[CIS PIDD] [cis-pidd] 12 year old with frequently recurrent episodes of facial HSV-1

[Seppänen Mikko]

Dear namesake Michael,

atopy itself does predispose, but in this case hardly only that, 

TH: 
...in my practice of adult uncomplicated herpetic eczema (appr 200 HSV-2, 50 HSV-1 adult patients treated over the years, with 8-24 episodes/year), the best medication is valacyclovir 500mg 1-2x2-3. Due to the metabolism and pharmacokinetic properties of vala, OD dosing is never effective in such patients (needs to be given at least 2, often 3x/day, the company chose OD probably for marketing reasons, nothing in premarketing or clinical or experimental studies suggest less frequent than twice daily dosing, and e.g. 250mg x2 >>> superior to 500mg OD).

Thus therapy-wise valacyclovir 500mg 1-2x2-3 (partly depends on how much the child weighs) and if this high a dose causes nightmares, GI disturbance or headache (in total in less than 5%), You can also try Famciclovir 500mg x2/day. 
The only problem for the 95% is the cost of vala (but at least in Europe the patent is gone and the price is now actually cheaper than acyclovir for many doses). Other than increased MCV I have not noted any troublesome long-term side effects, but long term use data is scarce with these doses and I do explain that this is an experimental approach. About 97-99% of patients with HSV2 reach CR, while (due to sunshine, flus??) CR is achieved in max 70% in HSV-1.


DG: 
If the child has no 
- DOCK8, 
- GATA2 (at 12-y of age, monocytopenia may not be that clear??), she does resemble C Biron's "first GATA-2" in NEJM, with NK def
- No other known NK def (both Jordan Orange and JL Casanova have authored very recent, excellent reviews on the topic, check them) 
- no signs of other combined immune deficiency (like CD3gamma def, in which almost all described mutation carriers have thyroid problems and also other autoimmunity is common, as well as atopy, but most but not all do have their CD8s low. Do You have stimuli other than mitogens available? tetanus toxoid?), 
- RAG1, RAG2, JAK3 hypomorphic mutation?
- of the known AI PIDDs, CD25, STAT5b and STAT1 GOF do have excess herpesvirus infections, as well as atopy and autoimmunity (see for example Verbsky JW, Chatila TA Curr Opin Pedatr 2013;25:708-14)

If all these seem to fail (DOCK8 testing, which is not covered in WES --> + WES, since that is over 10 candidates ????), ...

...due to the familial seizures and HSV, I might also be eager to contact prof Jean-Laurent Casanova and his group, to exclude hypomorphic TLR3-IFN-pathway mutations (described in one Finnish patient, the paper should come out soonish, has been submitted). Testing requires fibroblasts to be reliable. 

Good luck to Your search and I hope this helps,

Mikko Seppänen, 
Helsinki, Finland

-----Alkuperäinen viesti-----
Lähettäjä: michael clayton [mailto:mhclayton at msn.com] 
Lähetetty: 11. helmikuuta 2014 22:49
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] 12 year old with frequently recurrent episodes of facial HSV-1

Dear Colleagues:  

I wonder if you could offer advice on treatment of a 12 year old girl who has had frequently recurrent episodes of facial HSV-1 (culture confirmed) over the past 8 months.  She typically has an outbreak over her right cheek with a sense of tinglng, pain and warmth preceding the outbreak of vessicles.  No systemic symptoms.  No eczema or skin trauma.  Frequency is about every 10-14 days, and the longest interval between outbreaks has been 3 weeks.  She occasionally has an outbreak over lateral arm on same side and more rarely, over the lower arm.  She is developing chronic skin changes at these sites with thickening, mild hyperpigmentation and persistant stinging between outbreaks.  Stress and menstrual periods obviously make the episodes more severe, but starting an OCP has had no significant effect, nor did use of a high SPF sunblock daily over these areas.    The primary care provider previously had her use a daily regimen of acyclovir 400 mg BID with valacyclovir added in at onset of rash (500 BID).  Topical antivirals were not helpful.  I changed her prophylactic regimen to daily valacyclovir, also with no benefit. 
 
Other health history:
-Very atopic girl with multiple food sensitivities, both type I and II as well as environmental sensitivities.
-Long standing (earliest childhood) history of potentially autoimmune problems including alopecia, granuloma annulare, recurrent episodes of urticaria, intermittent joint swelling and pain with normal ANA, RF
-Suspected seizure activity with "drop attacks" associated with intense exercise, and emotional outbursts that are sustained and suggestive of a partial complex sz. disorder, but normal EEG and negative cardiac workup.  
-Obstructive sleep apnea.
-Asthma, step II well-controlled.
-Menorrhagia.
-Two outbreaks of varicella after receiving her varicella vaccine.

Family History:
Younger brother with eczema and seizure disorder.  Mother has alopecia areata, Two maternal aunts have Crohn's disease, maternal grandmother has lupus.  Virtually all adult females on maternal side have hypothyroidism.
No known immune deficiencies, or problems specifically with herpes or zoster.

Labs:
Nl CBC with diff
Immunoglobulins:  IgG 1230, IgA 138, IgM 229 (30-211)
Tetanus IgG= 2.5
Pneumococcal serotypes= 8/13 protective range
CH50= nl.
Immune deficiency panel (CD 16/56= 5%, absolute CD4= 1046, all others normal, as well)
Lymphocyte mitogen response panel normal
NK cytotoxicity profile at Mayo:  Diminished but not absent natural NK cell cytotoxicity which was comparable to shipping control.  Normal NK cell number (86 cells/ul.)
Negative Celiac Panel.
ANA, RF (-)

I plan to repeat the NK cytotoxicity panel, but wonder if anyone has other ideas regarding workup or treatment?  She is scheduled to see a Pediatric ID consultant within the month, and is followed by a Pediatric Rheumatologist without a diagnosis, thus far.  Thanks in advance,

Michael H. Clayton, MD, MPH
Albuquerque, NM
505-228-7958
mhclayton at msn.com






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