report a problem) data show worse signs of COVID-19 if treated with anti-CD20. This is seen in the Swedish data too

DMTs and Covid19 severity in MS: a pooled analysis from Italy and France.Sormani MP, Salvetti M, Labauge P, Schiavetti I, Zephir H, Carmisciano L, Bensa C, De Rossi N, Pelletier J, Cordioli C, Vukusic S, Moiola L, Kerschen P, Radaelli M, Théaudin M, Immovilli P, Casez O, Capobianco M, Ciron J, Trojano M, Stankoff B, Créange A, Tedeschi G, Clavelou P, Comi G, Thouvenot E, Battaglia MA, Moreau T, Patti F, De Sèze J, Louapre C; Musc-19; Covisep study groups.Ann Clin Transl Neurol. 2021 Jul 7. doi: 10.1002/acn3.51408. Online ahead of print. We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon. Both in Italy and France, the number of patients on rituximab was low (n = 20 in Italy and n = 34 in France). However, separating the effect of anti-CD20 agents into rituximab and ocrelizumab, it was possible to detect a higher risk for rituximab (ORItaly = 3.78, ORFrance = 2.56, pooled OR = 3.04 (95%CI = 1.63, 5.67, p < 0.001)) versus other therapies. The effect of ocrelizumab alone was also significant (ORItaly = 1.79, ORFrance = 1.73, pooled OR = 1.77 (95%CI = 1.15, 2.72, p < 0.001)).

So no matter how hard the manufacturers may want us/you to think otherwise (COVID-19 in ocrelizumab-treated people with multiple sclerosis.Hughes R, Whitley L, Fitovski K, Schneble HM, Muros E, Sauter A, Craveiro L, Dillon P, Bonati U, Jessop N, Pedotti R, Koendgen H.Mult Scler Relat Disord. 2021 Apr;49:102725), this story is repeated in many studies in MS and other conditions. However any increased risk is small and remember the benefit that effective treatments have.

Indeed we are seeing over and over again that CD20 antibody inhibits antibody response. What about a T cell response? Whilst we have seen 100% T cell response in some studies, the Swiss report below that the T cell response is reduced in addition to a reduced B cell response. Now some of this is depends on the assay system used, but most studies reported so far in other conditions where the antiibody response is reduced, do not show a 100% T cell responsiveness (Remeber I’m a glass half-empty-type of person…ProfG is half-full). The study below is not MS, but a number of different conditions where B cell depleting agents are used. The T cell response is inhibited too. As I have suggested already vaccine response is better the more B cells you have and a longer interval between dosing.

Humoral and cellular responses to mRNA vaccines against SARS-CoV2 in patients with a history of CD20-B-cell depleting therapyMatthias B. Moor, Franziska Suter-Riniker, Michael P. Horn, Daniel Aeberli, Jennifer Amsler, Burkhard Möller, Linet M. Njue, Cesare Medri, Anne Angelillo-Scherrer, Luca Borradori, Susanne Radonjic-Hoesli, Andrew Chan, Robert Hoepner, Vera Ulrike Bacher, Laila-Yasmin Mani, Joseena Mariam Iype, Cédric Hirzel, Britta Maurer, Daniel SidlermedRxiv 2021.07.04.21259848; doi: https://doi.org/10.1101/2021.07.04.21259848. Background B-cell depleting therapies increase COVID19 morbidity and mortality. For this specific population, evidence-based vaccination strategies are lacking. Here, we investigated humoral and cell mediated immune responses to SARS-CoV2 mRNA-based vaccines in patients receiving CD20-B-cell depleting agents for autoimmune disease, malignancy, or transplantation.Methods Patients at the Bern University Hospital with a treatment history of anti-CD20 depleting agents (rituximab or ocrelizumab) were enrolled for analysis of humoral and cell-mediated immune responses (by interferon-γ release assay) after completing vaccination against SARS-CoV2. Primary outcome was the the anti-spike antibody response in anti-CD20-treated patients (n=96) in comparison to immunocompetent controls (n=29).Results Anti-spike IgG antibodies were detected in 49% of patients 1.79 months after the second vaccine dose (interquartile range, IQR: 1.16-2.48) compared to 100% of controls (p<0.001). SARS-CoV2 specific interferon-γ release was detected in 17% of patients and 86% of healthy controls (p<0.001). Only 5% of patients, but 86% of healthy controls showed positive reactions in both assays, respectively (p<0.001). Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/µl), and CD4+ lymphocyte count (>653/µl) predicted humoral vaccine response (area under the curve [AUC]: 62% [CI 56-78], 67% [CI 58-80] and 67% [CI 54-79], (positive predictive value [PPV]: 0.76, 0.7 and 0.71).Conclusion This study provides evidence for blunted humoral and cell-mediated immune responses elicited by SARS-CoV2 mRNA vaccines in patients with CD20-depleting treatment history. Lymphocyte subpopulation counts are associated with vaccine response in this highly vulnerable population. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)

The Dutch join the Italians and show that if you need to delay the dosing of ocrelizumab in the short term this can be done relatively safetly

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID19 pandemic.van Lierop ZY, Toorop AA, van Ballegoij WJ, Olde Dubbelink TB, Strijbis EM, de Jong BA, van Oosten BW, Moraal B, Teunissen CE, Uitdehaag BM, Killestein J, Kempen ZLV.Mult Scler. 2021 Jul 9:13524585211028833. doi: 10.1177/13524585211028833. van Lierop ZY, Toorop AA, van Ballegoij WJ, Olde Dubbelink TB, Strijbis EM, de Jong BA, van Oosten BW, Moraal B, Teunissen CE, Uitdehaag BM, Killestein J, Kempen ZLV. Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic. Mult Scler. 2021 Jul 9:13524585211028833. doi: 10.1177/13524585211028833. In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks (Thus dosing was delayed by 6 to 14 weeks) . No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

They delayed infusions in South America also

Chertcoff- A, Bauer J, Silva BA, Aldecoa M, Eizaguirre MB, Rodriguez R, Chereque A, Rodríguez Heudebert ML, Milanesi V, Morales L, Castellón M, Mejía Pineda S, Ferrandina F, Henestroza P, Ruiz Peraza M, Vallecillo Rivas F, Cedeño Lopez L, Herrera L, Sosa M, Cruchet Muñoz V, Barahona AS, Ramírez Gudiño LM, Carballido S, Walton C, Peeters LM, Rijke N, Garcea O, Carrá A, Alonso R. Changes on the health care of people with multiple sclerosis from Latin America during the COVID-19 pandemic. Mult Scler Relat Disord. 2021 Jun 30;54:103120. doi: 10.1016/j.msard.2021.103120.

There is nothing new here, if you are a regular blog reader, but the fact that we are seeing this over and over again suggests the original observations were more or less correct and that you don’t need to examine hundreds of thousands of people to get the answer.

Lastly we can learn from other conditions and this time it is Lupus. However in terms of vaccine response there are boogie drugs like there are in MS, but again the suggestion of one factor that relates to vaccine response is the levels of B cells and notably the number of naive (mature) B cell numbers. Here you can see antibody response and the level of B cells and you can see levels about Q1 (Quartile (Quarter 1) bottom 25%) resulted in better antibody response

BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in Systemic Lupus ErythematosusMoyon, Q., Sterlin, D., Miyara, M., Anna, F., Mathian, A., Lhote, R., Ghillani-Dalbin, P., Breillat, P., Mudumba, S., de Alba, S., Cohen-Aubart, F., Haroche, J., Pha, M., Boutin, T. H. D., Chaieb, H., Flores, P., Charneau, P., Gorochov, G., Amoura, Z.10.1101/2021.07.07.21260124 — Posted: 2021-07-08

Q1 median was Q1 =9 cells/uL (less than 25), Q2 =41 cells/uL, Q3 68 cells/ul, 133 cells/ul

Do we measure B cell numbers?. I don’t think the neuros do.

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

50 comments

  • Isn’t it Euro 2020?
    I’ll be cheering England today (because 55 years of waiting isn’t fair)

  • It’s not just the UK powers that be that conveniently ignore the issue around vaccinating immune suppressed patients…

    All official communications seem to ignore it.

    • There have been trials….but unsurprisingly they filled the studies with people with cancer. It is clear to me it is the immune cancers and their treatments which create the issue. I am sure the Joint Committee will eventually see this. We should be doing trials so that we can advise better. At the moment I see the booster being a problem, if you didnt respond for the first two you are struggling there are things that should be done.

      • “Things that should be done.” Is it something like removing or chelating the anticd20 from your blood? I thought you may have implied that in a previous post. If so, what is that process?

        • No I have not suggested removing the anti-CD20…but this could contribute to more rapid recovery of your B cells…and perhaps reduce the efficacy of your treatment too. The amount of antibody given is so high that enough will hang around for months to cause depletion. In terms of my suggestions these needs dicussion internally before blogging

  • MD, thank you for this. It is extremely helpful.
    The Dutch study states:

    “Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks (Thus dosing was delayed by 6 to 14 weeks).”

    The Swiss study states:

    “Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/µl), and CD4+ lymphocyte count (>653/µl) predicted humoral vaccine response..”

    Questions:
    1. What is the normal range for CD19 B-cell count and CD4+lymphocyte count?
    2. In the Swiss study they stated amounts predicted for humoral response, so based on that study can one reasonably assume that if one’s B cell reaches > 27/uL and CD4 lymphocyte count reaches at least 653/uL there is a good chance to not have a blunted vaccine response?

    As always, thank you for your insights.

    • The lower limit of normal is about 80 cells per microlitre for CD20 the range is about 200-250. For CD4 the range is about 800-1000 and AIDS occurs when it drops below 200.

      “Predicted” ……be careful we have been listening to the imagers for too long….the prediction gives indications….as far as I can see there are exceptions to these predictions both ways. Also please be aware even when you make a vaccine antibody response from what I have seen it appears blunted. However with these limits it allows you to do the study and ask how many people benefit.

  • Thank you for sharing all the studies.
    So the Swiss use different tests and i dont understand them anyway.
    My wife is on OCR and there were no antibodies detectable in two tests (4 and 8 weeks after Pfizer jab given 6 months after last OCR dose ).
    So we did this ELISPOT t cell assay where we got the result for IFNg of 14 and IL2 of 24 (both with stimulation index threshold of >3 „significant reaction“).
    I heard the Elispot stuff is not reliable? What would be your interpretation – if you want to do that?
    Thank you very much!

    • Many people use ELISpots but there are different results depending on the test just as there are differnt results depnding on the antibody test. 6 months is not enough time for B cell recovery for the majority of people….we know that from repopulation studies as mentioned in the phase III to get to the lower limit of normal in some people took 3 years.

      ELISpot assay measures T cell response and the information suggests a T cell response was made which is good news. This is the good news that we and the manufacturers want to spin, but to me it is not clear if everyoe will make a good response.

          • well there are 2 certain things in life:
            a) its a b-cell problem
            b) england will never win a penalty shootout
            😆

          • Four certain things………
            c) The NHS is never safe in the hands of the Tories.
            d) The boneheaded, knuckle-dragging racists will direct vile abuse at the England squad at the first opportunity, sure as night follows day. Another reason I’m quite pleased the Italians triumphed.
            🙁

    • The strategy of a 3rd dose of mrna vaccine is a step in the right direction, but to mix metaphors, it may result in treading water, if indeed the recipient’s b cells have not repopulated to a point where an amtibody response can be generated. also, it has been observed that those on anti cd20 (i.e. Ocrelizumab) may have a diminished t cell response as well. my take away, and I could be completely off base here so don’t rely, is to wait until b cells repopulate and lymphocytes, then consider revaccination. as mentioned above, long interval between last dose and jab(s) likely needed. too bad monoclonal antibody cocktail not offered despite large scale trial showing it works as a prophylaxis. also wonder if bridge therapy such as natalizumab can be used if someone that is off anti cd20 waiting for b cells to repopulate before vax?

      • The third dose will get peoples antibody levels up and that gives sterilizing immunity that stops the virus infecting. However, I think thought needs to be given before we plough on. In terms of cancers there it has been found to be of value for solid tumours so it makes sense, but for blood cancers it may not work. Interesting idea of a bridge, but whether this happens I wonder.

        • Has there been any evidence of actual sterilizing immunity from covid vaccination? If I am not mistaken, sterilizing immunity means no ability to transmit the virus. Quite a high bar in the vaccine world I think. With covid I think an intranasal/mucosal vaccine will be needed to achieve sterilizing immunity but I could be wrong on this. Indeed, what we will eventually need is a pan-coronavirus vaccine so that we no longer have to chase variants. Such a vaccine is being pursued and hopefully will be successful in trials.

          • Has there been any evidence of actual sterilizing immunity from covid vaccination?

            Good point hard to know maybe call it asymptomatic immunity

        • “also wonder if bridge therapy such as natalizumab can be used if someone that is off anti cd20 waiting for b cells to repopulate before vax?“………Be mindful of carryover PML risk jumping between OCR and NAT.

          • (1) If one was to transfer (back) from Ocrevus to Tysabri, what is the best method to reduce the PML risk? (2) Is it correct that when changing back to Ocrevus the JCV test is no longer a reliable indicator of whether one is JCV + or not? Thanks for insights.

  • Hi MD, I’m on Ocrelizumab and I took the second BNT162B2 jab last Friday, had a little fever and a swollen lymph node. The lymph node on my neck is currently causing a lot of pain, affecting sleep, shooting sharp pain every few minutes and lasts for few seconds, it’s been like this since Saturday..

    May I ask if this is normal (to get so much pain from infections/vaccines) at all? What could be causing the shooting pain?

    So far I have not taken any painkillers for a better chance of mounting some immunity, it’s been very difficult.

      • I’m certainly no doctor, but as far as I know, paracetamol or any over the counter NSAID will have no effect on your immune system response at all.

        • Not quite true, paracetamol has a weak effect on prostaglandin synthesis, which is a pro-inflammatory immune mediator.

          • Ah, okay. But I’m assuming it would have no significant deleterious effect on vaccine response, since I was advised to take it prior to my 2nd shot to avoid incapacitation by my Uhthoff’s.

  • Superb play by Italy, and thank goodness, or we wouldn’t have heard the end of it in the “UK” for years.

    • Quite and Johnson and his goons would have been sleazing all over it and trying to bask in the reflected glory. The pics of Johnson, Patel and Sunak in their hastliy purchased England shirts were hilarious.

  • Living in The Netherlands
    As I posted since the beginning of Covid my neuro decided to postpone my Ocrelizumab until b-cells were close to lowlevel normal again (0,054/0,080) 41 weeks between my doses.

    I had nothing close to a relaps. (Knock on wood)
    But I guess I’m SPMS by now.
    Atrophy probably still getting worse.

    I’m happy the Dutch Neuro’s posted this paper.

  • Well, CDC is no better. They appear to not be prioritizing management and treatment options for those of us on anticd20 therapy; no antibody testing for vaccinated immune compromised and no booster. My consolation prize that monoclonal antibodies are available in my area should I contract Covid is less reassuring now too. It works best in early first days of infection and needs to be tailored to variant. Can my local hospital Id the variant strain so quickly? No, the FDA and CDC appear to be recommending choosing a monoclonal cocktail based on general known prevailing variant in area.. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Contrast with NY City Health Dept posted letter guidance a month ago that a certain monoclonal cocktail isn’t active against Beta and Gamma. https://www1.nyc.gov/assets/doh/downloads/pdf/covid/providers/covid-19-providers-dear-colleague-updates-06172021.pdf . Thus Survival of Covid if on anticd20 is now dependent on even more variables including: does your geographic location have adequate surveillance to determine variants circulating, is the chosen monoclonal cocktail going to be active against the variant strain contracted?, did you have access to quick Covid test results in time to get monoclonal antibodies early in course of illness? Self -isolation is best protective measure my govt can offer me??? Self-isolation is barely referenced.

    • “They appear to not be prioritizing management and treatment options for those of us on anticd20 therapy”; no antibody testing (maybe they know that most people make a blunted response) for vaccinated immune compromised and no booster (maybe they know there is limited value). Yes i am playing devils advocate, however boosting when there are no B cells to respond is proably a waste of time, unless proved otherwise. This should be being tested now…it will take a few weeks to get the answer.

      Antibodies available should I contact COVID…this is the wrong way to use them in B depleted people (this is opinion only) antibodies after infection have limited value

      • and yes CD20 patients might catch sars-covid2 but others as well as antibody levels will become too low…MD can we conclude from this older research of sars1 (https://pubmed.ncbi.nlm.nih.gov/25056892/
        Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection)
        that t-cell positive cd20 patients (Elispot or Igra test) should be well prepared and not just for months but maybe years-especially if sars covid2 follows the „usual“ pattern and gets less lethal by jsut staying in the upper respitatory tract?
        or i‘m too optimistic?

      • That’s why an effort should be made to offer the antibody cocktail (for example, Regeneron) as a prophylaxis against covid. A relatively large, double blind, placebo controlled trial found it safe and over 80% effective in household contacts of people diagnosed with covid. Alas, crickets, from health care policymakers on guidance for people with no response to vaccine.

        • Sadly, using this prophylactically on a regular basis is not an option as you would soon develop an immune response to the antibody cocktail, rendering it ineffective and would also be much too expensive to use in this way.

          • Is there evidence to the antibody cocktail’s durability? I haven’t seen data on that so if you have seen it I’d be grateful if you passed it along.

          • Off the top of my head, I’d say it probably has a half-life in the circulation of up to 21 days or so after infusion.
            You can find details here from Regenerons study (slide 36).
            Looks like I’m in the right ball park.

  • Again, I know we try, and then default to, the tweaking of data and its interpretation, in order to (in the end), give us confidence so that we can go out into the world and feel at least somewhat “normal” in the aspects of life that matter most to us (varies by the individual). This now involves not only the best MS treatment, but covid preparation (or at least consideration). Although I don’t understand nearly as much as I’d like regarding B cell depleting therapies, from what I read and can understand here and elsewhere, B-cell depletion is not the hoped-for end-all in MS and may not be the “super-dooper” treatment that you can’t live without. Existentially, we are all in the same boat, which, eventually will sink no matter what you do. Given this, I think it is very rational to consider a different therapy. Just like with vaccination- “anything is probably better than nothing”, you can say the same about other MS treatments too (which we know are much better than nothing). There is some additional time to waste while your immune system recovers, but the feeling of going out in public and not being too concerned about the potential idiot standing or sitting next to you, is a very nice, “freeing” feeling. Others can be an idiot, or immunocompromised, and you don’t have to care, just like before. You no longer have to be over concerned with- masks, visitors, strangers, covid treatments, employers, vaccination requirements you don’t fit into, airplanes… on and on.

    • But the feeling of going out in public and not being too concerned about the potential idiot standing or sitting next to you, is a very nice, “freeing” feeling…..Will it happen in the near future?

      • still there was no answer but i thought in the end that if you had a t-cell response it might protect you for a while? so that u can go on with caution but half way normal life?

        this was my question
        and yes CD20 patients might catch sars-covid2 but others as well as antibody levels will become too low…MD can we conclude from this older research of sars1 (https://pubmed.ncbi.nlm.nih.gov/25056892/
        Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection)
        that t-cell positive cd20 patients (Elispot or Igra test) should be well prepared and not just for months but maybe years-especially if sars covid2 follows the „usual“ pattern and gets less lethal by jsut staying in the upper respitatory tract?
        or i‘m too optimistic?

    • I’m genuinely trying to understand your comment. Is your point that the risks or burdens of B cell depleting DMT, whether related to covid vaccination or otherwise, is not worth the benefits?

      • Who are you asking the question too. I am certainly not saying risks od anti-CD20 are not worth it

        • Nope, not your comment, MD. It was in reply to TOMPHD. I may have misread his comment. Apologies.

          • Boots on the ground give you best insight as to the the way the war is going: Springfield Missouri Local hospitals report they stopped using bamlanivimab etesevimab monoclonal cocktail late June after The U.S. Department of Health and Human Services put a pause on its distribution because Federal health officials say it’s not effective against the Gamma or Beta COVID-19 variants, which are spreading in that area. Hospitals there planned to switch to casirivimab and imdevimab cocktail, but big but, need to work out “logistics.” Essentially monoclonal antibidody infusions use up a lot of out treatment space and resources which are neede to treat other ailments. KY3 News puvblished July 8; 2021 https://www.ky3.com/2021/07/09/antibody-infusion-treatment-give-hospital-ozarks-hope-covid-19-cases-spike/. I just saw a hospital administrator on US National news tonight explaining why monoclonal antibodies aren’t available in Their hospital at moment because of lack of out patient facilities to take on volume.

  • Are monoclonal cocktails beneficial to preventing death for immune compromised pwms on anticd20 and other B cell depleting therapies, that contact Covid???. If yes, Regional policy makers please please plan now on how to deliver monoclonal therapies to pwms. Missouri is harbarginger. 28% test positivity rate this week. Hospitals are currently asking for undefined state funds to build off site field hospitals to perform infusions and transfer stable Covid patients. MO Covid rates https://www.mayoclinic.org/coronavirus-covid-19/map/missouri. MO hospitals want state funds https://thehill.com/policy/healthcare/563296-missouri-county-requests-funds-for-alternate-hospital-site-to-relieive. If no, what therapy should pwms who contract Covid take other than Tylenol!?! (CDC recommendation for at home recovery)

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