Undiagnosed Immunosuppression

[undiagnosed]

My health has been deteriorating with new issues compounding at a seemingly exponential rate. I don't have a diagnosis and don't meet the CFS criteria but am looking for advice in case anyone has had similar issues. I am not really getting anywhere with doctors which is very frustrating. For context, I'm a 28 year old male with a BMI of 20.3, not taking any medications.

I have had a number of lab tests done which resulted in a couple results outside the reference range and a number of results approaching the limits. Table 1 shows all lab results that were in the bottom 10% of the reference range. The Percent column was calculated using the CDF assuming a normal distribution with a 95% reference interval. Therefore 2.5% represents the lower reference interval limit.

IgG Subclass 1 is below the reference interval and in the bottom 0.89% of the reference population. I recently discovered this deficiency and am not sure if it would affect antibody production and invalidate the results of previous antibody tests. I am concerned about the possibility though. As can be seen, a number of other immune system related markers are approaching the lower limits as well.

My primary suspicion has been an infectious disease, possibly HIV, but the tests so far don't paint a clear picture. First of all, HIV tests as shown in Table 2 have been negative. The CD4 percentage and CD4/CD8 ratio are both in the bottom 5-6% of the reference population which could indicate a progressive loss of CD4 cells. I don't have enough data yet to determine the trend. Generally, immunoglobulin levels would be raised so the low total IgM and low IgG subclasses don't necessarily fit that. Although, maybe there could be multiple independent conditions. I'm less confident in the HIV-2 test result as it only detects antibodies. If my antibody response is weakened from the IgG Subclass 1 deficiency, maybe it wouldn't be detected.

Another thing I might expect is inflammation markers to be somewhat elevated. However as shown in Table 3, ESR and CRP are both approaching the lower limits of the reference range.

Also, I recently attempted to have the Spectracell Micronutrient test performed and found out that it failed. Apparently my lymphocytes didn't sufficiently respond to mitogen stimulation. The lab said the blood was fine, no hemolysis, sufficient volume, and sufficient lymphocyte count. However, they did ask if I was taking any immunosuppressant medication or had a known deficiency. They have the following message on the website for the test:

***IMPORTANT NOTE: If a patient has leukemia, HIV/AIDS, Auto-Immune Condition or is known or suspected to have a low white blood cell count, please collect 3 CPT tubes of whole blood. A low white cell count can result in too few viable cells available for culture and testing***

I figured since all of my lymphocyte counts were within reference ranges (not by a lot in some cases though) that it would work without the extra blood, but I guess not. The lab did say that the test doesn't work for some people, but it sounded rare.

For reference, here are the symptoms currently impacting my quality of life:

- Persistent Fungal Infections (skin and nails)
- Chronic Dry Mouth
- Vision Problems (increased floaters, reduced acuity)
- Joint Stiffness & Cracking (especially knees and ankles)
- Muscle weakness (especially legs, loose kneecaps, sore tendons)
- Foot Pain (foot pad atrophy)

 

[JaimeS]

Well, your IgG1 and IgG4 are both pretty low. That means you have IgG subclass deficiencies.

Generally, immunoglobulin levels would be raised so the low total IgM and low IgG subclasses don't necessarily fit that.

Generally, it appears that immunodeficiencies can arise in response to an infection. Hornig et al (2015) showed an initial period of immune hyperexcitation in ME, followed by a period of immune exhaustion. That is simplifying the study a great deal, however. You might like to read it.

Have you been tested for IgA? IgE? IgA deficiency often goes hand-in-hand with IgG deficiency. When you added your IgG subclasses all together, what was the total? This matters.

don't meet the CFS criteria

Which criteria are you referencing?

Hang around here, you're in good company. But I'd certainly look into IgG deficiency and intravenous immunogloblin as a potential therapy. Start looking for a good immunologist now, because they are few and far between.

Here are some other things for you to look at re: CVID, common variable immune deficiency.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904582/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267274/

http://www.ncbi.nlm.nih.gov/pubmed/19738033

Good luck!

-J

 

[undiagnosed]

Thanks, I'll check out that paper. Ya, I was tested for the other immunoglobulins. There were no deficiencies in the total immunoglobulins. Here are the results for the other immunoglobulins:

Test Result Units Range
IgG 955 mg/dL 700-1600
IgA 300 mg/dL 91-414
IgE 20 IU/mL 0-100

Regarding CFS, I was going by the CDC criteria listed at http://www.cdc.gov/cfs/case-definition/index.html. It's kind of subjective but for points 1 and 2, I do have fatigue but I wouldn't call it severe. Certainly some of the symptoms I have interfere with daily activities and limit what I can do, but it's more pain/discomfort than fatigue. For point 3, it says you need 4 out of 8 of the listed criteria. I appear to meet only two of those criteria.

It doesn't look like I meet the criteria for CVID as the total immunoglobulin levels are not deficient.

 

[Hip]

For reference, here are the symptoms currently impacting my quality of life:

Do you have any mental / psychological symptoms like anxiety, depression or brain fog? Any increased fatigue?


Your dry mouth symptom possibly suggests Sjögren's syndrome, whose symptoms are listed here.

 

[Kati]

Thing is... @undiagnosed,It's tricky for lay people, in this case, patients to make a diagnosis out of your labs and brief history. You need to know that immune globulin abnormality is not diagnosis of ME and you need to know that physicians who diagnose patients with ME or by all mean other diseases such as rheumatologic illnesses, do so with the help of various labs plus a very detailed history of onset of illness and its course.

Often times chronic fatigue syndrome is a waste basket and many patients who have been casually diagnosed by physicians hoping this difficult patient would simply go away, are diagnosed with something else down the road.

The best you can do for yourself would be to discuss your health concerns with a competent physician who will perform the right set of tests until you guys get satisfied that the diagnosis is solid.

Every single patient deserve this really.

Sending best wishes.

 

[Jonathan Edwards]

Thanks, I'll check out that paper. Ya, I was tested for the other immunoglobulins. There were no deficiencies in the total immunoglobulins. Here are the results for the other immunoglobulins:

Test Result Units Range
IgG 955 mg/dL 700-1600
IgA 300 mg/dL 91-414
IgE 20 IU/mL 0-100

Regarding CFS, I was going by the CDC criteria listed at http://www.cdc.gov/cfs/case-definition/index.html. It's kind of subjective but for points 1 and 2, I do have fatigue but I wouldn't call it severe. Certainly some of the symptoms I have interfere with daily activities and limit what I can do, but it's more pain/discomfort than fatigue. For point 3, it says you need 4 out of 8 of the listed criteria. I appear to meet only two of those criteria.

It doesn't look like I meet the criteria for CVID as the total immunoglobulin levels are not deficient.

Dear undiagnosed,
I agree with kati. Don't look here for help with diagnosis because that has to be done by a physician in the context of all the clinical findings and all the other lab tests.

Your immunological tests look pretty much within normal variation to me. The IgG1 is lowish but everyone has something lowish if you test 20 tests (by definition about one in 20 will be low on the reference ranges). IVIg is not appropriate unless there is a good clinical reason - which in the context of low IgG has nothing to do with ME symptoms, it is overt infections. Low IgG is not associated with ME as far as I am aware.

 

[msf]

Overt infections? So no IVIG for covert infections? I guess that makes sense, since you can´t prescribe something for something that you don´t know is there.

 

[undiagnosed]

Do you have any mental / psychological symptoms like anxiety, depression or brain fog? Any increased fatigue?


Your dry mouth symptom possibly suggests Sjögren's syndrome, whose symptoms are listed here.

Ya, I have had some increased anxiety. Regarding brain fog, the only thing that I've noticed is some difficulty speaking fluently. I take a lot of pauses to figure out what to say next.

I have a lot of the Sjogren's syndrome symptoms you linked to. I've had problems with dry mouth since 2014. Dry eyes has been more recent, a few months that they've been bothering me. I had the anti-SSA and anti-SSB antibody tests for Sjogren's which were negative. I also had an antinuclear antibody test that was negative.

 

[undiagnosed]

Thing is... @undiagnosed,It's tricky for lay people, in this case, patients to make a diagnosis out of your labs and brief history. You need to know that immune globulin abnormality is not diagnosis of ME and you need to know that physicians who diagnose patients with ME or by all mean other diseases such as rheumatologic illnesses, do so with the help of various labs plus a very detailed history of onset of illness and its course.

Often times chronic fatigue syndrome is a waste basket and many patients who have been casually diagnosed by physicians hoping this difficult patient would simply go away, are diagnosed with something else down the road.

The best you can do for yourself would be to discuss your health concerns with a competent physician who will perform the right set of tests until you guys get satisfied that the diagnosis is solid.

Every single patient deserve this really.

Sending best wishes.

Thanks for the advice. Unfortunately, I've exhausted my options with doctors at the moment. I really don't have anywhere to go that I feel confident would lead anywhere. My hope in putting this out there is to connect with people in a similar situation and share information. In the mean time I plan on collecting more data to see if it supports my hypothesis. I'm also going to see an ophthalmologist soon so if anything unusual turns up there, that could be a potential lead.

 

[Kati]

Thanks for the advice. Unfortunately, I've exhausted my options with doctors at the moment. I really don't have anywhere to go that I feel confident would lead anywhere. My hope in putting this out there is to connect with people in a similar situation and share information. In the mean time I plan on collecting more data to see if it supports my hypothesis. I'm also going to see an ophthalmologist soon so if anything unusual turns up there, that could be a potential lead.

Your blood work doesn't include Natural Killer cell function or NK cell cytotoxicity which is as close biomarker of ME as one can get.

Best of luck, @undiagnosed it's sure not easy.

 

[JES]

Thanks for the advice. Unfortunately, I've exhausted my options with doctors at the moment. I really don't have anywhere to go that I feel confident would lead anywhere. My hope in putting this out there is to connect with people in a similar situation and share information. In the mean time I plan on collecting more data to see if it supports my hypothesis. I'm also going to see an ophthalmologist soon so if anything unusual turns up there, that could be a potential lead.

If or when you have ruled out every possible diagnosis with a doctor, there are still a number of treatments you can engage in yourself, many of them described in the treatment section on this forum. Some of the most interesting ones I find include methylation, LDN, antiviral protocols and probiotics. By no means will they cure a low IgG subclass, but many find them helpful for symptoms at least.

 

[Kati]

Dear undiagnosed,
I agree with kati. Don't look here for help with diagnosis because that has to be done by a physician in the context of all the clinical findings and all the other lab tests.

Your immunological tests look pretty much within normal variation to me. The IgG1 is lowish but everyone has something lowish if you test 20 tests (by definition about one in 20 will be low on the reference ranges). IVIg is not appropriate unless there is a good clinical reason - which in the context of low IgG has nothing to do with ME symptoms, it is overt infections. Low IgG is not associated with ME as far as I am aware.

Would you suggest that the IgG subclasses get repeated in say, 3 months time, to see where it's at, if the health status has not changed? It seems to me it would be a fair thing to do.

 

[undiagnosed]

Dear undiagnosed,
I agree with kati. Don't look here for help with diagnosis because that has to be done by a physician in the context of all the clinical findings and all the other lab tests.

Your immunological tests look pretty much within normal variation to me. The IgG1 is lowish but everyone has something lowish if you test 20 tests (by definition about one in 20 will be low on the reference ranges). IVIg is not appropriate unless there is a good clinical reason - which in the context of low IgG has nothing to do with ME symptoms, it is overt infections. Low IgG is not associated with ME as far as I am aware.

That's basically what the rheumatologist told me about the low IgG1. However, she didn't answer my question about whether low IgG1 could cause false negative antibody tests, especially to viral proteins. I'm not sure if that's a valid premise, but I am still curious.

 

[undiagnosed]

If or when you have ruled out every possible diagnosis with a doctor, there are still a number of treatments you can engage in yourself, many of them described in the treatment section on this forum. Some of the most interesting ones I find include methylation, LDN, antiviral protocols and probiotics. By no means will they cure a low IgG subclass, but many find them helpful for symptoms at least.

Thanks for the information, I'll check those out. That's basically the direction I was heading in which is why I tried to get the SpectraCell Micronutrient test. I wouldn't be surprised if I had some significant oxidative stress but I want some data to go from so I'm not just guessing.

 

[Jonathan Edwards]

That's basically what the rheumatologist told me about the low IgG1. However, she didn't answer my question about whether low IgG1 could cause false negative antibody tests, especially to viral proteins. I'm not sure if that's a valid premise, but I am still curious.

I think there might be a case for repeating the IgG subclasses but it would depend on the clinical picture.

I don't think a low IgG1 would in itself give you false negative antibody tests. Antibody tests really only mean something if the levels multiply by at least fourfold and preferably tenfold. Very often they are reported as doubling titres with at least two steps change being of interest. An IgG of 3 is quite low and might be clinically important but it is about half of what most people have so logically would only reduce an antibody level by half. That might make a difference between being in a reference range or not but in the clinic I would not normally take much note of such a difference. People talk a lot about viral antibody titres but to be honest I doub they mean anything much in ME because we have no published studies indicating consistent differences in ME.

 

[wastwater]

I was looking at immune stuff and don't think I have an immunodeficiency,but possibly immunodysregulation,but I'm not sure that is easily tested for or known about.Could allergy even fall under immunodysregulation.

 

[kangaSue]

Have you been tested for antibodies to voltage-gated calcium channels. Leg muscle weakness can be found in Lambert-Eaton Myasthenic Syndrome (LEMS) which has some overlap of symptoms similar to CFS.

https://en.wikipedia.org/wiki/Lambert–Eaton_myasthenic_syndrome
[In LEMS, antibodies against VGCC, particularly the P/Q-type VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be released from the neuromuscular junction. Apart from skeletal muscle, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS.[1][3] P/Q voltage-gated calcium channels are also found in the cerebellum, explaining why some experience problems with coordination.]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360501/ Voltage gated calcium channel (VGCC) antibody-related neurological diseases.

 

[wastwater]

I had low white blood cell count but had suspected virus at the time

 

[undiagnosed]

I think there might be a case for repeating the IgG subclasses but it would depend on the clinical picture.

I don't think a low IgG1 would in itself give you false negative antibody tests. Antibody tests really only mean something if the levels multiply by at least fourfold and preferably tenfold. Very often they are reported as doubling titres with at least two steps change being of interest. An IgG of 3 is quite low and might be clinically important but it is about half of what most people have so logically would only reduce an antibody level by half. That might make a difference between being in a reference range or not but in the clinic I would not normally take much note of such a difference. People talk a lot about viral antibody titres but to be honest I doub they mean anything much in ME because we have no published studies indicating consistent differences in ME.

Thanks for the insight.

 

[undiagnosed]

Have you been tested for antibodies to voltage-gated calcium channels. Leg muscle weakness can be found in Lambert-Eaton Myasthenic Syndrome (LEMS) which has some overlap of symptoms similar to CFS.

https://en.wikipedia.org/wiki/Lambert–Eaton_myasthenic_syndrome
[In LEMS, antibodies against VGCC, particularly the P/Q-type VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be released from the neuromuscular junction. Apart from skeletal muscle, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS.[1][3] P/Q voltage-gated calcium channels are also found in the cerebellum, explaining why some experience problems with coordination.]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360501/ Voltage gated calcium channel (VGCC) antibody-related neurological diseases.

No, I have not been tested for this.