[CIS PIDD] [cis-pidd] IgG2 subclass deficiency with recurrent infections

[Seppänen Mikko]

Dear Stan,
(and thanks to Charlotte Cunningham-Rundles, see furthest below)
recurrent viral mening(oencephal)itis, even w/o clinical HSV2-infection (in 50% of pts), if patient is HSV2 seropositive in gC1/2-based anti-HSV ELISA, would direct my thoughts to recurrent HSV2(/rarely 1)-meningitis, patients suffering from it are often atopic, in my experience have a lot of mucosal problems (asthma, allergies, polyposis, atopy etc.) and are often MBL2-deficient (and have HLA-DRB1*01 tissue type).
HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration may predispose to herpes-associated recurrent lymphocytic meningitis.<http://www.ncbi.nlm.nih.gov/pubmed/19879913>
Kallio-Laine K, Seppänen M, Aittoniemi J, Kautiainen H, Seppälä I, Valtonen V, Färkkilä M, Kalso E, Lokki ML.
Hum Immunol. 2010 Feb;71(2):179-81.
Recurrent lymphocytic meningitis positive for herpes simplex virus type 2.<http://www.ncbi.nlm.nih.gov/pubmed/19624935>
Kallio-Laine K, Seppänen M, Kautiainen H, Lokki ML, Lappalainen M, Valtonen V, Färkkilä M, Kalso E.
Emerg Infect Dis. 2009 Jul;15(7):1119-22.

Mannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection.<http://www.ncbi.nlm.nih.gov/pubmed/19480845>

Seppänen M, Lokki ML, Lappalainen M, Hiltunen-Back E, Rovio AT, Kares S, Hurme M, Aittoniemi J.

Hum Immunol. 2009 Apr;70(4):218-21

Since her disease was not clear encephalitis (?), I would not be very eager to test for TLR3-pathway deficiencies.
C. Biron's original article describing NK def (NEJM 1989) turned out to be MonoMAC/DCML/GATA2 (?right?): is she monocytopenic?
The MCM4 def/ NK def includes growth failure, adrenal insufficiency  etc. There are yet to be found ones still out there, for sure.
Patients with recurrent sinusitis have often slight disturbances in IgG-SC profile. Like prof Cunningham-Rundles and J Routes pointed out, her IgG2 seems pretty normal, for clear IgG2-deficiency one would love to see IgG2 also less than 10% of total IgG. Anti-PnP-titer after Pneumovax was normal, so I would not think of PAD in the form of IgG2D+S(P)AD, though admittedly serotype-specific assay was not used. See for discussion:

Controversies in IgG replacement therapy in patients with antibody deficiency diseases.<http://www.ncbi.nlm.nih.gov/pubmed/23540617>

Gelfand EW, Ochs HD, Shearer WT.

J Allergy Clin Immunol. 2013 Apr;131(4):1001-5.
..and in border-line cases it is often meaningful to systematically go through all possible typical Ab-deficient patient's manifestations that would point towards IgGRT, prof Cunningham-Rundles and Agarwal  have just published an - in my mind very worthy - article on the subject, which could serve as opening to more studies and systematic approach in s.c. "possible CVIDs". See:

Treatment of hypogammaglobulinemia in adults: A scoring system to guide decisions on immunoglobulin replacement.<http://www.ncbi.nlm.nih.gov/pubmed/23518142>

Agarwal S, Cunningham-Rundles C.

J Allergy Clin Immunol. 2013 Mar 18. doi:pii: S0091-6749(13)00196-6. 10.1016/j.jaci.2013.01.036. [Epub ahead of print]
...in everyday practice this may become one of Your favorite articles...? Should be formally tested/repeated in different cohorts of course, but it also gives - in a nutshell - a nice frame to evaluate systematically new patients (and is much in the same vein as in our unit). I personally would probably have liked to see EUROClass added to the list of lab.tests, if vaccine responses are abnormally low and there is no secondary cause for that? It is however one of my very favorite articles on Clin Immunol in recent years, tackling an everyday problem. Many warm thanks to authors from Finland!!!!!!!!!!!!!!!
Hope this helps, Stan. It is Labor Day's Eve, a big celebration in Finland, and I head off from work!
mikko
__________________________________________________
Mikko Seppänen, MD, PhD, Docent (Associate professor/Senior Lecturer)
Specialist in Internal Medicine and Infectious Diseases
Senior Consultant, Physician in charge (PIDD)
EM(E)A Expert, PIDDs and Intravenous Immunoglobulin Therapy

Immunodeficiency Unit
Division of Infectious Diseases
Department of Medicine
Helsinki University Central Hospital
Hospital District of Helsinki and Uusimaa
Aurora Hospital, Ward 4-2 and Outpatient Clinic
P.O.Box 348
FI-00029 HUS, Helsinki
FINLAND
phone +358 9 47175923, fax +358 9 47175945
_________________________________________


Lähettäjä: Stan Ress [mailto:Stan.Ress at uct.ac.za]
Lähetetty: 30. huhtikuuta 2013 0:15
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] IgG2 subclass deficiency with recurrent infections

Dear Colleagues,

I've been referred a 54 year-old lady for evaluation of Ig deficiency. She gave a history of recurrent sore throats & especially sinus infections during childhood, with repeated courses of antibiotics. These continued into adulthood, and in her 20's she had 2 episodes of viral meningitis. She gives a history of "encephalitis" with fever and was hospitalized twice for this diagnosis, in 2010 & 2012. She was treated with IV antibiotics, but says it was "felt to be viral".  Since September 2010 here have been recurrent sore throats, sore ears, and sinusitis treated with antibiotics. She has been under an ENT & a sinus scan was apparently clear. In June 2012 serum Ig results showed normal IgA, IgM 0.45 (0.5-2.5 G/L), IgG 6.89 G/L (7-16 G/L) IgG1 4.66 (4.05-10.11) IgG2 1.24 (1.69 -7.86) IgG3 0.12 (0.11 - 0.85) IgG4 0.09 (0.03-2.01). She was given intramuscular Ig for 2 months. In August 2012 there was an apparent "PUO" and after oral antibiotics she was treated with IV antibiotics for 10 days. In January 2013 IgG2 was again subnormal 1.53 G/L. Flow cytometric absolute counts: CD19 B-cells 346 (200-400), CD3 1835 (11-1700), CD4 1350 (700-1100), CD8 490 (500 -900), CD4/8 ratio 2.76, NK cells 196 (200-400). C3 normal, C4 0.19 (0.2 -0.5). CT chest - NAD.

She was given a course of IVIG in October 2012 and again on 7 February 2013. After this in February 2013 she had 3 courses of antibiotics for recurrent sinusitis. In January 2013 while off IVIG, IgG ELIZA baseline vaccination status was determined: Tetanus toxoid was 0.66 (sufficient protection), H. Influenza  was 0.57 (>1.5 for adults), Strept. Pneumonia was low at 32.82.

I first saw the patient & repeated her Ig levels in April 2013, 2 months after her last IVIG injection. IgG 7.42, IgM 0.66, IgG subclasses again isolated reduction in IgG2 1.58 (1.69 -7.86). Repeat of pneumococcal IgG ELIZA 3 weeks after pneumovax 24 vaccine, was >270 indicative of a good response (although we are unable to measure individual pneumococcal serotypes in our setting). I will also give her H. Influenza vaccine, it is currently out of stock.

She may be evolving into CVH & the plan will be to monitor & carefully document all infections, with isolation of organisms if possible. Most of her infections seem to be viral without an acute phase response (raised CRP, etc).

I would appreciate advise regarding the following questions:

1. She travels extensively for her work and is about to embark on a 7 week trip to Morocco, Japan & USA. Aside from normal hygiene measures, she asks what protective measures she could take for this trip? Would there be a role for empirical IM immunoglobulin prior to departure & perhaps again after 4 weeks while abroad? Any role for prophylactic antibiotics?

2. Given her clinical picture, and the reduced IgG2 with total IgG either reduced or on lower limit of normal, is there an indication for Ig replacement? (perhaps SC weekly "push" IG would be easier to motivate for insurance cover, than monthly IVIG). It's difficult because of her good response to pneumovax 24, although of course this conclusion is tempered by lack of information on individual serotypes, and the response to H. Influenza still needs to be done .

Any advice on these questions & further investigation and/or management of the patient would be appreciated.

Thanks & Regards,

Stan Ress


--
Stanley Ress
Associate Professor of Medicine
Head: Division of Clinical Immunology
Department of Medicine
H47 Old Main Building-room 26
Groote Schuur Hospital and UCT
Observatory 7925
Cape Town
South Africa
TEL:INTERN. + 2721-4066201 or 4066197
FAX:   "    + 2721-4486815
Cell: 0833115482
email: stan.ress at uct.ac.za<mailto:stan.ress at uct.ac.za>


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