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January 2015

Lyme Disease: Chronic Lyme (part 3)

The next three posts will be on the phenomenon of Chronic Lyme disease with specific attention to those patients who test negative in validated laboratory tests. Please wait until these Chronic Lyme posts are complete to engage in discussion with me about this. There is a lot of information to present and this makes it easier for me to present it in a way that is understandable for people who are not familiar with Lyme disease. Thanks!


“Chronic Lyme disease” is a term applied to multiple patient populations of different characteristics. It is sometimes used to refer to “Post treatment Lyme disease syndrome,” a condition affecting up to 1/3 of Lyme diagnosed patients that causes persistent symptoms for some time following the completion of antibiotics. It sometimes refers to untreated, disseminated, late-stage Lyme diseases, particularly those with Lyme arthritis or neuroborreliosis. It sometimes refers to a patient group with various ongoing symptoms who demonstrate no objective evidence of previous or current Lyme infection.

Right now, I am going to address PTLDS and what I call “negative serology Lyme,” which I am defining as follows:

PTLDS: patients with well documented laboratory evidence of Lyme disease who continue to have persistent symptoms for many months after antibiotic therapy is discontinued.

“Negative serology Lyme”: patients who demonstrate no laboratory evidence of current or previous Lyme infection, but who have ongoing, serious symptoms attributable to Lyme disease. Importantly, doctors who diagnose this condition believe that these people are continuously infected with Borrelia. They do not believe that symptoms are from a previous infection, but from an active one.

I want to be clear about the fact that my naming this group “negative serology Lyme” rather than “chronic Lyme” does NOT mean that I don’t believe that they have Lyme derived health problems. I am going to review the available data with you guys and give you my thoughts on what causes each distinct pathology. I am simply differentiating between them since both are called chronic Lyme in literature and it can be really confusing.

Both of these patient groups report a variety of symptoms, including fatigue, night sweats, sore throat, swollen glands, stiff neck, joint and muscle pain, palpitations, abdominal pain, nausea, diarrhea, sleep disturbance, poor concentration, irritability, depression, back pain, headache and dizziness. Some report a severe level of disability.

One paper (Klempner 2001) reported on two trials done by the same group, one on 78 PTLDS patients and one on 51 negative serology patients. These trials were double blind, randomized, placebo controlled trials, the gold standard. All patients in both groups were required to have a history of acute Lyme contracted in the US, with at least one of the following: history of at least one bull’s eye rash; early neurologic or cardiac symptoms attributed to Lyme disease, radiculoneuropathy or Lyme arthritis. Documented previous treatment of Lyme with recommended antibiotic regimen by a knowledgable doctor was also required. All patients in both groups had at least one of the following: widespread musculoskeletal pain, cognitive impairment, radicular pain, paresthesias or dysesthesias. Profound fatigue was a noted symptom in some, but not all, patients. These symptoms started within six months of contracting Lyme disease and persisted for some time between 6 months and 12 years. Patients in the PTLDS group were blot positive for Borrelia IgG.

Enrollees could not have previously received IV antibiotic therapy for 60 days or more for current symptoms, have active inflammatory synovitis, had a coincident diagnosis that could explain some or all symptoms, or could not discontinue medications that could affect treatment response, like pain medications or steroids. They were also excluded if they had a positive PCR test for B. burgdorferi in plasma or cerebrospinal fluid. (Remember this – I’m coming back to it later.)

In each group, half received antibiotics, while half received placebo. The antibiotic treatment selected was 30 days of IV ceftriaxone, 2 gm/day, followed by 60 days of oral doxycycline, 100 mg twice daily. The placebo group received an IV dextrose solution the same color as the IV ceftriaxone, and placebo capsules identical looking to the doxycycline.

The objective of the study was to determine if the patients’ health related quality of life improved, which was determined by a self reported survey called the SF-36. This survey assesses physical functioning, vitality, bodily pain, general health perceptions, social functioning, emotional limitations on typical daily activities, social functioning, and mental health. Additional questionnaires measured pain, cognition, and how well patients could execute basic daily activities.

55% of patients in the antibiotic group had improved health status, as well as 42% of the placebo group. 14% in the antibiotic group had worsened health status, as well as 19% in the placebo group. There was no statistically significant difference between the two groups. Statistically, the antibiotic group and the placebo group had similar outcomes. During the six month period encompassing the treatment and three months after, 36% in the placebo group reported an improved health status, 39% had worsened health status and 25% had no significant change. So without any treatment, 36% improved. Two major adverse events occurred, both in the antibiotic group: one had a life threatening pulmonary embolism, and the other had fever, anemia and GI bleeding.

Another study (Krupp 2003) with 55 PTLDS patients with severe fatigue received either ceftriaxone or placebo for 28 days. 22% of patients receiving ceftriaxone saw an improvement in fatigue, compared to 9% placebo group, in a self reported survey. There was no significant difference in cognitive improvement or reported health status when surveyed. However, patients in the ceftriaxone group were much more able to correctly identify their treatment protocol than placebo patients, meaning the study may have been compromised and that the improvements in fatigue may have been due to the placebo effect.

A variety of other studies have been done on both PTLDS and negative serology patient groups. Some of them report improvement with long term antibiotic treatment of negative serology patients. However, as these studies were uncontrolled, the findings cannot be considered reliable. Additionally, criteria for acceptance to these studies were very broad, and unvalidated tests have been used to interpret findings. As a researcher, these particular aspects are very troubling.

(Continued in the next post)



Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92

Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923-1930

Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit 2003;9:I-136.

Stricker RB, et al. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med. 2011; 4:639-46.

Fallon BA, Tager F, Fein L, et al. Repeated antibiotic treatment in chronic Lyme disease. J Spirochetal Tickborne Dis 1999;5:94-102.

Stricker RB, et al. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis. 2007; Jul 15; 45(2):149-57.

Anticholinergic use and dementia

I am going to take a quick break from the Lyme series to discuss something that has a lot of people concerned: whether or not antihistamines cause dementia.

A paper released online this week (“Cumulative use of strong anticholinergics and incident dementia,” by Gray and colleagues, JAMA Internal Medicine) was widely interpreted by the general media as proving that anticholinergic use causes dementia. It doesn’t. Studies like this get a lot of attention by the media – including reputable media – and they get sensationalist headlines.   This is generally not helpful. I think I have established well my distaste for tactics that scare the general public and this is a good example. Whether it is misinterpreted or intentionally misrepresented, news articles reporting on papers like this usually get it wrong.

Let’s look at what the paper actually says.

I actually like studies like this, because they have huge data sets to work with, and scientists usually like big data sets. (I’ll explain why that is in another post.) The study included 3434 patients 65 years of age or older who had no history of dementia when the study began. They were recruited to the study from 1994-1996 and then again from 2000-2003. Patients were followed up with every two years.

The purpose of this study was to determine if cumulative anticholinergic exposure over 10 years was linked to dementia, including Alzheimer’s disease. What is also interesting about this study is that the researchers had access to computerized pharmacy records for all these patients. This is important because it removes the uncertainty associated with patient reported information.   The researchers developed values for anticholinergic medications so that different medications could be compared meaningfully.

A lot of medications are anticholinergic. The more common medications include some antihistamines, tricyclic antidepressants, some antipsychotics, antispasmodics for the GI tract, bladder antimuscarinic medications, and medications used to treat Parkinson’s disease. In various studies, 8-37% of adults over the age of 65 have been found to regularly use anticholinergics. Cognitive disturbances (with memory, attention, “feeling slow,” etc) are well known side effects of anticholinergic medications. Older adults are thought to be more sensitive to these effects because of age related changes to the central nervous system.

Most researchers feel that these cognitive deficits are reversible by discontinuing the offending medication. However, some researchers have found that these deficits may be sustained, culminating in a range of effects from mild cognitive impairment to dementia. These studies had some noted limitations: they did not have solid proof of medication dosages or usage; they did not have information regarding dose or duration of therapy; the follow up periods were short; and they did not account for anticholinergic use to manage insomnia and depression, which can be seen in early, undiagnosed Alzheimer’s. This last one is very important because then the association would not be that anticholinergics cause dementia, but that they are used to manage symptoms of dementia.

The researchers also tried to control for health status, like a self-reported “poor” health status; hypertension; diabetes; APOE gene status; coronary heart disease; depressive symptoms; and benzodiazepine use, among other things. Some of these data were self-reported and some used a proxy, like the use of benzodiazepines for sleep or anxiety disorders.

78.3% of patients filled at least one anticholinergic prescription in the ten years before the study started. Antidepressants, antihistamines and bladder antimuscarinics accounted for more than 90% of all anticholinergic exposure. The most common medications from each of those categories were doxepin, chlorpheniramine and oxybutynin.

23.2% of patients (797 people) developed dementia in a mean period of time of 7.3 years from entry into the trial. 79.9% of those patients (637) were diagnosed with Alzheimer’s disease. This study found that patients in the highest exposure category had a statistically significant increased risk for dementia or Alzheimer’s. Participants in the next highest exposure category had a slightly elevated risk for dementia and Alzheimer’s compared to people who did not use any anticholinergics.

This is the take home message: this study found that people who used higher amounts of anticholinergics had an increased risk of dementia. They found that people with the most exposure took at least one of the following medications daily for more than three years: oxybutynin chloride, 5mg; chlorpheniramine maleate, 4mg; olanzapine, 2.5mg; meclizine hydrochloride, 25mg; doxepin hydrochloride, 10mg.

However, the study does not find that the medications CAUSED dementia. This is really important. It’s important because it’s possible that the conditions that required these medications may be linked to dementia. Or that these medications taken in conjunction with other medications to treat specific conditions might cause the increased risk of dementia. This study found an association. It found that high use of anticholinergics was correlated to increased risk of dementia. It did not find that high use of anticholinergics CAUSED increased risk of dementia. Associations like this are called correlative, not causative.

This study was well done. This was good science. I am a big believer in reducing anticholinergics where possible. I have a lot of lower GI problems and my need for huge doses of anticholinergics pretty much ground my motility to a halt. So I think it’s a good idea to examine medication regimens and reduce anticholinergics if possible, simply for the fact that they cause a lot of side effects.

The reality is that mast cell patients generally cannot avoid taking high doses of anticholinergic medications. I did a previous post on anticholinergic activity of antihistamines, so feel free to refer there. This is a topic I will keep an eye on, but I want to be clear: there is not yet any proof that anticholinergic medications cause dementia or Alzheimer’s disease.



Grey, Shelley L., et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015.

Campbell, Noll L., Boustani, Malaz A. Adverse cognitive effects of medications: Turning attention to reversibility. JAMA Intern Med. 2015.

Cai X, et al. Long-term anticholinergic use and the aging brain. Alzheimers Dement. 2013; 9(4):377-385.

Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J Am Geriatr Soc. 2011;59(8):1477-1483.



Lyme Disease: CDC Recommended Diagnostics (part 2)

Diagnosis of Lyme disease is a complicated affair. Part of the complication is the way our immune system responds to Lyme disease, and part of it is the current tests available to test for infection.

An antigen is anything that generates an immune response inside your body. Borrelia spp., the causative agents of Lyme disease, are antigens. They enter your body, your immune system recognizes it as a threat, and generates a specific IgM in response to Borrelia. This IgM is present in your serum about a week after infection, and persists in good quantities until about 12 weeks after infection, with concentration of specific IgM peaking around 4-6 weeks.

About 4 weeks after infection, your body generates Borrelia spp. IgG. This change from making IgM to IgG is called seroconversion. This IgG persists in good quantities for about 9-10 months after infection. While both IgM and IgG titers decrease over time, they can persist in serum for years after infection is resolved.

The standard Lyme diagnostics look for IgM and IgG. To be honest, I was pretty surprised at the abundance of different Lyme diagnostics, including others that look at that antigen and PCR based tests. There are multiple types of tests, and for each type of test, there are multiple companies that make them. It is a bit of a hot mess. So let’s look at the CDC recommended testing first, and then I’ll get to the others.

The CDC recommends a two step process for diagnosing Lyme. The first step is an ELISA and the second is a Western blot.

The Lyme ELISA (enzyme linked immunoassay) tests look for IgM and/or IgG, the antibodies made in response to the infection. These tests are sensitive, meaning that almost everyone with Lyme will test positive IF TESTED FOUR WEEKS AFTER SYMPTOMS PRESENT. (Note: I saw the phrase “almost everyone with Lyme will test positive” in relation to ELISA testing for Lyme several times. This test is most likely to correctly identify positives after patients have seroconverted.) However, these tests are not that specific, so they will provide 5-7% false positives. So with this test, if you have Lyme, you are likely to get a positive result, but if you don’t have it, you might still get a positive result. If the ELISA test is positive, then blot testing is done to confirm the result. If the ELISA test is negative, then the blot is not run, and the patient is told they do not have Lyme disease.

Western blots look for proteins specific to the organism in question. Western blots for Lyme testing are usually called immunoblots. These tests look for the specific IgG and IgM. Like the ELISA, the blot for IgG is more accurate, but requires the patient to have seroconverted. Blots for IgM are more likely to give false positives, so people who don’t have Lyme disease may have a positive test. The CDC guidelines recommend only running IgM blots in the first four weeks of illness due to the higher risk of false positive.

A Western blot works by showing “bands” to demonstrate that particular antigens were found. The bands are visible to the person reading the result. In order for an IgM blot to be considered positive, two of three possible bands must be positive. In order for an IgG blot to be considered positive, five of ten possible bands must be positive.


Let’s review.

You have had symptoms for two weeks. Your IgM ELISA is positive. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) Your IgM blot shows 3/3 bands. Your IgG blot is negative. You are diagnosed with Lyme disease.

You have had symptoms for two weeks. Your IgM ELISA is positive. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) Your IgM blot shows 1/3 bands. Your IgG blot is negative. You are not diagnosed with Lyme disease.

You have had symptoms for two weeks. Your IgM ELISA is negative. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) No blots are run. You are not diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is positive. Your IgG ELISA is positive. Your IgM blot shows 2/3 bands. Your IgG blot shows 5/10 bands. You are diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is negative. Your IgG ELISA is positive. Your IgM blot is negative. Your IgG blot shows 5/10 bands. You are diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is negative. Your IgG ELISA is positive. Your IgM blot is positive. Your IgG blot shows 4/10 bands. You are not diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is positive. Your IgG ELISA is negative. Your IgM blot shows 3/3 bands. Your IgG blot shows 4/10 bands. You are not diagnosed with Lyme disease.


So let’s talk about this two step process. It has been studied, a lot. The two step process was implemented in the mid-90’s due to the lack of specificity, meaning that people were being treated for Lyme disease who didn’t have it. When the two step process is run and interpreted by skilled operators, according to recommendations, it has 99% specificity. This means a 1% chance of calling someone negative when they really have Lyme disease.

But this doesn’t seem to translate well to clinical practice. A key weakness of these diagnostics in practice is their inability to correctly diagnose people who are newly infected. One study found that the sensitivity and specificity for the two tier test was 100% and 99% for people who no longer had the bull’s eye rash, which happens during the acute phase. But it only had 29% sensitivity for patients in the acute phase with the rash. (Steere 2008) Another study looking particularly at clinical practice found that 50/182 patients had a false positive IgM blot. 78% of them received unnecessary antibiotics. (Seriburi 2012)

I understand why these tests work fine in some studies and not in others. As far as ELISAs giving false positives, that’s no surprise to anyone who has run them before. They’re “sticky.” They crossreact with a lot of things. The reagents are optimized to minimize this, but it is a persistent problem with this type of test. Instead of getting an exact match for your target (Borrelia spp.), you get a “close enough.” You get a positive result if you get a close enough match, and things that match close enough include antibodies for anaplasmosis, leptospirosis, syphilis, Epstein Barr virus, and lupus, among others.

Western blots are also problematic. They are time consuming and complicated. There are a lot of steps and there is a lot of repetition. Reading the results can be confusing. You are comparing the intensity of a band to a control. So let’s say the darker it is, the more positive it is. Just seeing a band does not make it positive. It has to also be as dark as the control for the same band. And things like darkness are subjective.

A sticking point for a lot of people seems to be the fact that they have some bands on their Western blots but not enough to meet the positive criteria. A lot of people feel that if they are positive for some bands that this should be sufficient for a diagnosis. I understand why this is confusing. It’s confusing because it seems like if these blots test for proteins specific to Lyme disease that having any of them should be indicative of infection. But that’s not true.

Remember how I said ELISA tests are sticky, that you can get a good enough match that’s not specific? There’s some of that happening in Western blotting, too. And remember how I said that the procedure is difficult, that the results are subjective? Those facts mean that you can get a few bands through operator error. That’s why it is so important that ALL the required bands show up.

Diagnostic development involves employing a lot of measures to ensure you compensate for errors borne out of biologic crossreaction (like sticky antibodies) and procedural inadequacies. The result is very specific criteria for what is considered positive and what is not. The FDA requires this.

Another thing to keep in mind for later is that diagnostics that are FDA validated are designed for very particular uses. That means that if you have an FDA validated test for Lyme IgG in serum and you use that test to test whole blood or cerebrospinal fluid or synovial fluid, and you get a positive result, it is meaningless. It is not positive. It is nothing. If you have an FDA validated test that tells you to use 100 ul of serum and 100 ul of something else per tube, and you use 150 ul of serum and 150 ul of something else per tube, and you get a positive result, it is meaningless. This also generates a lot of confusion because people feel like if you are looking for the same thing (Lyme IgG), it shouldn’t matter where you find it. But it does.

It matters because sample matrices (like serum or whole blood or whatever) have their own specific “backgrounds.” This means that they contain different proteins and have different fluid dynamics and they could cause additional crossreaction or they could cause less crossreaction. The chemistry involved in diagnostics is very fine. Tests that have a large tolerance for changes like this are called “robust.” The Lyme diagnostics discussed here are not robust.



Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for Lyme disease. Clin Infect Dis. 2008;47(2):188–195. doi: 10.1086/589242.

Wormser GP, Carbonaro C, Miller S, Nowakowski J, Nadelman RB, Sivak S, Aguero-Rosenfeld ME. A limitation of 2-stage serological testing for Lyme disease: enzyme immunoassay and immunoblot assay are not independent tests. Clin Infect Dis. 2000;30(3):545–548. doi: 10.1086/313688

Klempner, M. S., C. H. Schmid, L. Hu, A. C. Steere, G. Johnson, B. McCloud, R. Noring, and A. Weinstein. 2001. Intralaboratory reliability of serologic and urine testing for Lyme disease. Am. J. Med. 110:217-219

Reed, Kurt D. Laboratory Testing for Lyme Disease: Possibilities and Practicalities. J Clin Microbiol. Feb 2002; 40(2): 319–324.

Ang, C. W., et al. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis. Aug 2011; 30(8): 1027–1032.

Woods, Charles R. False-Positive Results for Immunoglobulin M Serologic Results: Explanations and Examples. J Ped Infect Dis (2013).

Seriburi, N. Ndukwe, Z. Chang, M. E. Cox and G. P. Wormser . High frequency of false positive IgM immunoblots for Borrelia burgdorferi in Clinical Practice. Clin Microbiol Infect 2012; 18: 1236–1240

Branda, John A, et al. 2-Tiered Antibody Testing for Early and Late Lyme Disease Using Only an Immunoglobulin G Blot with the Addition of a VlsE Band as the Second-Tier Test. Clin Infect Dis. (2010) 50 (1): 20-26.

Lyme disease: Disease staging and typical treatment recommendations (Part 1)

Vectorborne diseases are infectious diseases transmitted to people via blood sucking arthropods, like mosquitos, flies and ticks. Lyme disease, caused by spirochete bacteria of the genus Borrelia, is the most common such disease in North America. In the US, more than 20,000 cases have been reported annually in the years since 2002. 94% of cases occur in New England, the Mid-Atlantic, and the upper Midwest. (CDC, 2010) Every year, 1-3% of people living in endemic regions of the US become infected. Cumulatively, you can see infection rates of as high as 15%. (Tugwell 1997)

Most people with Lyme are diagnosed in early disease. A hallmark erythema migrans (EM) rash, commonly called the Bull’s eye rash, is found at the site of the tick bite in the majority of Lyme patients. Accompanying symptoms include fever and headache. However, up to 16% of patients never develop a rash. In the absence of this rash, many people think they had a virus and do not seek treatment. (Steere 2003)

Lyme disease has three distinct phases:

  1. Early localized infection. This is the initial presentation of viral type symptoms, like headache, soreness, fever, tiredness, and often the Bull’s eye rash. At this point, the infection is in the skin where the tick bite occurred. (Auwaerter 2004)
  2. Early disseminated infection. This is when the bacteria enter the bloodstream and spread. The EM rash may occur in places other than the site of the bite. In Europe, patients may develop borrelial lymphocytomas, which are darkly colored bumps. This symptom is specific to the European species of Borrelia. Neurologic problems affect 10-15% of patients in this stage. It can cause meningitis, facial palsy, memory loss, shooting pains, psychiatric changes and sleep disturbances. Some patients may also experience cardiac problems such as atrioventricular block (AV block.) (Stanek 2012)
  3. Late disseminated infection. Untreated or undertreated patients can progress to this stage after several months. About 5% of untreated patients develop chronc neurologic problems, including polyneuropathy and Lyme encephalopathy. (Seltzer 2000) Encephalomyelitis can cause cognitive impairment, weakness in the legs, difficulty walking and balance disturbances, among other things. Psychosis, panic attacks and anxiety can all occur. Lyme arthritis can occur, usually in the knees, but sometimes elsewhere. (Puius 2008)

Early localized or early disseminated infection (without neurologic or cardiac symptoms) is treated with short courses of antibiotics: doxycycline 100mg twice daily; or amoxicillin 500mg three times a day; or cefuroxime axetil 500mg twice daily, for 14 days. In the presence of neurologic symptoms of early disseminated disease, the recommended treatment is ceftriaxone 2gm daily IV for 14 days; or cefotaxine 2gm IV every 8 hours, or penicillin G 18-24 million units per day, in divided doses every 4 hours, for 14 days; or oral doxycycline 200-400 mg daily in 2 divided doses for 10-28 days. These recommendations are for adults. Patients with cardiac issues secondary to Lyme should be treated with either oral or IV antibiotics for 14 days while hospitalized. Ceftriaxone is usually used for this purpose. (Wormser 2006)

In late disseminated infection, Lyme arthritis can be treated successfully with doxycycline, amoxicillin or cefuroxime axetil as detailed above. Adults with arthritis and evidence of neurologic disease should receive IV ceftriaxone for 2-4 weeks. If joint swelling recurs, retreatment for 4 weeks of oral antibiotics or 2 weeks of IV antibiotics is recommended. Late neurologic disease can be treated with IV ceftriaxone for 2-4 weeks. Existing inflammation may take some time to wane and response to treatment may be slow. (Wormser 2006)

About 10-20% of patients treated for Lyme disease with 2-4 weeks of antibiotics continue to have fatigue and joint/muscle pain for some time after treatment is completed. These ongoing symptoms can last upwards of six months and indeed can last for years. This is termed Post-Treatment Lyme Disease Syndrome (PTLDS) and the exact reason for this is unknown. Many people also refer to this as “chronic Lyme disease.” (Aucott 2012) We are going to go through the competing theories on “chronic Lyme” and the evidence presented for both sides in the upcoming posts.



John N Aucott, Ari Seifter and Alison W Rebman.  Probable late lyme disease: a variant manifestation or untreated Borellia burgdorferi infection.  BMC Infectious Diseases 2012, 12:173.

Wormser, Gary P. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. (2006) 43 (9): 1089-1134.

Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED (February 2000). “Long-term outcomes of persons with Lyme disease”. JAMA 283 (5): 609–16.

Puius YA, Kalish RA (June 2008). “Lyme arthritis: pathogenesis, clinical presentation, and management”. Infect. Dis. Clin. North Am. 22 (2): 289–300, vi–vii.

Auwaerter PG, Aucott J, Dumler JS (January 2004). “Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment”. Expert Rev Mol Med 6 (2): 1–22.

Stanek G, Wormser GP, Gray J, Strle F (February 2012). “Lyme borreliosis”. Lancet 379 (9814): 461–73.

Tugwell P, Dennis DT, Weinstein A, Wells G, Shea B, Nichol G, Hayward R, Lightfoot R, Baker P, Steere AC: Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997, 127(12):1109-1123.

Steere AC, Dhar A, Hernandez J, Fischer PA, Sikand VK, Schoen RT, Nowakowski J, McHugh G, Persing DH: Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Am J Med 2003, 114(1):58-62.

Centers for Disease Control. Lyme disease data, 2010.

Mast cell mutations: SRSF2 in SM-AHNMD

SRSF2 is a splicing protein, which means it is involved in cutting RNA so that a gene makes the correct protein. SRSF2 mutations at position 95 (p95) have been found in 24-37% of SM patients. In nearly all cases, this mutation is found in patients that have SM-AHNMD. SRSF2 mutations at p95 are associated with myelodysplastic syndromes, leukemias and other hematologic diseases, including mastocytosis. After CKIT D816V mutation, it is the most common mutation found in systemic mastocytosis patients.

SRSF2 mutation occurs early in disease. One study indicates that it occurs in the time period between the initial TET2 mutation and the initial CKIT D816V mutation. Like TET2, it may predispose progenitor cells to develop subsequent mutations that cause disease. Patients with SRSF2 mutations are more likely to also have a TET2 mutation, and even more likely to have a mutation affecting another gene with epigenetic activity. SRSF2 alone does not drive neoplastic behavior in mast cells. SRSF2 has been found in patients without the CKIT mutation.

Importantly, SFSR2 is strongly associated with patients who develop SM-AHNMD. One study with a cohort of 72 patients with various forms of mastocytosis, including clonal MCAS (monoclonal mast cell activation syndrome) found that of 17 SM-AHNMD patients, 15 (88%) were positive for SFSR2 mutation. The associated conditions included AML, CMML, MDS, MSD (AREB), MPN, MPN/MDS and Waldenstrom’s macroglobunemia. SRSF2 mutations are not associated with any specific AHNMD and it does not predict survival time. This cohort included three patients who tested positive for the mutation but developed an AHNMD later in the study.

In SM-AHNMD patients, the SRSF2 mutations were found in both mast cells and monocytes in the bone marrow. This indicates that the mutation may cause transformation in both disease portions: SM and the AHNMD.



Hanssens K., et al. SRSF2-P95 Hotspot Mutation is Highly Associated with Advanced Forms of Mastocytosis and Mutations in Epigenetic Regulator Genes. Haematologica 2013 [Epub ahead of print.]

Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.

Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.

Mast cell mutations: TET2 and mutation profiles of aggressive subtypes

TET2 (Tet methylcytosine dioxygenase 2) is found to be mutated in 20.8-29% of SM patients. Of note, dozens of mutations have been identified in this gene, including missense, nonsense, frameshift and deletion mutations. These mutations cause formation of a defective and less active TET2 enzyme. TET2 is located at chromosome 4q24 and mutations at this location are associated in both MPN and MDS conditions.

TET2 is involved in DNA methylation and demethylation, although the exact nature of this involvement is not clear. When a methyl group is added to a cytosine at a specific place in front of a gene, the gene is turned off and is not expressed. This is called “methylation.” TET2 adds a hydroxyl group to 5-methylcytosine, but it is not well understood if this turns the gene off. TET2 may also be involved in demethylating DNA, or removing those specific methyl groups. It has been shown to be involved with DNA demethylation during bone development.

One study looked at the mutational profiles of patients with various forms of SM, including ISM, SSM, SM-AHNMD, ASM and MCL, all of whom were positive for CKIT D816V mutation. 15/39 had a TET2 mutation. None of those patients had ISM or SSM. Of those with an aggressive form and a TET2 mutation, 67% had more than one TET2 mutation.

In this study, 24/27 patients with advanced SM (SM-AHNMD, ASM, MCL) had mutations beyond the D816V mutation. 5/5 SM-AHNMD patients and 19/22 ASM or MCL patients had multiple mutations (CKIT and something else.) In contrast, only 3/12 ISM or SSM patients had additional mutations. In advanced SM, 78% had at least 3 mutations, and 41% had at least 5.

These mutational profiles have clear implications clinically. 96% patients with major blood abnormalities (anemia <10 g/dL and/or thrombocytopenia < 100 x 10e9/L in addition to monocytosis > 1 x 10e9/L and/or eosinophilia >10%) had at least one additional molecular mutation regardless of SM subtype.

Advanced SM patients in this study all had one of the following multiple mutation profiles: 26% KIT-TET2-SRSF2, 18% KIT-SRSF2-RUNX1, 13% KIT-TET2-CBL, 10% KIT-SRSF2-ASXL1 10%, and 10% KIT-TET2-ASXL1. Patients with advanced SM (and therefore multiple mutations) were also found to be significantly older (68 years of age on average) than those with just the CKIT mutation (48 years of age on average.)

Having a TET2 mutation seems to predispose myeloid cells to become neoplastic later in life. It is important to distinguish that the TET2 mutation seems to “allow” this transformation rather than causing it. In mice who don’t have the TET2 gene and thus don’t have the TET2 enzyme, stem and progenitor cells have trouble maintaining balance and spontaneously become neoplastic later in life. In TET2 deficient cells, mast cells with D816V mutation show increase in proliferation and survival as opposed to those without with normal TET2 levels. Presence of TET2 in addition to the presence of CKIT D816V mutation is associated with more aggressive forms of SM (including ASM, MCL and SM-AHNMD.)



Damaj, G., Joris, M., Chandersris, O., Hanssens, K., Soucie, E., Canioni, D., et al., 2014.ASXL1 but not TET2 Mutations Adversely Impact Overall Survival of PatientsSuffering Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast-Cell Diseases. PLoS ONE 9 (1), e85362.

Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.

Soucie, E., Hanssens, K., Mercher, T., Georgin-Lavialle, S., Damaj, G., Livideanu, C.,et al., 2012. In aggressive forms of mastocytosis. TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 120 (December (24)), 4846–4849.

Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.

Burning down

A lot of my doctors remember that I was applying to medical school before I got sick. I think this is funny, but I suppose my story is strange enough to be memorable. When I saw my surgeon to discuss my upcoming surgeries, he asked if I was still planning to go.

“I would never survive medical school,” I said casually. I briefly described how I anaphylax when overtired, that stress is dangerous for me, that sometimes I sleep through entire days.

“I think you’d be fine. Never say never,” he replied.

Inside, I was shaking my head. I want to go to medical school. I think I would do well in medical school. But this disease is such a constant unknown. I can’t predict what it will do, and all I can do is try to live around it. I don’t know that I can justify going to med school when four very stressful weeks could disable me permanently. Even more than I’m already disabled, I mean.

Then there are the more practical concerns. Like how I almost never drive anymore. If I drive somewhere, there is always the chance that I will react and need IV meds that make me unable to drive. When that happens, I need someone to come get me and drive my car home. I also can’t take pain medication if I need to drive. And also, it irritates my hips. So I would need to find someone to drive me.

And that most basic adult life skill: waking up to an alarm. Can’t do that either. I have a deaf alarm clock that shakes the bed and two other alarm clocks. They don’t wake me. I have to be woken up by my parents every morning, which is really humiliating. Every time I fall asleep, I’m afraid I won’t wake up in time to do whatever I need to do the next day.

There are more things, of course. There are dozens of things I can’t do by myself anymore. I can’t lift things. I need help to make my bed. If I’m in pain, I can’t walk my dogs. I sometimes can’t take out my trash. When I had a PICC line, it took me forever to do dishes in a way that didn’t soak my dressing and if I covered my site, it made it harder for me to use that hand functionally. Cleaning is really time consuming because I’m allergic to dust. And so on.

I can’t remember when I started losing my independence. It feels like there should be a moment, a specific point in time I can point to. There isn’t. It must have started slow and progressed that way for a while, the change so gradual it didn’t draw attention. And then one day I realized that I was dependent upon other people to execute basic functions of my life. And there was nothing I could do about it. It was like my house was burning down and I didn’t realize even though I was living in it.

Now I am dealing with the reality of again being completely dependent on others for several weeks of my life while undergoing and recovering from my surgeries. This time, I am doing it with the added complication of living alone. After my last bowel surgery, I couldn’t be alone for almost three weeks. I couldn’t lift anything. I couldn’t stand long enough to cook anything. I was at increased risk of anaphylaxis. I am fortunate to have many friends and relatives who signed up to babysit and care for me during that time. I am grateful to the people who cared for me then, but the complete lack of privacy and personal space during that time was one of the hardest parts of my recovery.

It is not lost on me how closely my current situation mirrors the lead up to my ostomy surgery, and how badly things went afterward looms heavily in my mind. Both personally – needing to move out of my apartment very quickly, my longterm relationship ending – but also physically. I wasn’t supposed to have obstructions after the ostomy. I did. The ostomy helped, but the reality that I still had so many problems was difficult. I know I need these surgeries, but I am preparing for the disappointment when new complications arise. And I would venture that the disappointment is harder than the physical recovery.

The last few weeks have been really stressful on pretty much all fronts. I’m taking this weekend to figure out a way to address that, as what I’m doing now is not sustainable.

I can’t be everything I want to be all the time. Sometimes I can’t even be a functioning adult for myself.

Progression of mast cell diseases (Part 5)

What is the typical age of onset for children with mastocytosis?

“Mastocytosis [cutaneous, in children]… 55% of cases presenting from birth to 2 years of age, 10% in children younger than 15 years old, and 35% in those over the age of 15. There has, however, been no gender bias noted in the cases of pediatric mastocytosis.” (Frieri 2013)


Do symptoms outside of the skin mean my child has systemic, not cutaneous, mastocytosis?

“Systemic symptoms are typically a result of mast-cell mediator release but do not prove systemic mast-cell hyperplasia [overproliferation].” (Frieri 2013)

“Clinical presentation was evaluated in an earlier study conducted by the National Institutes of Health (NIH) in which 83% of the children presented with pruritis, 65% with flushing, 53% with vesicles, 41% with abdominal pain, 18% with bone pain, and least commonly 12% with headache.” (Frieri 2013)

“Systemic mastocytosis in children is extremely rare.” (Frieri 2013)


What do studies say about kids growing out of mastocytosis?

“Pediatric mastocytosis is generally a benign disease that is transient in nature, as there is generally a spontaneous regression of the condition by puberty.” (Frieri 2013)

“There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial [] evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis.” (Frieri 2013)

“10 of 15 of patients had complete resolution of cutaneous disease and symptoms at follow-up approximately 20 years later. This resolution of disease, based on cutaneous findings and symptom scores, occurred in the absence of use of topical or systemic steroids, PUVA or cytoreductive agents including imatinib… the natural history of disease is improvement.” (Uzzaman 2009)

“In one [] pediatric report where records and follow-up examinations were available for 25 children with UP, and an average follow-up was approximately 5 years, 76 % improved, 16 % remained unchanged, one had complete disease resolution, and one was worse.” (Uzzaman 2009)

“In a second [] study, 55 children with UP were followed for at least two years after initial examination, during which time 9% had involution of all lesions. In this study, where the average follow-up was 4.1 years, 36% had shown improvement over 6.1 years, and in 55% disease remained unchanged.” (Uzzaman 2009)

“In a third [] study, records of mastocytosis patients [] were available to assess disease outcome over a 1–15 year period. Thirty-five of 62 patients with UP (56%) showed complete disease resolution.” (Uzzaman 2009)

“In a fourth [] study, of 72 cases of UP, 20% cleared disease over an average of 13 years, while 50% improved, 18% were no different, and 10% were worse.” (Uzzaman 2009)

“The age of inception of pediatric-onset cutaneous mastocytosis has been reported to have prognostic implications. In previous studies, skin lesions characterized as hyperpigmented red brown macules or papules typically were reported to appear prior to two years of age. In five such studies with 180, 112, 71, 55 and 17 patients, disease-onset prior to age 2 years was seen in 78, 92, 98, 92, and 82%, respectively. In the majority of patients, these lesions were reported to fade or resolve by late adolescence or early adulthood. Fading or resolution of UP is also reported in some adults (around 20%), although bone marrow disease persisted.” (Uzzaman 2009)


How do biopsies of children with mastocytosis differ from adults with mastocytosis?

“In order to analyze the extent of mast-cell hyperplasia, [] bone-marrow biopsies were performed and analyzed. In one study, it was found that in 10 of 17 children with mastocytosis, there were focal areas of mast-cell hyperplasia, which had [] aggregates of mast cells, eosinophils, and early myeloid cells.(Frieri 2013)

“Another study found that the bone-marrow lesions of children had small, [] clusters of mast cells with round and oval nuclei rather than spindle-shaped mast cells, as found in adult bone-marrow lesions.” (Frieri 2013)

“Overall when quantifying mast-cell hyperplasia, there was a higher load of mast cells in children with mastocytosis than in adults with mastocytosis.” (Frieri 2013)

“[T]he difference in presentation between adult and pediatric cases of mastocytosis may result from the difference not only in the mast-cell load but also the distribution of where the mast cells are most likely to be found.” (Frieri 2013)


Do increased mast cells in the bone marrow mean my child will not grow out of their disease?

“Five patients had increased mast cells and three patients had spindle shaped mast cells on the initial bone marrow biopsy. One of these patients had complete resolution of clinical and constitutional symptoms at follow-up. Three of the remaining four patients were re-evaluated. One of these was the patient with continued systemic disease, one had persistent DCM and one had continued UP. However, two other patients with continued UP had neither an increase in mast cells nor spindle shaped mast cells noted on original bone marrow examination. Thus, while the presence of increased mast cells and of spindle-shaped mast cells was more often observed in those with persistent disease, the association was not sufficient to predict outcome.” (Uzzaman 2009)


Are children with mastocytosis CKIT+?

“Earlier studies by Verzijl found that 25% of pediatric patients with UP had an activating D816V mutation present. Another Longley study found that 36% of pediatric patients had another mutation at codon 816. (This is where the D816V mutation is found.)…One study found that 25% of pediatric patients with the UP form of mastocytosis had a D816V mutation. It was also found that 10 out of 12 patients had another [non-D816V] mutation at the location.” (Frieri 2013)

“A later study by Bodemer in 50 pediatric patients with ages ranging from birth to 16 years found 86% of them had a c-KIT mutation, with 36% being a D816V point mutation, 2 out of 50 cases being a D816Y mutation, and one case being a D816I mutation. There were also 29 of 50 patients with [no mutation] at the 816 codon.” (Frieri 2013)

“44% of the patients were found to have a mutation outside of c-KIT with the mutations lying in exons 8, 9, and 11. There was also a subset of 28% of the patients with a M541L mutation at exon 10. [T]he patients with a M541L mutation had [no mutation] at codon 816. When the blood sample of 13 patients was analyzed, it was found that there was no c-KIT mutation, which suggests that the mutation is somatic rather than germline, meaning that this mutation is not inherited from a patient’s parents.” (Frieri 2013)


Do mastocytosis children generally have problems with anesthesia?

Note: always follow appropriate premedication protocols for mast cell patients and work with managing physician.

“Twenty-two patients with pediatric mastocytosis, with a median age of 3.2 years (range 6 months to 20 years) at the time of the procedure, were anesthetized for 29 diagnostic and surgical procedures. All variants of the disease are represented in this series. Most patients had a history of flushing, pruritus, gastroesophageal refux disease (GERD), and abdominal pain; one patient had history of spontaneous anaphylaxis. Routine anesthetic techniques were used, and despite the complexity of the disease, the perioperative courses were uncomplicated and without serious adverse events.” (Frieri 2013)


Note: These quotes are all drawn from two papers which extensively referenced previous publications. I ran down the articles referenced, but felt that these two reviews gave excellent summaries, and so I quoted them exclusively.



Frieri, Marianne, et al. Pediatric mastocytosis: A review of the literature. Pediatr Allergy Immunol Pulmonol. Dec 1, 2013; 26(4): 175-180.

Uzzaman, Ashraf, et al. Pediatric-onset Mastocytosis: A long term clinical follow-up and correlation with bone marrow histopathology. Pediatr Blood Cancer. Oct 2009; 53 (4): 629-634.

Kettelhut BV., Metcalfe DD. Mastocytosis. J Invest Dermatol 1991; 96:115S–118S.

Lange M., Bogusław Nedoszytko B., Górska A., Żawrocki A., Sobjanek M., Kozłowski D. Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci 2012; 8:533–541.

Bodemer C., Hermine O., Palmérini F., Yang Y., Grandpeix-Guyodo C., Leventhal PS., Hadj-Rabia S., Nasca L., Georgin-Lavialle S., Cohen-Akenine A., Launay JM., Barete S., Feger F., Arock M., Catteau B., Sans B., Stalder JF., Skowron F., Thomas L., Lorette G.Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P. Pediatric mastocytosis is a colonal disease associated with D816V and other activating C-KIT mutations. J Invest Dermatol 2010; 130:804–815.


Progression of mast cell diseases (Part 4)

If ISM is life threatening, why is not considered as dangerous as ASM or MCL?

ISM is not life threatening. Anaphylaxis is life threatening. They are not the same. Many people with ISM never experience anaphylaxis. ISM can make anaphylaxis more dangerous, but ISM is not the same as anaphylaxis. Outside of anaphylaxis, ISM is not life threatening.

“Indolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis.)” (Pardanini 2013)


Is MCAS more or less dangerous than ISM?

“From a clinical standpoint, MMAS and MCAS share many similarities with systemic mastocytosis (SM), a primary disorder of mast cells in which patients experience symptoms ranging from pruritus and flushing to anaphylaxis.” (Picard 2013)

Again, the real danger here is anaphylaxis rather than these entities themselves. Statistically, the numbers don’t have a lot of uniformity regarding frequency of anaphylaxis in SM, what constitutes a severe reaction, and so on. Additionally, there are multiple definitions of MCAS and how that is distinguished from IA, which is really important to understanding the true frequency of anaphylaxis in MCAS. However, the data currently shows a trend of anaphylaxis being less common in MCAS than in SM. Still, it is important to realize that this may be due to less research being available on MCAS than mastocytosis.

“In our cohort 3 [MCAS] patients (17%) had a history of anaphylaxis. These patients were included in our cohort because they had primary symptoms characteristic of MCAS that responded to medications and had other laboratory evidence of MC mediator release…There likely exists a spectrum of disease for MCAS in which the more severe form includes anaphylaxis and a spectrum of IA in which a form includes MCAS symptoms.” (Hamilton 2011)

It is well known that people with mastocytosis are more likely to experience anaphylaxis than the general public. In adults with any type of mastocytosis, 49% experience anaphylaxis. Patients with systemic mastocytosis were more likely to anaphylax than those with cutaneous mastocytosis. In adults, 48% of the anaphylactic reactions were severe, with 38% causing unconsciousness. 60% of those reactions were Grade III anaphylaxis. (Brockow 2008)

“In 4 of the 137 [SM] patients (3%), severe life-threatening anaphylaxis resulting in a severe handicap with or without transient or permanent disability occurred.” (Wimazal 2012)

“Prolonged hypotension following anaphylaxis and cerebral hypoxia were identified as major factors leading to a substantial handicap, clinical deterioration or even death in these patients.” (Wimazal 2012)

“However, in both patients in whom recurrent life-threatening anaphylaxis was recorded, the smoldering subtype of SM with a huge burden of MCs was diagnosed, whereas most patients in whom only one documented severe life-threatening event had occurred were found to have low-grade SM with a low burden of MCs.” (Wimazal 2012)

“Thirty-six [SM] patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear etiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively.” (Gulen 2014)


Does an elevated GI mast cell count tract (in the absence of aberrant receptors, clustering or spindled mast cells) indicate MCAS or SM?

“Our immunohistochemical analysis led us to the conclusion that there was no significant difference between the numbers of intestinal mucosal MCs in our patients with MCAS and our reference standard. We recognize that there is currently no consensus for what constitutes a normal number of MCs in the various intestinal tissues. We therefore chose data from a recently published study by one of the authors to be the reference standard. In this study normal numbers of MCs were tabulated for each tissue site. Although we did not find appreciably increased numbers of MCs or abnormal morphology, it is possible that patients with MCAS have a different threshold for MC activation and differentially release MC mediators on activation or that peripheral tissues have an abnormal response to these mediators. We also recognize that a population of patients with chronic diarrhea has been described and labeled as having mastocytic enterocolitis. These patients had a greater number of MCs per hpf in duodenal and colon biopsy specimens compared with the control population (>20 vs 13 MCs/hpf). We were not able to verify this observation in our cohort because many of our control population biopsy specimens had more than 20 MCs/hpf.” (Hamilton 2011)


What is the relationship between CM and MCAD (including SM and MCAS)?

“[M]ost patients with adult-onset MIS [mastocytosis in the skin (commonly called cutaneous mastocytosis,CM)] have demonstrable bone marrow (BM) involvement with clonal mast cells when modern-era diagnostic tools are used, in most instances, satisfying WHO diagnostic criteria for SM. While historical series of patients with MIS revealed an 18% to 50% prevalence of systemic involvement based on conventional histologic criteria, more modern series suggest that only a minority of adult patients have skin-limited disease. Further, approximately 50% of adults with apparent skin-limited mastocytosis may have a clonal BM mast cell infiltrate that falls short of the diagnostic threshold for SM (satisfies major criterion only or only 1 or 2 minor criteria), suggesting prediagnostic or early stage of ISM.” (Pardanini 2013)

“The relationship between systemic MCAD and cutaneous mastocytosis (CM, synonyms: paediatric or childhood onset mastocytosis) remains unclear. Early studies suggested that CM and systemic MCAD were separate disease entities, because the majority of CM patients were found to lack mutations of the tyrosine kinase KITgene. However, subsequent studies have demonstrated that the frequency of clonal KIT mutations is similar in patients with CM, SM and MCAS, and that they are present in up to 86% of patients from each diagnostic group.” (Haenisch 2012)

“Interestingly, in contrast to adult-onset systemic MCAD, more than 50% of paediatric cases of cutaneous mastocytosis appear to enter long-term remission spontaneously, though whether such remissions are permanent or relapse in adulthood as systemic MCAD is unknown.” (Haenisch 2012)

“In contrast, most adults with CM have an underlying SM and should undergo a bone marrow biopsy regardless of the presence of associated systemic symptoms of mediator release. Conversely, 80% of SM patients have cutaneous disease that manifests as urticaria pigmentosa. In contrast, patients with MMAS and MCAS never have CM, and patients with ASM or MCL frequently lack CM.” (Picard 2013)



Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy, Volume 63, Issue 2, pages 226–232, February 2008.

Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.




Progression of mast cell diseases (Part 3)

What causes aberrant mediator release in mast cell activation diseases (including MCAS and SM)?

“Selective release of mediators during mast cell activation may be accomplished in three important and possibly interrelated ways. One is by activation via one of the mast cell’s non-IgE receptors, for instance, through the activation of the IL-1 receptor… Another way in which mast cells may selectively activate is through ‘piecemeal’ release of mediators stored in the secretory granules (such as histamine and serotonin)… Lastly, downstream signaling pathways may affect mast cell activation… Differential activation of mast cells in any of these ways may clinically manifest as nc-MCAS.” (Cardet 2013)

“It is also conceivable that mast cells in this group of patients may aberrantly possess a lower threshold to release mediators… It is also conceivable that patients with nc-MCAS are symptomatic because of an abnormal tissue response to physiologically appropriate release of MC mediators.” (Cardet 2013)

“The mutations underlying systemic MCAD drive aberrant mediator production/release with or without readily histologically detectable mast cell accumulation. Mast cell accumulation is due predominantly to a decrease in mast cell apoptosis (refs 30,31 and further references therein). On a limited scale, it is also due to an increase in proliferation.” (Haenisch 2012)


Do all SM patients have elevated n-methylhistamine and prostaglandin F2a?

71% had elevated urinary histamine in 24 hr test; 81% had elevated urinary n-methylhistamine in 24 hr test; 75% had elevated urinary PGF2a in 24 hr test. (Lim 2009)


If my tryptase is normal, does that mean I don’t have SM?

In patients tested, 96% had elevated tryptase over 11.5 ng/ml. (Lim 2009)

“20% to 30% of SM patients have serum tryptase levels below the WHO-defined threshold of 20 ng/mL (sensitivity 80%, specificity 98%).” (Pardanini 2013)


If my blood test for the D816V mutation is negative, I definitely don’t have it, right?

“The sensitivity of KITD816V detection in peripheral blood is suboptimal, and tests for non-KITD816V mutation screening may not be readily available.” (Pardanini 2013)

“I prefer using DNA from BM aspirate for KITD816V screening given the low sensitivity of peripheral blood in this regard… Using this approach, we found 78% of ISM patients to harbor KITD816V.” (Pardanini 2013)

“Although, the sensitivity of KITD816V detection may be higher when using sorted or purified mast cells, this option is not routinely available. Consequently, the inability to detect KITD816V in peripheral blood does not exclude SM [].” (Pardanini 2013)


How often do SM patients not meet the major diagnostic criteria (mast cell aggregates)?

“Attempts at validating the WHO diagnostic criteria reveal that approximately 20% of ISM patients lack mast cell clusters in the BM and approximately 30% exhibit a serum tryptase level < 20 ng/mL.” (Sanchez 2011)


Is MCAS the same as HIT (histamine intolerance)?

“[S]ome have proposed that a deficiency in the enzymes responsible for histamine metabolism, diamine oxidase (DAO) and histamine N-methyltransferase, leads to excess levels of histamine and therefore histamine intolerance, with clinical manifestations not unlike those described for nc-MCAS… There is no scientific literature to support their relevance to nc-MCAS.” (Cardet 2013)


Are MCAS patients usually positive for the three most commonly tested mediators (tryptase, n-methylhistamine, PGD2?)

“Although all of our patients with MCAS had a positive test result for at least 1 MC mediator, only 33%, 56%, and 44% of the patients had positive test results for tryptase, histamine, and PGD2, respectively.” (Hamilton 2011)


Will my MCAS symptoms ever get better?

“Most patients with MCAS in our cohort who were treated with anti-MC mediator medications responded dramatically. After an average of 4.6 years of MC-related symptoms, 66% of the patients with MCAS achieved a complete or major regression in symptoms to MCAS treatment.” (Hamilton 2011)

“It is important to mention that no defining characteristics (eg, presence of allergies or history of anaphylaxis) could be identified that distinguished those who had a complete regression in symptoms versus those who did not.” (Hamilton 2011)

“The most impressive treatment responses were for abdominal pain (14/17 of the patients who initially had the symptom responded), headache (12/15), poor concentration and memory (7/12), and diarrhea (9/12); there was a more modest response to flushing (6/16). We also found that all but 1 of our patients with MCAS had a sustained response to anti-MC mediator medications. Patients in our cohort were followed for an average of 2.8 years (range, 1-4 years).” (Hamilton 2011)

“In patients with MCAS the rate of response to antimediator therapy is rather good, with 33% showing complete response, 33% a major response, and 33% a minor response after 1 year of treatment.” (Picard 2013)


How prevalent is MCAS?

“MCAS seems to be a more common disorder. Evidence has been presented that MCAS may be an underlying cause of various clinical presentations, e.g. in subsets of patients with fibromyalgia and irritable bowel syndrome. Hence, the prevalence of MCAS is likely to lie within the single-digit percentage range.” (Haenisch 2012)

“Mast cell activation disease in general has long been thought to be rare. However, although SM and MCL as defined by the WHO criteria are truly rare, recent findings suggest MCAS is a fairly common disorder. Evidence has been presented for a causal involvement of pathologically active mast cells not only in the pathogenesis of SM and MCAS but also in the etiology of idiopathic anaphylaxis, interstitial cystitis, some subsets of fibromyalgia and some subsets of irritable bowel syndrome.” (Molderings 2011)



Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

LimKH, TefferiA, LashoTL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.