Can IgA antibodies ever cause HDFN in humans?

[Mabel Adams]

We have a 27 wks pregnant lady in with anti-E that has had a tube titer of about 1-2 since Aug. Her last baby was born in 2011 and at 6 wks old still had a bili of 17 after peaking at about 25 at 1 wk old. It wasn't till that baby's 6 wk test that we found that mom had an antibody--prenatal screen was neg and she is A pos so no DAT at birth. Baby still had a pos DAT of about 2+ at 6 weeks and we found anti-E in his plasma--albeit at lower strength than mom had at the time. So, I am grasping at straws to explain why he had such a persistent high bilirubin and pos DAT and wondered if humans ever have IgA anti-E in breast milk that causes HDFN. I know that horses get HDF (foal?) entirely from the antibody being in colostrum so I don't think I am totally nuts (at least about this). Below are those bili results.

Other explanations welcome too.

[TABLE=width: 515]

[TR]

[TD=class: xl25, width: 79, bgcolor: transparent]birth 7/18/11[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/20[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/26[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/27[/TD]

[TD=class: xl27, width: 32, bgcolor: transparent]Aug[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]8/31[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]9/2[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]9/5[/TD]

[/TR]

[TR]

[TD=class: xl23, bgcolor: transparent]T. Bili[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]6.3[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]24.2[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]25.2[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]19.9[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]16.9[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]13.9[/TD]

[TD=class: xl23, bgcolor: transparent] [/TD]

[TD=class: xl24, bgcolor: transparent, align: right]17.0[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]13.7[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]7.4[/TD]

[/TR]

[TR]

[TD=class: xl22, bgcolor: transparent]D. Bili[/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent, align: right]0.4[/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent, align: right]0.4[/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[TD=class: xl22, bgcolor: transparent] [/TD]

[/TR]

[/TABLE]

[Malcolm Needs ☆]

I must admit that I have never heard of IgA antibodies causing clinically significant HDFN in humans Mabel, particularly at such a low titre, but that does not mean that it hasn't happened.

On this occasion, however, there is another thing that spring to mind that should be investigated to ensure that the baby's positive DAT is not just a "red herring". Have the mum and bay been tested for parvovius infection?

The other thing is, have you tested the father's red cells against the mother's plasma (after adsorption, to take out her anti-B, if they are not ABO compatible, and to take out her anti-E), just in case she has made an antibody that is directed against a very low incidence antigen that is expressed on both his and their son's red cells? SUch an antibody may not be detected with routine screening and antibody panel cells, but may cause the results you are finding with their baby son. It's a long shot, I admit, but it may be the answer.

[PAWHITTECAR]

Excellent suggestion Malcolm! Having worked for many years in pediatric blood banking I have seen this many times. Mom's antibody screen is negative at the referring hospital and then we have a positive screen and identify a low incidence antibody.

[Mabel Adams]

Mom's antibody screen was found to be positive with anti-E at the same time as we discovered that the baby had a pos DAT. The weird thing is that the baby was 6 weeks old at that time. Also, my titer is an IgG titer and it was first done Aug 2012. I have no way to titrate IgA (should it be present or even possibly meaningful). I am looking for a reason that the anti-E was still detectable in the baby's plasma (reacted 3 E + cells and neg with 3 E- cells) when he was 6 weeks old when it was such a low titer at the time of delivery. In Dec 2010 mom's antibody screen was neg and by Sept 2011 it was pos (when baby was 6 wks old). So if that pregnancy was a primary sensitization, she should have made IgM anti-E for awhile and maybe still had some of that at the time of delivery. If it was an anamnestic response then she might have had all IgG so it could all cross the placenta. Maybe it is more common than I think for antibody to be detectable that long in a baby but we usually don't test 6-week-olds who got a dose of passive antibody. Or maybe, as you suggest, the mom also has an antibody to a low freq antigen that is a much higher titer and so would be expected to still cause a pos DAT of 2+ at 6 weeks of age. But I still think it is weird that the anti-E was still detectable in the baby that strongly after 6 weeks.

[PAWHITTECAR]

Having the anit-E still detectable in the baby at 6 weeks would not be that unexpected. It sometimes takes several months for an antibody passed from mom to become undetectable in baby. I do have a couple of questions (excuse me if you have already answered them). Did you do an antibody screen on baby right after birth or just the DAT? also did you antigen type baby for E?

[Malcolm Needs ☆]

Having the anit-E still detectable in the baby at 6 weeks would not be that unexpected. It sometimes takes several months for an antibody passed from mom to become undetectable in baby.

True PAWHITTECAR, so have I, but never when the titre is so low. If you think about the fact that the t-a-half for IgG is 21 days (and that for IgA is 6 days), it still seems very unlikely that the maternal anti-E is the answer - not impossible, but very unlikely.

The other thing is that Prof. Jack Hobbs did some work on IgG concentrations in mothers' blood and babies' blood and found that the concentration in the babies' blood is higher than that in the mothers, and yet, in this case, the reactions with the mother's plasma at 6 weeks was higher than that of the baby's plasma. That, of course, could be because the mother had been producing more anti-E between birth and 6 weeks post-natal, but???????????????

The mystery about why IgM anti-E (if it were a primary sensitisation) is easily answered in that IgM production for a "genuine" immune antibody directed against an Rh antigen usually only lasts a very short time, whereas a "naturally occuring" IgM anti-E tends to "hang around" as IgM for ages. On the other hand, I would agree with Mabel that it is not an anamnestic responce.

I'm really not convinced that the anti-E is at the root of the problem - but I'm not at all sure what is either!!!!!!!!!!!!!!!

[PAWHITTECAR]

Though very rare it would not be inpossible for the baby to be making the antibody himself...But I agree that it is much more likely to be something other than this anti-E that is causing the problem.

It could even be something totally unrelated to immunohematology that is causing the increase biliruben...diet? liver problems??

[Mabel Adams]

Blood bank knew nothing of this baby until he was 6 wks old in Sep of 2011. At that time he had a 2+ pos DAT, anti-E in his plasma and an eluate that contained anti-E. He is positive for the E antigen. He is A pos and his D control was negative as expected so I trust the E typing. His mother was then tested at the same time and found to have anti-E reacting 3-4+ in gel (not titrated then). When she had prenatal work for the current pregnancy in Aug of 2012 she had an IgG tube titer of anti-E that was and has remained 1-2 including one run today. Her anti-E reacts 2-3+ in gel at this time--so a bit weaker than in 2011.

When cells coated with antibody are removed by the RE system is the antibody removed from the circulation or is it realeased back into the circulation after the RBC is removed? It seems like that would affect the half-life of the IgG--if the baby's RBCs were adsorbing it out. If it should get removed, then would the avidity of the anti-E affect the antibody-antigen equilibrium and, if less avid, shift it toward being free in the plasma rather than attached to the RBCs?

This matters now because this mom is in-house with a complete previa. She came in bleeding 3 weeks ago at 24 wks gestation and that has subsided but they are afraid of hemorrhage so are keeping her in. I am looking at the previous baby's history and wondering if they need to be checking this baby via ultrasound for hydrops. If it was a low freq that caused the previous HDFN then the odds of this baby being positive are probably 50% but the titer could be even higher so if she loses the toss it could be more serious. If it is just the anti-E that was behaving a bit strangely then watching the titers might be sufficient, right?

[PAWHITTECAR]

I would be more apt to believe that it was a low freq and would strongly suggest monitoring the baby closely for hydrops. Better to err on the side of caution.

[Malcolm Needs ☆]

I would be more apt to believe that it was a low freq and would strongly suggest monitoring the baby closely for hydrops. Better to err on the side of caution.

I entirely agree, but I would still go that extra step (if it is possible) and test the father's red cells against the mother's plasma.

Obviously, you would have to adsorb out the anti-E, as the father is obviously E+ (otherwise the previous baby would not have inherited the RHE gene and be expressing the E antigen on his red cells), and, as I said in an earlier post, you may have to adsorb out the mother's anti-B, if the mother and father are ABO incompatible, but it may be worth doing.

One thing that I would say is that any plasma from the mother should be split into two and each adsorbed with a different souce of group B, E+ red cells, just in case the one that you choose happens, by Murphy's Law, to express the very same low incidence antigen as, perhaps, does the father, and you adsorb out the, possible, antibody directed against the low incidence antigen in the mother's plasma.

It's a lot of work, but it may be worthwhile.

If, after all that, there is still only the anti-E present, we will have to have another think, but you may be able to get a short publication out of it to put on your CV!!!!!!!!!!!

[galvania]

I'm sure I don't need to say this, but have you ruled out the possiblity that something might be 'blocking' the reaction in the titre? Maybe the buffer you use to suspend the red cell? Or that you use to dilute the plasma/serum? Or that there might be a prozone? A 3-4+ reaction in gel seems a bit strong for a titre of only 1-2 for a 'real' anti-E.

[Mabel Adams]

We dilute the red cells and the plasma in saline with no additives. If the previous anti-E titer had been really high (prozone) I would have expected the previous baby to be even more badly affected, don't you think? We feel like we have seen quite a few patients that react 3 to 4+ in gel but have tube titers that are still pretty low. In my experience about everyone with a titer above 4 or 8 reacts strongly 4+ with all cells in gel. I appreciate all input because I hadn't really considered what you suggested, Anna, until you mentioned it. Thanks. And feel free to correct my thinking in response to your comments.

Malcolm, we don't really have the experience and resources to do the adsorptions you recommend--assuming we could get Dad's sample. It seems like we could keep this baby safe by just monitoring by ultrasound for hydrops (even if we don't know all antibody specificities). They will probably be doing US anyway for the previa. Although I would really like to know the answers to the tests that you propose.

[Malcolm Needs ☆]

Malcolm, we don't really have the experience and resources to do the adsorptions you recommend--assuming we could get Dad's sample. It seems like we could keep this baby safe by just monitoring by ultrasound for hydrops (even if we don't know all antibody specificities). They will probably be doing US anyway for the previa. Although I would really like to know the answers to the tests that you propose.

Actually, from the point of view of how the baby is healthwise, you are correct that ultrasonology is absolutely the way to go. Even if there is an antibody present directed against a low incidence antigen, the actual specificity is neither here nor there, as it would be easy to find compatible blood, if required. But like you say, it's frustrating not to know for sure!!!!!!!!!!!!!

[StevenB]

See: Transfer of antibody via mother's milk, Van de Perre, P Vaccine, vol. 21, issue 24, 28 July 2003.

[Yanxia]

We have a 27 wks pregnant lady in with anti-E that has had a tube titer of about 1-2 since Aug. Her last baby was born in 2011 and at 6 wks old still had a bili of 17 after peaking at about 25 at 1 wk old. It wasn't till that baby's 6 wk test that we found that mom had an antibody--prenatal screen was neg and she is A pos so no DAT at birth. Baby still had a pos DAT of about 2+ at 6 weeks and we found anti-E in his plasma--albeit at lower strength than mom had at the time. So, I am grasping at straws to explain why he had such a persistent high bilirubin and pos DAT and wondered if humans ever have IgA anti-E in breast milk that causes HDFN. I know that horses get HDF (foal?) entirely from the antibody being in colostrum so I don't think I am totally nuts (at least about this). Below are those bili results.

Other explanations welcome too.

[TABLE=width: 515]

[TR]

[TD=class: xl25, width: 79, bgcolor: transparent]birth 7/18/11

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/20

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/25

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/26

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]7/27

[/TD]

[TD=class: xl27, width: 32, bgcolor: transparent]Aug

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]8/31

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]9/2

[/TD]

[TD=class: xl26, width: 64, bgcolor: transparent, align: right]9/5

[/TD]

[/TR]

[TR]

[TD=class: xl23, bgcolor: transparent]T. Bili

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]6.3

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]24.2

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]25.2

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]19.9

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]16.9

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]13.9

[/TD]

[TD=class: xl23, bgcolor: transparent][/TD]

[TD=class: xl24, bgcolor: transparent, align: right]17.0

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]13.7

[/TD]

[TD=class: xl23, bgcolor: transparent, align: right]7.4

[/TD]

[/TR]

[TR]

[TD=class: xl22, bgcolor: transparent]D. Bili

[/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent, align: right]0.4

[/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent, align: right]0.4

[/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[TD=class: xl22, bgcolor: transparent][/TD]

[/TR]

[/TABLE]

I think it maybe ABO HDFN.

[Mabel Adams]

Both mom and baby were A pos.

[Auntie-D]

Cross posted with Mabel

[Auntie-D]

Did we ever get to the bottom of this OP??