22 October 2010
Suppressed and Exposed: A Clinical Dilemma
A student in Pharmacy wrote with this question she's facing, which offers a good opportunity for you 7630'ers to comment. A grandmother has been taking care of her young grandkids, one of which has just developed chicken pox. Grandma is on long-term low-dose prednisone (a glucocorticoid steroid) for her rheumatoid arthritis. It is known that chicken pox can be severe, even deadly, in the immunosuppressed. She cannot remember if she ever had chicken pox, but has heard that there is a vaccine against the virus just for older people. She wonders if she should get that vaccine right away, or, because it's live virus and she's on prednisone, avoid it. What do you (or your sources) recommend?
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If this grandmother truly has not had chicken pox and has not received the Varicella immunization in the past, she should be considered to be non-immune and to be at risk for contracting Varicella given her household contact exposure from her grandchild.
ReplyDeleteAccording to the Red Book (The Report of the Committee on Infectious Diseases) 2009 edition, "Potential interventions for people without evidence of immunity exposed to a person with varicella include either:
1. Varicella vaccine administered ideally within 3 days but up to 5 days after exposure or,
2. When indicated, VariZIG (1 dose up to 96 hours after exposure).
3. If VariZIG is not available, IGIV (1 dose up to 96 hours after exposure) can be used.
4. Prophylactic administration of oral acyclovir beginning 7 days after exposure also may prevent or attenuate varicella disease.
To go through the options, the grandmother should NOT receive option 1. Varicella vaccine, due to the fact that she should be considered to be immunocompromised due to her chronic steroid use. According to the Red Book, a person receiveing 20mg/day of prednisone (or equivalent) for 14 days or more should not receive the live Varicella vaccine. "The recommended interval between discontinuation of corticosteroid therapy and immunization with varicella vaccine is at least 1 month."
She SHOULD receive passive immunoprophylaxis with option 1. VariZIG or 2. IGIV (specific immunoglobulins to Varicella) due to the fact that she is immunosuppressed. Immunoprophylaxis should ideally be given within the first 96 hours of exposure.
To be "extra" cautious, the grandmother would also be a candidate to receive option 4. oral acyclovir, beginning 7 days after exposure to help prevent or attenuate varicella disease.
For help with future discussions regarding need for Varicella vaccine in this grandmother once she is off steroids, it would also be beneficial for her to have Varicella IgG and IgM titers drawn prior to administration of passive immunoprophylaxis to help determine if she was ever truly non-immune. One should not hold treatment while awaiting these results, however.
Interesting, thanks StaceyM. I did see on the CDC site that anyone born before 1980 is considered to be immune to chicken pox. I guess it was so common at that time. That would surely include grandma... Everything else you said, they agree with, though some other groups seem to have different opinions.
ReplyDeleteAlso, the vaccine older (60+) folks get is tested just to prevent shingles (zoster); do you think it would also prevent a primary chicken pox attack?
Shingles is caused by the reactivation of the latent varicella zoster virus (VZV). According to the CDC Morbidity and Mortality Weekly Report,the zoster vaccine contains the same strain of VZV as the varicella vaccine, but has a 14-fold higer minimum PFU-content. The zoster vaccine could prevent primary a chickenpox infection, but the chickenpox is normally administered in two doses. The MMWR recommends that if the shingles vaccine is accidently given before a primary chickenpox infection, a second varicella vaccine should be given. This provides immunity against a primary varicella infection only.
ReplyDeleteWhat is the mechanism or immune suppression with corticosteroids or glucocorticoid? Why do physicians use steroids instead of more specific immune suppressive drugs like rapamycin, cyclosporin A, or FK506? How do these two groups of drugs compare to say OKT3 (assuming that you want to suppress Tcells)?
ReplyDeletePrimary varicella infection in the elderly:
ReplyDeleteThere is a nice case report from UK about a 94-year old woman who contracted primary varicella infection from her husband who had a secondary zoster ophthalmitis. Te work-up of the case is very neat: the IgM to varicella zoster virus (VZV) on day 2 of presentation was positive while the IgG was negative. IgM level increased further 2 days later with still a negative IgG and 15 days later seroconversion to VZV-IgG positivity occurred with IgM remaining positive. So there is no question this was a primary case of varicella infection in this old woman.
This case was treated with famciclovir and despite initial good recovery within a week, she died 10 days later with acute stroke and unilateral hemiplegia (postmortem was not done nor CSF examination).
In the discussion, there is reference of several other cases of primary varicella in the elderly (87, 86 and 88years) ..all of whom except one have died with later complications. Although the authors argue for reduced cell-mediated immunity in elderly, I would say based on our course material so far that it is rather that an elderly who has never been exposed to varicella before would be at increased risk of complications.
I like to quote this from the article conclusion:” In the UK, and other countries, the use of varicella vaccine in healthy children remains controversial; longer scrutiny of the cost benefits appears to be required. However, given the high risks associated with primary VZV infection in adulthood, it is hard to conceive why varicella vaccine cannot be offered to all susceptible adolescents and adults. If elderly persons are considered, in general, to be an unreliable group to question about a past history of chickenpox, either routinely or after exposure, at least the vaccination of younger adults may prevent even more serious disease when they are much older” 1
(1) Bendig J and Sindall F. Chickenpox at Ninety Four: A Case for Extending the Use of Varicella Vaccine in the UK. Case Reports in Medicine Volume 2010, Article ID 561707, 3 pages. doi:10.1155/2010/561707
Based on our work with latent VZV in human ganglia more that 93% of the human population is sero positive for VZV. I would first get her sera tested for antibodies for VZV. If she is sero negative, acyclovir should be given immediately. If she is seropositive for VZV, it really does not matter because exposure to the chickenpox virus will boost her immunity any way.
ReplyDeleteHi Elizabeth,
ReplyDeleteI find the review of the mechanism of immunosuppression by different drug groups that is written by Taylor et al. from Cambridge a nice one. Regarding steroids, it mentions the following anti-inflammatory and immunomodulatory effects: “stabilization of lysosomal membranes, suppression of prostaglandin synthesis, reduction of histamine and bradykinin release and lowering of capillary permeability. Corticosteroids cross into the cytoplasm and bind to glucocorticoid receptors, anchored in the cytoplasm by a complex of heat shock proteins. Binding permits release of heat shock proteins allowing the corticosteroid/ glucocorticoid receptor complex to translocate to the cell nucleus where it influences gene transcription, including transcription of the nuclear activating factor family of genes. These genes are important in activating the transcription and production of several pro-inflammatory cytokines and the net result is a decrease in the inflammatory response through reduced production of cytokines, including IL-1, IL-2, IL-6, IFN-δ and TNF-α. Corticosteroids also impair monocyte/macrophage function and decrease the number of circulating CD4+ T cells” 1.
Regarding why not to use some of the more specific immunosuppressants, well:
1. It depends on the clinical situation, the specific disease pathogenesis and the defined desirable target or outcome and this is usually based on clinical studies with control groups ..etc.
2. different drugs of course target different points in the immune system but also have different potencies as well as different side effects
So for example, if we are to discuss immunosuppression in the context of organ transplantation, it will be completely different from when we are discussing it for example in the context of altering the natural course in autoimmune type 1 diabetes (Note that type 1 diabetes is relatively benign when glycemic control is “adequate”! so the risk benefit of immunosuppression is a big issue in this context and if immunosuppression is to be used, then issues like specificity of the drug used, side effects would come on the top).
In the review I am referring to1, there is a table (table 1)1 that compares different drugs with regards to immunoseppressive potency, nephrotoxicity, neurotoxicity, skin rash, diabetogenesis, hepatotoxicity, diarrhoea, hirsutism and marrow suppression. With steroids, there is obviously also the risk of adrenal suppression and, therefore, withdrawal has to be carefully done. The review also goes through clinical evidence for each category of immunosuppressant drug in the context of solid organ transplantation.
I hope you find this useful
(1) Taylor AL, Watson CJE and Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Critical Reviews in Oncology/Hematology. 2005 ; (56): 23–46
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ReplyDeleteHi Ravi,
ReplyDeleteI think there are two different scenarios:
A. a patient exposed to a varicella case and is seronegative: then there are several important things
• According to the CDC (1) and the case study paper I referred to earlier (of primary varicella in elderly), serologic testing may be cost-justified. We are , however, talking about either an IgM response specifically (a four-fold increase in IgG takes time and simple IgG seropositivity could be of past immunity)
• In this case, and according to the CDC, varicella vaccination may prevent or significantly modify the disease if administered within 3 days of exposure and possibly up to 5 days post exposure. This is “post-exposure prophylaxis”(1).
• I think we should note, however, that chicken pox is infectious from 3 days before the development of rash.
• If there is a contraindication to the vaccine: such as in the case JJ posted, and the patient is at high risk of complications (eg elderly, immunocompromised..etc) then an VZIG is indicated (1) as Alyson detailed
B. A patient who has been exposed and now has the symptoms (eg rash), then treatment with an antiviral (acyclovir, famciclovir..) is indicated. In this case, diagnosing whether the patient is seronegative and this is a primary attack of varicella (initially IgM and IgG negative) or seropositive (with four fold rise in IgG) and is developing rather a reactivation zoster attack, would make a difference in the management: specifically antivirals are beneficial only when used within the first 72 hours of the rash in case of zoster (2) and corticosteroids are commonly used in treatment of zoster (2) whereas antiviral therapy in varicella is given only in elderly and high risk individuals and steroids have no place. Obviuosly, varicella and zoster have a different clinical picture too but serology would sure be of help early (as in the case report I posted earlier)
(1) http://www.cdc.gov/vaccines/pubs/surv-manual/chpt17-varicella.htm#top
(2) http://www.aafp.org/afp/20000415/2437.html