A lot of people with CFS are individuals triggered by some event in the past, often with years passing since the triggering event. A flu like sickness is often cited, I suspect it was actual influenza. My conclusion is that Chronic Fatigue Syndrome and Post Infection Fatigue are the same thing. Extending it a little further Chronic Lyme is another example of Post Infection Fatigue, with the infection being Lyme.

There are several cases reported in the literature where a population got a shared infection, recovered and a percentage came down with post infection fatigue. A reader forwarded me a link today to a study that I was not aware of, so I thought it would be good to consolidate the literature.

Fatigue following Acute Q-Fever: A Systematic Literature Review, May 2016

• “it was noted in 1990 that 4% of acute Q-fever cases had prolonged fatigue”
• “In 1992, it was stated that approximately 23% of study subjects developed QFS within 12 months following acute Q-fever”
• “Ever since, several studies on fatigue following acute Q-fever reported different prevalences. It was stated that 5–10% of patients experience residual asthenia six months after acute Q-fever and only few after one year”
• “a substantial proportion of acute Q-fever patients have symptoms similar to QFS for 6–9 months after the acute infection and then recover, but 8–10% of patients exhibit symptoms for at least a year”
• “In Australia, QFS is the most common sequel of acute Q-fever reported to affect 10–15% of patients”
• ” Higher percentages were described, with up to 28% of patients meeting the Centres for Disease Control and Prevention criteria for CFS 5 to 14 years after acute Q-fever, compared to none in the control group”
• “ten years after acute Q-fever, 68% of patients reported fatigue of any duration [54], of whom 20% met the CFS criteria”
• “Excluding co-morbidity, 8% of patients met the CFS criteria compared to none of the controls”
• “Post-infective fatigue following Epstein-Barr virus, Ross River virus or C. burnetii infection, was reported in 35% of cases after six weeks, 27% after three months, 12% after six months, and 9% after 12 months, regardless of the infective agent”
• “In patients with a lower respiratory tract infection who were C. burnetii seropositive 10–19 months after the acute illness, 40% reported clinically relevant fatigue, compared to 64% of seronegatives, concluding that patients have long-term health problems after a lower respiratory tract infection in general”

Antibiotics

“Treatment with either 3 months of minocycline 200mg/day (n = 18), levofloxacine 200mg/day (n = 1), or erythromycin 400mg/day (n = 1), improved performance status and reduced fatigue [6], concluding that minocycline was useful in treating QFS [6]. In a pilot-study, treatment with three months of minocycline 100mg/day (n = 29), doxycycline 100mg/day (n = 26), or levofloxacin 200mg/day (n = 3), showed improvement in performance status, headache, and mean weekly temperature [39].”

NOTE: These are the same antibiotics with my gut bacteria model that are predicted to help shift the gut towards normal, see this page.

NOTE: the article does NOT discuss the microbiome or probiotics.

Influenza

• Influenza Virus Affects Intestinal Microbiota and Secondary Salmonella Infection in the Gut through Type I Interferons[2016]. “we found that influenza pulmonary infection can significantly alter the intestinal microbiota profile through a mechanism dependent on type I interferons (IFN-Is)…. promote the depletion of obligate anaerobic bacteria and the enrichment of Proteobacteria in the gut, leading to a “dysbiotic” microenvironment. “

Bergen Norway – Post Giardiasis Fatigue

n 2004, Bergen, Norway had a major epidemic of giardiasis. Th… ey verified by lab tests that the giardiasis was successfully treated. They also found that infections of cryptosporidum parvum increased as a side effect. “One-third of the patients experienced recurring symptoms after treatment” [2009]

So 1/3 did NOT return to normal within a year.

• At 2 years: “among 82 patients with persisting abdominal symptoms elicited by the Giardia infection…We found that 66 (80.5%) of the 82 patients had symptoms consistent with irritable bowel syndrome (IBS) and 17 (24.3%) patients had functional dyspepsia (FD)” [2009]
• “Fatigue was reported by 41%, whereas 38% reported abdominal symptoms, and there was a highly significant association between these symptoms. Increasing age was a highly significant risk factor for fatigue. The symptoms were not due to chronic infection in this cohort.” at 2 years after the infection [1262 patients] [2009]
• “Patients with post-giardiasis IBS suffer very little somatic comorbidity, suggesting that the aetiology of this form of postinfective IBS is predominantly biological in origin and may thus differ from the more common, non-postinfective forms of IBS.” [2009]
• At 3 years, “The prevalence of IBS in the exposed group was 46.1%…  Chronic fatigue was reported by 46.1%” [2012]
• “A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmedgiardiasis were diagnosed with CFS … At the time of referral (mean illness duration 2.7 years) 16% reported improvement, 28% reported no change, and 57% reported progressive course with gradual worsening. ” [2012]
• “The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study. Improvement of chronic fatigue in the period from three to five years after giardiasis was found.” [2013]
• “Giardia infection in a nonendemic setting is associated with an increased risk for irritable bowel syndrome and chronic fatigue 6 years later. The prevalences of both conditions decrease over time, indicating that this intestinal protozoan parasite may elicit very long-term, but slowly self-limiting, complications.” [2014]
• ” In conclusion, patients with Giardia-induced gastrointestinal symptoms developed both IBS and FD. They exhibited gastric hypersensitivity with lower drinking capacity and delayed gastric emptying.” [2007]
• “Sporadic IBS was associated with increased risk of overactive bladder syndrome (OAB), whereas post-infectious IBS was not. An apparent association between OAB and previous Giardia infection can be ascribed to comorbid functional disorders.”[2015]

This outbreak, like CFS, mainly affected females “Young women have previously been reported as the predominant group infected during a waterborne giardiasis outbreak, due to elevated water consumption. Here, the demographics of those subsequently infected are described, and young women again predominate. As secondary cases were not waterborne, this cannot be attributed to drinking habits.” [2008]

In 2007, ” Both these findings subsided overtime. Increasingly, investigations could not determine a definite cause for the persistent symptoms. The very long-term post-giardiasis diarrhoea, bloating, nausea and abdominal pain documented here need further study.”

” Our findings indicate that Giardia induces functional changes in commensal bacteria, possibly making them opportunistic pathogens, and alters host-microbe homeostatic interactions.” [2015]

Bottom Line

There are many infections that follow the identical pattern after the infection is resolved. The model that I use to explain this is a simple one, the bacteria shift aka microbiome (which includes bacteria in the mouth, throat, guts and lungs) that resulted during the active infection, persists afterwards. The body was unable to restore its normal equilibrium quickly in some.

“Here, we use a large-scale text mining-based manually curated microbe-disease association data set to construct a microbe-based human disease network and investigate the relationships between microbes and disease genes, symptoms, chemical fragments and drugs. We reveal that microbe-based disease loops are significantly coherent. Microbe-based disease connections have strong overlaps with those constructed by disease genes, symptoms, chemical fragments and drugs. Moreover, we confirm that the microbe-based disease analysis is able to predict novel connections and mechanisms for disease, microbes, genes and drugs” [2016]

In the past I have written about the histamine subset of CFS patients. When there is too much histamine, the supplement/enzyme diamine oxidase can quickly reduce the histamine reaction. Often migraines will be shorten by this supplement.

• “We found that 10 out of 14 patients had serum DAO activity<10 U/mL, which was the threshold suggested as a cutoff for probable histamine intolerance…n patients with symptoms triggered by histamine-rich food, measuring the serum diamine oxidase activity can help identify subjects who can benefit from a histamine limitation diet and/or diamine oxidase supplementation.” [Serum diamine oxidase activity in patients with histamine intolerance. 2016]

” In humans, enzymatic inactivation of histamine occurs through the operation of two types of enzymes, diamine oxidase (DAO) and histamine N-methyltransferase (HMT) that have different characteristics (Rangachari 1992) …Laboratory findings of elevated plasma levels (> 2 ng/ml) of histamine and reduced DAO activity (0.7 nkat/L) have been suggested as indicators of reduced histamine catabolism (Jarisch and Wantke 1996; Bischoff and Manns 1998)… Diamine oxidase activity seems to predominate in the intestine, whereas, N-methyltransferase activity predominates in the brain (Holcslaw et al 1985; Schayer and Reilley 1973). DAO tends to exhibit a histamine-degrading capacity ten times higher than that of HMT (Huertz and Schwelberger 2003).

In contrast, 99% of histamine entering the [healthy] body in the digestive tract is prevented from reaching the circulation (Naranjo 1966) ” — thus intestinal barrier breakdown can be a significant contributor.

“The levels of urinary histamine and its metabolites seem to be greatly influenced by the level of histamine consumed in food, by the activity of bacteria in the digestive tract, and possibly in the vagina (Keyzer et al 1983).”

“Histamine from dietary sources and from the activity of intestinal microorganisms will normally be catabolised by diamine oxidase within the digestive tract before gaining access to circulating blood. However, if the enzymatic activity at this site is reduced, histamine will be transported from the gut lumen into circulation and augment the level of plasma histamine from endogenous sources ”

“At the present time there is no research data that may suggest a mechanism whereby up-regulation of diamine oxidase production or activity in human tissue can be achieved in situ.”

” Some preliminary research indicates that certain strains of bacteria, such as species of Lactobacillus, Leuconostoc, Escherichia faecium, Weisella and Sarcina (Figure 3) can produce diamine oxidase (Dapkevicius et al 2000; Leuschner et al 1998). ”

• “After intravenous administration of heparin, DAO is released from its capillary binding sites in the lamina propria into the peripheral circulation.” [1994]
• “The levels of diamine oxidase and D‑lactic acid in the plasma were analyzed as markers of the intestinal permeability” [2016]
• ” investigate the effects of cello-oligosaccharide (COS) on intestinal microbiota and epithelial barrier function … reduced plasma DAO
• “Increased D-lactate levels and DAO activities were observed in the model [respiratory issues] group (P < 0.01). Sequencing results revealed the presence of 3780 and 4142 species in the control and model groups, respectively. The percentage of shared species was 18.8419%

Diamine oxidase rs10156191 and rs2052129 variants are associated with the risk for migraine [2015].

Possible Model

We know that histamine is produced by bacteria, it also appears that diamine oxidase is also produced by some bacteria

• “hat the mean DA concentration is significantly higher in samples positive for microbial pathogens.” Enzymatic assay to test diamines produced by vaginal bacteria[2015].
• “PI-IBS mice treated either alone with Bifidobacterium or Lactobacillus (but not Streptococcus), or the mixture of the three exhibited not only decreased abdominal withdrawal reflex score and contractile response, but also reduced plasma DAO and D-lactate.” [2014]
• Bacterial translocation secondary to small intestinal mucosal ischemia during cardiopulmonary bypass. Measurement by diamine oxidase and peptidoglycan [2004].
• “Enzyme stimulation by S boulardii was associated with significant increases indiamine oxidase activity and mucosal polyamine concentrations.” [1999]

Bottom Line

I have written about S boulardii in an earlier post and concluded “There is no clean evidence of any significant improvement with CFS or any related condition“. There is just a single study (on rats). Histamine intolerance is a small subgroup of CFS patients — if you have  histamine over-sensitivity, you may wish to try S boulardii. You should track the amount of DAO you needed monthly before starting and then see if your need for DAO is reduced.

A reader asked about soy  — is it good or bad (or neutral)?  I will look at the microbiome, coagulation and any studies dealing with CFS/ME/IBS/FM that I can find.  I will not look at other health claims / problems with soy (see Soybead Foods – The Good, Bad and Ugly if interested). Tunnel vision is sometimes needed to prevent over-saturation of information

• “Soybean oligosaccharides, raffinose and stachyose were utilized by bifidobacteria except for Bifidobacterium bifidum, but most strains of Escherichia coli and Clostridium perfringens could not use them.” [2012]
  • So does not help E.Coli growth 😦
• Soy Protein Compared with Milk Protein in a Western Diet Increases Gut Microbial Diversity and Reduces Serum Lipids in Golden Syrian Hamsters[2016]. – no details on the shifts.
• ” The number of Bacillus spp. was higher (p<0.001) in all groups (Bacillus fermented) except for Lactobacillus fermented Soybean meals compared with control diet-fed chicks.” [2016]
• “SOY increased the Firmicutes to Bacteroidetes ( ratio due to an increased proportion of Lactobacillus spp.)” [2015]
  • So it appears to increase lactobacillus which is good if E.coli also increases, but lactobacillus tend to inhibit e.coli
• Consumption of different soymilk formulations differentially affects the gut microbiomes of overweight and obese men [2012].
  • low glycinin soymilk (LGS)
    • Bacteroides-Prevotella and Lactobacillus increased
    • Bifidobacterium was significantly reduced
    • Bacterial diversity decreased
  • conventional soymilk (S)
    • No change in Bacteroides-Prevotella and Lactobacillus
    • Bifidobacterium was significantly reduced
    • Bacterial diversity decreased
  • bovine milk (M)
    • Bacteroides-Prevotella and Lactobacillus increased
    • Bacterial diversity decreased (less decrease than the above)
• Fecal bacterial community changes associated with isoflavone metabolites in postmenopausal women after soy bar consumption[2014]. reports “This study demonstrates that a week of a diet supplemented with soy is sufficient to significantly change the gut microbiome and these changes can be related to soy fermentation metabolites.” and table below (lactobacillus went down in this study)

IBS and Soy

• “There was no significant changes in mean differences of symptoms severity score between the two groups (soy, placebo); however soy isoflavone supplementation could significantly improve the quality of life scores” [2015]
• “A 2-wk oral treatment with a phytoestrogen-rich soy germ fermented ingredient (SG) prevented the stress-induced hyperpermeability and visceral hypersensitivity in cyclic rats through ER activation, and blocked the increase in colonic proteolytic activity, suggesting that SG can be promising in IBS management.” [2013]
• “In conclusion, the anti-inflammatory properties of a fermented soy germ extract (FSG – Primasoy) treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.”[2015]
• “Soy germ fermented with Aspergillus niger M46 resulted..has the potential to be a good dietary supplement for prevention of oxidative stress-related diseases,” [2014]
• “Patients with food hypersensitivity (FH) differed from other IBS patients in that they had a longer duration of clinical history, a history of FH as children, and an increased frequency of self-reported FH; they also had hypersensitivities to other antigens (eg, egg or soy).” [2010]

Fibromyalgia

• “Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo.” [2011]

Misc

• “soy milk consumption had no significant effects on tumor necrosis factor-α, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde levels.” [2012]
• Dietary supplement with fermented soybeans, natto, improved the neurobehavioral deficits after sciatic nerve injury in rats[2009].

Bottom Line

Preferring soy has no apparent benefit unless it is fermented with the right bacteria.

There are major difference between non-fermented soy products and fermented soy products.  Some, like Natto (soy fermented with Bacillus subtilis var. natto) is on my recommended list — not because of the soy, but because of the nattokinease produced by the bacillus subtilis.  Soy fermented with lactobacillus is not recommended, neither is regular (unfermented) soy milk (Bifidobacterium decreased, diversity decreased).

Soy is not used by E.Coli, which means unless you are actively feeding E.Coli by other means you are starving the little E.Coli you have.

In this post I want to clarify that the model that I am using is re-entrant (a computer term). This means simply that you can stop at any time and restart at any point later without a problem as long as you are rotating probiotic and anti-infection agents (herbs, antibiotics, etc).

Some people report a smooth progression with greater energy and activities. Other people have severe reaction from a probiotic or herb or vitamin that very few have problems with. Your DNA and your very unique microbiome determines that.

There is NOT a protocol that you must keep religiously too. There is no magical path of taking a set of supplements. Many supplements have studies reporting that the average person improved / reduced symptoms. When you read the studies, you will find that 80% improve, 15% have no change and 5% had adverse reactions. Your odds are 16:1 that any change will be to the better, not worst. Worst does happen… so what should you do?

The answer using the model is simple — significantly  cut back on everything (even stopping everything is fine). Give your system an opportunity to stabilize itself, then add back one item at a time  — no more than one a week. Yes, you are impatient for recovery but going too fast may sabotage your recovery. 

The approach that I would use for myself after stabilizing is to resume with the last item added. I would take this in the evening –likely with an evening snack.  Then I would note if there are any of the following changes:

• Longer or shorter sleep
• Dreams – more often or less often
• Night sweats
• Do I wake up more or less refresh.

There is no preferred answer to the above — the important thing is that a change occurred. My preferred scenario is deeper more solid sleep, with night sweats and waking refresh. Other times, I went to a shorter deep sleep and notices more energy and alertness in the morning. There is no magic set of symptoms to look for — what is important is the change.

If the response is uncomfortably too severe, then I would stop. In 6 months, I may try again because my microbiome may have changed enough that this response may not happen then.  Effectively we are dealing with a constantly moving target and responses.

Re-entrant

Let me take a look at some simple examples.

• Vitamin D
  • if you supplement at 10,000 IU or more, you should have your levels check every three months — some people report that their level stayed low and suddenly jump high – why, I do not know.
  • this accumulate in the body — stopping supplement simply stops the level building (and it may naturally reduce)
• Minocycline
  • Our goal is not to eliminate all of one bacteria with this — it is reduce those that are sensitive to it.
  • The next herb or antibiotic will likely work better in eliminating those left than more of the same antibiotic. It’s mechanism will likely be different and the bacteria will have to adapt again.

There is an excellent article in the Economist explaining what antibiotic resistance is

“The genes needed for resistance can thus be quite readily available. But like any biological attribute, resistance is not a free good. Building extra bacterial bilge pumps or special drug-smashing enzymes costs a micro-organism energy and materials; changing the shape of molecules to make them drug-proof is likely to leave them working less well than they did. Simply copying the DNA of the resistance gene imposes a metabolic load. And different antibiotics require different resistance genes; the more a bug needs to use, the greater the costs.”

By frequently changing the anti-infection agent (antibiotics, herbs, probiotics) we attempt to saturate it’s defense mechanisms.

Bottom Line

Be kind and nice to yourself, herx only to the degree that you are comfortable with — ideally for only part of the day. Herbs and antibiotics are likely to have a peak herx within an hour and then reduce to nothing. Probiotics may keep going if the probiotics successfully establishes itself.

There is nothing that is required.  I look for items with good odds, but nothing has perfect odds.

In 2013, I looked at whether some bacteria may be causing  postural orthostatic tachycardia syndrome in this [post] where Clostridium septicum is one species associated with tachycardia and another CFS symptom, hypotension (low blood pressure). In early 2016, I wrote about Ivabradine, a medicine that looked promising in this [post] as well as some vacines that can cause POTS in this [post].

• From Mayo clininc “Only 33 (19%) respondents reported complete resolution of symptoms… 2-10 years after diagnosis.” [2016]
• “POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome.” [2016]
• “Apart from symptoms of orthostatic intolerance, there are many other comorbid conditions such as chronic headache, fibromyalgia, gastrointestinal disorders, and sleep disturbances. Dermatological manifestations of POTS are also common and range widely from livedo reticularis to Raynaud’s phenomenon….The most commonly reported symptom was rash (77%). Raynaud’s phenomenon was reported by over half of the patients, and about a quarter of patients reported livedo reticularis. The rash was most commonly found on the arms, legs, and trunk. ” [2016]
• “Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity.” [2012]
• “Numerous symptoms such as excessive tachycardia, lightheadedness, blurry vision, weakness, fatigue, palpitations, chest pain, and tremulousness are associated with orthostaticintolerance. Other co-morbid conditions associated with POTS are not clearly attributable to orthostatic intolerance. These include chronic headache, fibromyalgia, functional gastrointestinal or bladder disorders, cognitive impairment, and sleep disturbances.” [2015]
• ” Other observed dermatological manifestations of this systemic disease include Raynaud’s phenomenon, koilonychia, onychodystrophy, madarosis, dysesthesia, allodynia, telogen effluvium, increased capillary refill time, and livedo reticularis. The treatment of this disease poses a great challenge. The author reports the unprecedented use of an oral angiotensin II type 1 receptor antagonist [Losartan] resulting in remarkable improvement.” [2014]

And the gut bacteria aspect is clear:

• “The most commonly reported GI symptoms were nausea (86%), irregular bowel movements (71%), abdominal pain (70%), and constipation (70%). Additionally, 82% of patients reported having GI symptoms more than once per week, and 71% reported having seen a GI specialist, and symptoms did not improve with changes in position….GI disturbances are common, frequent, and prolonged in patients with POTS, likely impacting quality of life. Given the importance of the enteric nervous system to normal GI functioning, the same autonomic impairment leading to POTS may result in abnormal gut motility and ultimately subjective GI discomfort.” [2015]
• “Over 70 % of patients had nausea and/or vomiting, which was the most common GI symptom; other common symptoms were abdominal pain (59 %), bloating (55 %), and postprandial fullness/early satiety (46 %). Over one-third of patients had abnormal [i.e., rapid (27 %) or delayed (9 %)] gastric emptying.” [2013]
• “Two-thirds of patients with POTS and GI symptoms had abnormal, most frequently rapid gastric emptying.” [2015]
• “Nonorthostatic symptoms included dry eyes or mouth, gastrointestinal complaints of bloating, early satiety, nausea, pain, and alternating diarrhea and constipation. Half of the patients reported an antecedent illness presumed to be of viral origin.” [1999]

And mast cell involvement in some patients:

• “Mast cell activation+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse.” [2005]
• ” POTS is a “final common pathway” for a number of overlapping pathophysiologies, including an autonomic neuropathy in the lower body, hypovolemia, elevated sympathetic tone, mast cell activation, deconditioning, and autoantibodies. Not only may patients be affected by more than one of these pathophysiologies but also the phenotype of POTS has similarities to a number of other disorders, e.g., chronic fatigue syndrome, Ehlers-Danlos syndrome, vasovagal syncope, and inappropriate sinus tachycardia.” [2015]

Microbiome Data is Still Lacking

“POTS, which often accompanies ME/CFS, is a fainting disorder associated with an abnormal increase in heart rate and low blood pressure. The mechanism is unknown, but some people develop it after contracting viral or bacterial infections like mononucleosis, pneumonia or Lyme disease…. found two blood-borne microbes — Human Herpesvirus-4 and the coxsackie virus — known to cause chronic disease and POTS. Though Montoya wasn’t sure if these viruses were at the root of Erin’s illness or merely collateral infections, he started her on a high dose of the antiviral drug famciclovir.” [Stanford 2014]

Losartan is cited in one study as being effective, it has risks to it. This drug has a major impact on S. Aureus (the bacteria that keeps showing up connected to CFS!!), but zero impact on E.Coli. [2002] In other words, it’s antimicrobial profile matches what my model would deem to be a very good candidate.

 
On my wish list is for a research MD to do microbiome analysis of a large set of POTS patients, and have this data, with co morbid conditions analyze by a good machine learning program – the results may give a nice bacteria strain to symptoms mapping.