The over-exuberant Stage-Five immune response

The Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. (MP) activates the immune system in order to kill the microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. of intraphagocytic bacteria which causes chronic inflammatory disease. The result of the MP's immune activation is increased symptoms due to immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. reactions. As immune function is restored, bacteria are killed and symptoms of disease tend to wane. While a patient may be feeling better over all, there is a danger of sudden increases in immunopathology known as an over-exuberant Stage Five reaction.

An over-exuberant Stage Five reaction can happen in latter stages of the MP, even in the absence of antibiotics, as the immune system becomes increasingly self-sustaining and uninhibited by bacterial ligands. As this happens, antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens. begin to successfully target the more entrenched pockets of bacterial infection in lungs, organs or joints, especially those encased by fibrotic tissue, adhesions, or scarring. Surges in immunopathology can be caused by physical stress on fibrotic tissue, by physical exertion, excessive coughing, or exposure to sunlight.

A Stage Five reaction is often erratic and may not be easily relieved by the usual techniques.

An over-exuberant Stage Five response can be managed through increasing the dosing or frequency of olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. , adjusting antibiotics, and adding palliative medications.

Characteristics of Stage Five

The characteristics of patients suffering from an over-exuberant Stage Five are as follows:

Some or all of these may be the case:

Very few have experienced any problems with Stage Five. I think it mainly gives trouble when pathogens other than the Th1 pathogensThe community of bacterial pathogens which cause chronic inflammatory disease - one which almost certainly includes multiple species and bacterial forms. are present, and have escaped the antibiotics. I got hit when the fibrosis in my lungs began to remodel, but I doubt that anybody else in the cohort was afflicted with fibrotic tissue as badly as I. Additionally, I hadn't been exercising (at all) during my recovery, so the remodelling began quite suddenly. On the other hand, the other early adopters have not had identifiable problems. We put out the documentation partly over an abundance of caution, and partly because we had to change the model to account for this (unexpected) glitch in recovery trajectory.

Unless your X-rays show the degree of damage which mine did, you should be fine with a very nominal amount of exercise. Do not do anything which tires you out. Walking around the neighborhood in the late evenings is probably a good choice (depending on your neighborhood, of course).

Trevor Marshall, PhD

Limiting the severity of an over-exuberant Stage Five response

MP patients whose symptoms begin to resolve are advised to introduce lifestyle modifications gradually, especially when it comes to light exposure. In latter stages of the treatment, vitamin D can actually drive the immune response.

Managing an over-exuberant Stage Five response


In the case of Stage Five, it is imperative to continue the olmesartan at all times, regardless of whether antibiotics are being administered. When in doubt, always increase the Benicar dosage.

As a first measure in response to Stage Five, the palliative action of olmesartan should be maximized by increasing the frequency to 40mg every 4 hours. In severe cases, it is often useful to add a sublingual bolus: 20mg sublingual along with each 40mg oral dose.

As the innate immune system becomes active again, the immunosuppressive actions of olmesartan become dominant over its role in activation of the VDR, because 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol. will recommence its endogenous role as the primary VDR agonistA substance such as olmesartan (Benicar) or 1,25-D which activates the Vitamin D Receptor and transcribes the genes necessary for a proper innate immune response.. Olmesartan then provides dose-dependent immunosuppression by acting on the remaining inflammatory pathways.


If minocycline and/or clindamycin are still acting as anti-inflammatory agents and are still helping to control the immunopathology, innate immunityThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. is not dominant, you are not in Stage Five. These antibiotics may be continued.

When a patient's symptoms surge after an extended period on the MP, the initial strategy is to discontinue azithromycin if it has been taken. N.B. the use of azithromycin is now strongly discouraged.

This will often result in a one-time exacerbation of symptoms, particularly from days 10 to 12 (and possibly even for some weeks), as the concentration of the azithromycin slowly wanes, but in the long run will lead to greater stability.

Progressively withdrawing minocycline and clindamycin, while modulating olmesartan, should keep immunopathology under control. In other words, at this stage of recovery, if the antibiotics are now causing too much immunopathology, it is necessary to stop them. For many members, indeed, ABx are used only to provoke IP when it has dwindled.

Please ask for moderator assistance on the MarshallProtocol.com study site before antibiotic use is modified. We are happy to assist you in any way we can.

Other palliative measures

Continue any effective palliative measures such as oxygen, guaifenesin, quercetin, pain medications, etc. An oxygen concentrator is especially helpful in dealing with shortness of breath. This phase of recovery is a transition period during which the body's innate immunity takes over the job initially done by the MP antibiotics, and the olmesartan-induced VDR activation. Everyone will experience this encouraging evidence of powerful innate immunity.

Duration of Stage Five

Stage Five may last quite a while, a year or two, getting progressively less intense during that time. Judge the severity of immunopathology by the frequency of Benicar needed to keep symptoms tolerable. Reduce olmesartan frequency to every six hours as symptoms wane; increase to every four hours if symptoms increase. Depending on the severity of illness, it may take quite a while for symptoms to resolve.

When someone whose immune system is in Stage Five is no longer experiencing immunopathology without antibiotics, they will need to reintroduce antibiotics carefully to determine if they are still needed. If the bacterial load remains high, the immune system may have stopped responding efficiently. Antibiotics may be needed again to provoke more immunopathology.

Extra risk for patients who have had lung biopsies

Sarcoidosis patients who have had a lung biopsy (or any patient who has had lung surgery) are at risk for pneumothorax due to the lung inflammation which occasionally results from extreme Stage Five immunopathology, because the tissue in that area of the lung has been weakened. This causes a sudden increase in shortness of breath (SOB) as a portion of the lung collapses. The tissue must heal on its own to reseal the barrier and allow the lung to inflate properly. The usual treatment is oxygen. If the leak is large enough, a chest tube may be necessary to help the lung expand and reduce SOB.

The experience of the MP staff has been that there is a low likelihood of survival should sarcoidosis patients seek immediate help from emergency room staff. Patients are advised that when they are in a hospital, neither their family, nor their own doctor, nor the ARF, have any ability to help them receive appropriate care. At least one member of the cohort has died after inappropriate hospital treatment. It is important to take all measures to palliate SOB and try to remain at home, under the care of your MP-prescribing physician.

Therefore, it is recommended that anyone who has had a thoracotomy, mediastinoscopy or bronchoscopy biopsy, or who has been dependent on oxygen at any time prior to starting the MP, should have emergency oxygen available in case of SOB during Stage Five, a recommendation made out of an abundance of caution. Patients will need a prescription from your physician in order to buy an oxygen concentrator or obtain an oxygen bottle and tubing/cannula/mask. Please understand that few cohort members will suffer from severe Stage Five immunopathology.

If patients' insurance won't cover the cost of oxygen, a second-hand concentrator, if they can afford the $400 out-of-pocket cost, may well allow a patient better peace of mind. Unfortunately, oxygen for human use is regulated by the FDA, under prescription, and so the ARF cannot talk as much as we would prefer about the other options - the law shifts that responsibility to the patients' physician.

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===== Notes and comments =====

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* There's confusion among members re stage 5, leading to fear of it from early in their MP journey. This page swings from painting a fearful picture of unrestrainable immune reaction to assurances that only some of the most ill experience this. It's self-contradictory as to whether the term 'stage 5' refers to anyone who continues to herx without abx, or only to those whose immune system is 'over-exuberant'. — Julia 2009/01/31 05:20

* Julia, perhaps people in the early phases of the protocol have enough to problems with worrying too much. But, since members on the MP have had to deal with this issue, it seems more responsible to provide the information for those who are in a position to need it. How can it be better organized to speak to both audiences? — Joyful 2009/02/02 01:21

* IMO, Stage 5 should refer to everyone who continues to herx without abx - i.e. their own immune system is functioning properly. Then there could be a warning that a few people have had this runaway reaction, while many are having a much more gentle stage 5. — Julia 2009/02/04 17:51

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