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Fever of Unknown Origin - 14 Years - Advice?
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Fever of Unknown Origin - 14 Years - Advice?

Hello All,
I’m going to apologize in advance because this is a long story.  If you could read through it and provide any advice, I’d really appreciate it.

I’m a 35 year old American male who has been experiencing periodic Fever of Unknown Origin (FUO) for about 14 years.  Up until 2001, I was healthy with no significant medical history.  In 2001, I experienced a sudden onset of severe epigastric pain (heartburn-like pain).  The pain was severe enough for me to visit the ER.  I was given a CT scan and bloodwork that all came back normal and was sent home with some acid reducers.  The pain continued to get worse and I kept going into the doctor without any diagnosis.  Then, suddenly, the pain went away completely and I developed a fever of 104F (40C).   After the fever persisted for a  couple weeks, I was given a complete workup.  Every scan and blood test that the doctors could think of.  I was referred to every specialty, even did some more invasive testing like a bone marrow biopsy.  All the scans and tests returned completely normal, except for a high  Erythrocyte Sedimentation Rate (ESR).  The fever continued for about 4 months. I was eventually given doxycycline (empirically).  Slowly (day by day) the fever reduced to only about 99, then went away completely.  It’s unclear whether the doxycycline helped, but the infectious disease doctor I was seeing at the time suspected that it did.  

From 2001 – 2004, I did not have any episodes of fever, but was not completely myself.  I was very easily tired and required an abnormal amount of sleep to function.  In 2004, during a period of emotional and physical stress (work-related), I again spiked a high fever.  After having it a few weeks and discussing my prior history, I was hospitalized this time.  Again, I did every test in the book with no significant results.  I was given doxycycline again, but it did not help.  The fever lasted for a few months and again went away.  I had a second episode in 2005 with the same course.

In 2006, the fevers came back again.  I had another in-hospital workup, this time the most comprehensive yet, at a well-respected hospital and with some of the best doctors in a huge city.  Again, no significant results.  I was discharged from the hospital, still with a 103 fever.   The doctors pretty much told me that there isn’t anything else to be done.  They were sure I had nothing “serious” and was just going to have to “learn to manage” the fevers.  In a few months, the fevers went away but I developed some intestinal issues – abdominal pain and alternating constipation and diarrhea.  A GI workup, colonoscopy, etc., found nothing.  The GI doc called it IBS.  

Since 2006, I’ve been having periods of recurring fever and intestinal issues – but never at the same time. When I have a fever, I never have the intestinal issues.  When I have the intestinal issues, I don’t have a fever.  There are times (although they are getting rare) when I have neither.  

It’s hard having a high fever at random times (sometimes for months) each year.  Not sure where to go from here.  The only thing doctors will offer is another complete workup with the same tests.  They admit even that it’s unlikely to find anything.  I've considered going to the Mayo clinic or another specialty clinic but I don't think I could handle the cost at this point.  Any advice?  
13 Comments Post a Comment
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Avatar_f_tn
Hi and sorry you have these fevers for so long. I am not a doctor. I am a microbiologist but I can give you some advice.

So you don't have any rash, joint pain, diarrhea,night sweats, cough or swollen lymph nodes? Did you have any foreign travel outside the U.S. before this started happening?

Have you been tested for Helicobacteri pylori or Lymes disease? If not I think it would be good to get tested. The way you responded to Doxycyline implies you could have lyme. But no guarantee of course. Also your stomach issues with a negative colonoscopy would make sense. For diagnosis of these.

1. the H.pylori you need a urea breath test. This is the gold standard. It is better than the stool test and the blood test just checks for past infection.

2. For lyme you can get the Enzyme Immuno Assay (EIA) test and if positive get the western blot to confirm.

http://www.cdc.gov/lyme/diagnosistesting/LabTest/TwoStep/

you don't always get the rash with Lymes disease or know you have been bitten by a tick. You can also have a doctor send your lab work to IgeneX labs.

There are other co-infections you can get by being bitten by a tick other than lyme such as Babesiosis, Erhlichiosis, and Bartonella. Also Babesia is also called anaplasmosis.

These infections can give you similar long term fevers and so forth. Lymes hides out in the lymph nodes and if you treat it too late then it is hard to treat and can become chronic. These other infections also can be harder to treat especially if they weren't found right away.  Igenex and some reference labs have tests for these.

http://www.cdc.gov/anaplasmosis/

You can look at tick borne diseases on the cdc web page. But there are other sites as well. Let me know if you need that.

Have they done a viral panel on you?
What did your complete blood count look like? You didn't have any anemia or any problems like that? No high white blood count or high eosinophils?

Ok, this a good place to start. Hope this helps.

mkh9
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Avatar_m_tn
Thank you so much for your reply. Sorry it took me a while to reply as I needed to look through my records.

I did not have any foreign travel outside the US before the onset of the illness.  Besides the fever, the only symptoms I've ever had were epigastric pain (at the first onset of illness only) and abdominal pain resembling IBS.  I had night sweats but only when taking high doses of ibuprofen to take the fever down.   Other than that, no other symptoms whatsoever.  

I had several negative blood tests for H.pylori but never had a breath test.  The doctors suspected Lyme for a while and I've had about 10 lyme tests but they all came back negative.  I have been tested negative several times for Erhlichiosis and Bartonella.  I can't find a specific test for Babesiosis but I would be surprised if they didn't test for it at some point.  It's difficult to get complete hospital records.  

My blood tests have always been just a little abnormal.  
WBC: Normal during the first occurrence in 2001, in subsequent occurrences, low.
Neutrophil: Mildly High during the first occurrence in 2001, in subsequent occurrences, normal.
Eosinophil: Mildly High during the first occurrence in 2001, in subsequent occurrences, normal.
ESR:  High in all occurrences
HCT: Mildly Low in all occurrences
CRP:  High in all occurrences
Monocyte: High in later occurrences

The only abnormality noted on radiological scans was mild to moderate splenomegaly.

Viral panels were done and did not show any positive results.

I found this online:  http://www.jabfm.org/content/25/3/390.long    
I had my stool tested for helminths once but from reading online, it could take 7 tests in a row to find these things.  I never had the blood test for it.  I'm actually considering taking ivermectin just on the off chance it could help.  Any thoughts on this?   I've been given empiric Doxycycline, Spranox, and Quinine to try and treat the fevers but never an anti-parasitic.  

The problem I'm having now is doctors are just throwing their hands up.  When I bring in my records they tell me that everything that could be tested, has been tested.  Nothing they can do for me.  The problem I think is that no doctor has ever sat down and studied my records, looked for patterns and such. Asked me detailed questions.  You know, really thought about it.  I understand why, they have other patients.  They simply can't spend a whole day or more on my case.  It's really frustrating though.

Anyway, thanks again so much for reading this and providing advice.  If you have any other thoughts, I would love to hear them.

Thanks!
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Avatar_f_tn
Ok, so how low was your WBC count when it went low? The elevated Eosinophil is a sign of a parasite although since it wasn't high it may not be. the ESR and CRP are inflammation markers. They can indicate an infection. The high monocyte count can indicate and infection as well as the enlarged spleen.

So you could get the stool ova and parasite test done. That would normally include the test for  Strongyloides as well as other fecal parasites.  You may want to ask for a blood test for Toxoplasma as well. Some drugs cause fever too. I dont' if you are on any of these long term.
Procainamide
Quinidine
Amphotericin B

Do you have any pain now or just the fevers?

Any diarrhea?
Any trouble breathing or any cough any time of the day? Have they Xrayed your chest?
mkh9
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Avatar_m_tn
My WBC count is usually around 3K to 4K when i'm having an episode of fever.

I'm not on any medicine long term, except flonase for nasal allergies.  I've never taken any of the medicines that you mentioned.  

As far as pain, I have generalized abdominal cramping and aching. I alternate between diarrhea sometimes and constipation other times.

I have been tested for Toxoplasma - negative.  

No trouble breathing or cough. I have had the following scans/tests, with no results other than  splenomegaly.  Many of these tests have been done several times.

Chest X-Ray
Sinus X-Ray
Sinus CT
Abdominal CT
Chest CT
Full Body Gallium Scan
Full Body PET CT
Abdominal Ultrasound
Ultrasound of the chest/Heart
Colonoscopy

I'm thinking about getting a stool test for parasites, but I'd have to convince a Dr., and it seems like I'd have to have several.  I read on the CDC website that it takes up to 7 negative samples on consecutive days before you can say for sure that someone doesn't have Strongyloides.  Not sure how this number of stool samples could be tested in the US medical environment without the patient being hospitalized?

Thanks again for your help.
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Avatar_f_tn
That is a pretty low white count. Also regarding the parasites you don't have to be hospitalized for it just take the anti-parasitic meds if they find the parasite. Usually, about 3 samples of a stool is good. They are supposed to concentrate it in the lab here. That helps with recovery and seeing the parasite. You could get it 1 day skip two and another day skip a couple of days. It may not be that but it is worth trying.  

You haven't taken any antibiotics? Before this happened? Sometimes after antibiotics you can get Clostridium difficile toxin. It gives you diarrhea and cramping.

Since you didn't have the H. pylori urea breath test then you may want to retest for that. The blood test only tells if you had past infection. But you would think it would have shown up positive if you were exposed. It depends on how long after exposure you did the test. It wouldn't show up if you did it less than a month after the test. But if several months or longer you should have antibody if you were ever exposed and never treated.

Could you have Hepatitis or HIV? What is your genetic background? Does your family come from Europe, are your northern European Jewish? There are some periodic fevers that are hereditary. I assume no one in your family has had anything like this?

If none of these fit I would still look at the parasite test. Also, maybe see a hematologist?
mkh9
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Avatar_m_tn
I hadn't taken any antibiotics in the months before the illness.  Probably had been over year since I had taken any.

I had the H. pylori blood test several times, and months and years after the initial infection, so it probably would have showed positive if I had ever had it.

I've had many hepatitis and HIV tests - all negative.  I'm a white american Male.  Mixed european family history if you back enough generations.  No one in my family has had anything like this.

I have been seen by a hematologist (actually a few).  

I have some medical records (with personal info removed).  Would you be interested in reviewing them?  I noticed it doesn't allow attachments here on posts or private messages. I'd have to get them to you another way.

Thanks again.  
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Avatar_f_tn
Well, I think we have "ruled out " quite  a number of things. You could have some type of autoimmune thing going on. But a lot of them are hereditary. The don't have to show up in the immediate family but I have to read more about them. Some show up when you are a child. Generally regular autoimmune diseases can show up in the teen or early twenties.  But I'm still thinking parasitic disease at this point or a virus. You can attach results or photos on here. But I'm not sure how as I have never tried. Many people have attached their photos. I would assume you could attach a link as well or give me link to show me data if you wanted to that had the personal info removed. I am going to re-read the info on Rickettsial diseaseses and that sort of thing to see if there is anything that fits. Usually, you get a rash from these things though. But I'll revisit that area.You really have done a lot of testing.

Parasites do cause fevers, low white blood count, high eosinophil count, and gastric problems and can cause spleen enlargement and high CRP and ESR tests and  so forth. So all of this fits in. It is a matter of seeing if this is what you have. There are blood parasites as well. But you get these from foreign travel. So, we'll just have to wait for you to try and see if you get the parasite test done and I'll look up some more information.  You have enough information to ask for parasitic tests I think. I don't see why they would say no.
mkh9
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Avatar_m_tn
Thanks again for your help and advice.  I sent you a private message with a link to some records.

I'll make an appointment to try and get checked for parasites.  

Hope you have a great weekend.
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Avatar_f_tn
I looked up some things. I don't think you have the hereditary types of periodic fevers, since you don't have a rash you wouldn't have rat bite fever, rickettsia, and I don't think chronic Q fever. So then back to Borrelia.
Borrelia miyamotoi is another new strain of Borrelia that you get from a tick bite. You often don't know you have been bitten by these ticks because they are so small. They are pin head size. They don't produce a rash either. So, I don't know who does the testing but I 'm sure reference labs can check for this as well. It can cause a relapsing fever.

http://www.nejm.org/doi/full/10.1056/NEJMc1215469

Also, endocarditis can cause relapsing fevers. You would be able to rule this out probably by a echocardiogram. I would think they would hear it but I'm not sure about that. I have a murmur and a lot of doctors have missed it because it is minor. But if you had this I would think they would catch it. You may get shortness of breath at times or palpitations. Also, petechiae or tiny purple spots under the skin.

The Epstein barr virus and CMV can cause this too but I'm not so convinced that it can cause this kind of recurrance.  Usually, you get both the EBV and CMV as a child and the symptoms are bad then or as mono when you are a teenager or 20 year old.  But EBV can cause lymphoma in 5% of people and other problems. So you never know about that virus.  I am grasping at straws. But that is all I can think of now.

The main one that stands out is the parasitic infection. So I would get that tested. There is no reason it has to be Strongyloides but it would be good to see if they find anything.

have a good night.
mkh9

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Avatar_m_tn
Borrelia miyamotoi sounds interesting as from what I read all the standard lyme panels that I had wouldn't have caught it.

I did have a few echocardiograms to check for endocarditis.  

There are some comments in my records about EBV/CMV.  One of the doctors suspected something to do with those for a while.  I think because they found EBV in my bone marrow.  

Please let me know if you have a chance to review the records I sent and if you find anything useful in them.

Thanks again.
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Avatar_f_tn
Sam32421,
So I did look through all those records, whew.  A lot of labs and tests. You have been through a lot. Sorry you had to have a couple of bone marrow tests those are painful. It looks to me like they didn't test for Erlichiosis as they thought at the time there wasn't a test in the U.S. but IgeneX and I think Reference labs tests for this now and IgeneX has good testing for Lyme as well and Erlichia. You were borderline for Lyme and Q fever at one point. So it may be worth getting that retested at IgeneX if you can afford to pay for it as I think insurance doesn't cover them. Or you could get a western blot since you were  borderline.  I noticed that you did have a rash that came and went with your fevers, high LDH. The LDH may be high because of the spleen. Since you have a intermittant rash it may open up some other things to look at. But you also had a low positive ANA (anti-nuclear antibodies) and this is often a positive with lyme as well. It is something to revisit. I have to look at the symptoms again for Q fever. And, go over the results again. I have more time on Monday. But I'll try to look again either later or tomorrow. IgeneX lab is at www.igenex.com

It is interesting that you had EBV in the bone marrow. I wonder how they found that out? I mean how do you see a virus in the bone marrow? Did they use an electron microscope or maybe they used some of the sample to test for it? Curious.

mkh9
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Avatar_m_tn
Thanks for looking through the records.  Yes, had a total of 3 bone marrow biopsies.  Those really do hurt.  

They suspected Erlichiosis while I was in Korea but didn't have a test there for it.  When I got back to the US and was again evaluated, they did test for it (negative).  It's mentioned on the last page of the records that I sent.  The Lyme and Q fever tests read borderline in Korea, but consistently negative in the U.S.  

The rash ended up just being because I was sweating so much at night.  I'd take ibuprofen before bed so I could sleep, then sweat all night.  The sweat pressing against my body all night was giving me a rash.  When I started sleeping on towels and waking every so often to change them, I no longer had a rash.

The ANA tests are weird...sometimes they are slightly elevated, other times not.  I just got another one a couple months ago and it was completely negative.  

As far as the EBV in the bone marrow, it mentions "in-situ hybridization" in the test results where they found the EBV.

For liver function tests, I believe that was caused by taking so much tylenol.  At one point, I was alternating tylenol and ibuprofen around the clock for months to keep the fever at a reasonable level.   Once I stopped the tylenol, my liver function tests returned to normal.  They haven't been elevated since I stopped taking tylenol all together.  So I'm not sure those can be used as a clue.

My problem now is finding a doctor to do anything.  The infectious disease doctor that wrote that last evaluation in my records is refusing to see me any further.  In fact, none of the 6 or so doctors in that office will see me.  They consider me a lost cause.  When I go to regular docs, they just tell me I need to see infectious disease docs, who are now rejecting my case. In a really tough spot here.  

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Avatar_f_tn
Yes What I'm thinking is that lyme is sometimes hard to detect and maybe you should get it tested through Igenex because the ELISA tests can be variable. Since your ANA is sometimes positive too it points toward Lyme. But you might be worse off physically if you had it by now. You could see a lyme literate doctor (LLMD) they would see you. I would get the website if you want to persue that route. I see what you mean with the rash and so forth.

EBV has been found in some cases in the bone marrow as you have and it could potentially cause more problems.  I would keep an eye on your complete blood count and your white count to see if it goes down more and also the LDH values. If these get worse you may want to revisit a hematologist if you can. At least the family practice doctor can keep an eye on these things. You don't want your white count going too low. You can always see a new doctor. You don't have to be referred. Just bring your results with you. I know you don't want any more testing. I just think you should have one just in case.

mkh9

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