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 Observations of Jarisch-Herxheimer Reaction in Sarcoidosis Patients
Author: Meg Mangin (
Date:   02-10-04 01:20

Observations of Jarisch-Herxheimer Reaction in Sarcoidosis Patients

Author: Meg Mangin R.N., Autoimmunity Research Foundation, Thousand Oaks, CA 91360


Paper Type: Letter
Paper Type: Comment upon "Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2"
Published: 7 Feb 2004

Please cite as: Mangin M: Observations of Jarisch-Herxheimer Reaction in Sarcoidosis Patients. JOIMR 2004;2(1):1

“You have to get worse, before you get better” is a common medical folklore proverb. A new, novel protocol for treating Sarcoidosis is proving that adage true, while showing the promise of a medication-induced remission and the potential for a cure. The Marshall Protocol (MP)[1,2] uses specific combinations of antibiotics in a pulsed regimen along with an angiotensin receptor blockade and avoidance of Vitamin D. Without exception, the improving patients are reporting periodic aggravation of their symptoms as an apparent direct response to the antibiotics. In other words, these patients say that their treatment makes them feel much worse before they experience symptom-relief.

This phenomenon is known as the Jarisch-Herxheimer Reaction (JHR) and is often referred to informally as Herx. JHR is believed to be caused when injured or dead bacteria release their endotoxins into blood and tissues faster than the body can comfortably handle it.[3,4,5,6,7} This provokes a sudden and exaggerated inflammatory response and is associated with the systemic appearance of cytokines. “The JHR is an elegant model of the human cytokine cascade in events resembling sepsis…”[8]

JHR was originally observed in patients with syphilis who received mercury treatment.[9] It has been reported that Rheumatiod Arthritis, Lyme and Louse-borne relapsing fever (B recurrentis) patients have also experienced this effect when treated with the appropriate antibiotics. JHR, however, is not reported in normal, healthy individuals who are treated with antibiotics for sepsis. In Sarcoidosis patients, the Herxheimer reaction seems to be a valuable indication that an antibiotic is reaching its target.

It is normal for the body to generate an immune response when challenged by foreign matter such as microbes and allergens. Sarcoidosis, however, is a run-away, hyper-inflammatory immune system response. Research has lead to a strong suspicion that this reaction is triggered by Cell Wall Deficient (CWD) or polymorphic L-forms microbes. [10,11,12,13] Evidently, these CWD bacteria have learned to live inside the actual macrophages (phagocytes) of the immune system.[14] Apparently, they fail to be destroyed by the very immune system cells (phagocytes) which are supposed to kill them because they have learned to live in the caustic 'cytokine soup' of a Sarcoidosis granuloma. A similar adaptive cell behavior has been seen by the H. pylori bacterium which has learned to live in the hostile environment of the stomach, causing gastric ulcers.

It is difficult (and maybe unnecessary) to determine which of the many species of CWD mycoplasma might be responsible for the granulomatous reaction of Sarcoidosis. The CWD bacteria are reportedly difficult to see even with an electron microsope, very slow growing and tedious to culture. This makes it impractical to cross-match species to find the appropriate antibiotics. Thus, the elicitation of a Herxheimer reaction is a key component of the Marshall Protocol to determine, by therapeutic probe, which antibiotics are effective. Renowned scientist, Dr. Friedrich Flachsbart, MD, Göttingen, Germany, states that "Jarisch-Herxheimer is in fact the maximum of evidence possible in search of occult microbes”.

The Marshalls have noted that Sarcoidosis patients have a high level of circulating 1,25-dihydroxyvitamin-D(1,25-D) and that many Sarcoidosis patients complain of symptoms similar to that of hypervitaminosis-D. One study has shown that Lipopolysaccharide is capable of stimulating sarcoid macrophages from BAL in-vitro to generate 1,25-D.[15] Since Lipopolysaccharide is known to come from gram-negative bacteria, they conclude that the high levels of 1,25-D generated in Sarcoidosis by macrophages are most probably coming from a bacterial source.

The Marshalls use 1,25-D levels as an indicator of both systemic inflammation and Herxheimer activity. They associate the JHR reaction with bacteriocidal actions AND the abnormal immune system response in Sarcoidosis patients. During the JHR, MP patients 1,25-D levels are noted to temporarily surge even higher, correlating with their reported exacerbation of symptoms. This would seem to provide further evidence that as the bacteria are killed by antibiotics, endotoxins are released, provoking a Th1 (bacterial) reaction.

The elicitation of a Herxheimer reaction is thought to be a key component in evaluating the efficacy of each MP antibiotic, antibiotic combination or dosing schedule. Indeed, the Marshalls advise that the lack of a Herxheimer reaction when Sarcoidosis symptoms are still present signals a need for a change in dosing schedule or antibiotic. Consequently the MP Sarcoidosis patient is expected to experience episodic JHRs as long as antibiotic therapy is needed. The gradual resolution of symptoms has been noted to require months or years depending on the extent of Sarcoidosis involvement and/or disease location. Remission of Sarcoidosis is determined by absence of symptoms, both objective and subjective.

Sarcoidosis patients report that a Herxheimer reaction makes them feel as though their disease symptoms have suddenly gotten worse. They report reactivation of previous symptoms and/or the exacerbation of presenting symptoms. Depending on the extent of the Sarcoidosis inflammation and the effectiveness of the antibiotic [16,17], the onset of JHR is from 1-2 hrs to10 days after the antibiotic/s are administered. The intensity of the reaction is dependent on many factors; location of the inflammation, appropriateness of the antibiotic/s, the antibiotic dosage, the presence of immunosuppressants, the level of dihydroxyvitamin-D [18] and the prophylactic dosing schedule of the Angiotensin Receptor Blocker (ARB) used to interrupt the inflammatory cascade [19].

Herxheimer symptoms wax and wane with antibiotic administration and MP patients report that they continue to experience this phenomenon as long as effective antibiotic therapy continues. Trial and error with carefully selected antibiotic combinations has reportedly provoked a resumption of the JHR when symptoms have subsided. Since Sarcoidosis patients are believed to have acquired many different species of mycobacteria over a long period of time, the effectiveness of an antibiotic probe with a positive JHR seems to demonstrate the presence of another species or of bacteria previously hidden within poorly perfused tissues.

Herxheimer symptoms may be subjective or objective, or both. The most common symptoms reported by Sarcoidosis patients include increased fatigue, joint or muscle pain, headaches, skin rashes, photosensitivity, irritability, paresthesia, dizziness, sleep disturbances, asthenia, muscle cramps, night sweats, hypertension, hypotension, headaches (especially migraines) and swollen glands. Also reported are heavy perspiration, metallic taste in mouth, chills, nausea, bloating, constipation or diarrhea, low grade fever, chills, heart palpitations, tachycardia, facial palsy, tinnitus, mental confusion, uncoordinated movement, pruritus, bone pain, flu-like syndrome, conjunctivitis and throat swelling. Physicians have managed these JHR symptoms in MP Sarcoidosis patients with the use of an ARB and by decreasing the dosage or frequency of the antibiotics.

Physicians may note hypercalcemia, calcium deposits in the lungs, lymphopenia, anemia and renal calculi, elevation of ESR, gamma globulin and total globulin or a fall in serum albumin and hematocrit during a JHR. Unexpectedly severe Herxheimer reactions needing Emergency Room treatment have occurred. Especially worrisome is the possibility of eliciting severe respiratory symptoms or cardiac symptoms. Cardiac Sarcoidosis is sometimes unsuspected and diagnosed only when the JHR elicits chest pain or arrhythmia. If physicians are aware of the possibility of a JHR, they can avoid unnecessary testing or medications. Discontinuing the antibiotics and increasing the ARB dosage is reportedly the most effective treatment for severe JHR. The Marshalls caution that the JHR should be given the utmost respect. Since these life-threatening JHRs are most likely to occur at the start of antibiotic treatment, they advise establishing an ARB blockade to lower the level of 1,25-D before initiation of antibiotic therapy and that the initial antibiotic doses be very low.

JHR is sometimes mistaken for a “hypersentivitiy reaction” or even the cause of a related, (probably preexisting) disease such as lupus.[20] Pruritus, hives and rash induced by JHR can be misdiagnosed as an allergic (Th2) reaction to the antibiotic. MP patients, however, have reported safely taking sulfa, although eliciting a JHR, despite a history of ‘allergy’ to sulfa. JHR might linger for weeks, rather than the hours that would be expected from an allergic reaction. Laboratory tests can help differentiate between a Herxheimer reaction to microbial toxins and an allergic reaction to medication. WBCs and 1,25-dihydroxyvitamin-D will be elevated in a Herxheimer reaction. But a marked increase in eosinophils ( about 30%) or the presence of specific antibodies is an indication of an allergic reaction.

The Marshalls report that as the number of dying bacteria is reduced with subsequent antibiotic doses, effective treatment requires increasing doses and changing antibiotic combinations to continue eliciting a Herxheimer response. The presence of a JHR is seen as evidence of continuing elimination of these very persistant bacteria. Although the JHR is often unpredictable, they report that it can be managed with the judicious choice of antibiotic combinations, careful dosing schedule, tapering of dosing and use of an ARB to establish an anti-inflammatory blockade. The Marshall Protocol does not advocate eliciting a more severe JRH than a patient can tolerate in order to eliminate the bacteria and the antibiotic dosing is individualized to each Sarcoidosis patient.

In my work with Sarcoidosis patients, it is my experience that recovering MP patients understand and welcome the Herxheimer reactions even when they must endure temporary increased suffering. They accept it as the price that they must pay in order to get well and they even seem to find it gratifying to experience tangible evidence of bacterial elimination. The gradual resolution of their Sarcoidosis symptoms as the treatment progresses seems to be ample reward to persist with this sometimes uncomfortable treatment. Many MP Sarcoidosis patients say that their doctors were initially unaware of the JHR phenomenon. An increased awareness of the Herxheimer reaction by those who treat Sarcoidosis would seem to be of benefit to patients. Antibiotics then might be seen as the ally they are proving to be in fighting this often fatal disease.

1.Marshall TG, Marshall FE: Sarcoidosis Succumbs to Antibiotics Implications for Autoimmune Disease. Autoimmunity Reviews. In press (Nov 19, 2003) doi:10.1016/j.autrev.2003.10.001
Available from URL

2.Marshall TG, Marshall FE: Antibiotics in Sarcoidosis Reflections on the First Year. JOIMR 2003;1(3):2
Available from URL

3.Herxheimer, K. and Martin, H: So-called Herxheimer reactions. Arch Derm Syph 13:115, 1926.

4. Fleischman, K., and Kreibich, C: Zum Wesen der Reaktion nach Jarisch-Herxheimer. Me. Klin. 21:1157, 1925.

5. Jadassohn, J: Beitrab zur Jarisch-Herxheimer Reaktion. Z Haut Geschlechtskr 19: 158, 1965.

6. Mahoney, J.F., Arnold, R.C., and Harris, A: Penicillin and the Jarisch-Herxheimer reaction in early, cardiovascular and neurosyphilis. Amer J Public Health 33: 1387, 1943.

7. Gudjonsson, Haraldur: The Jarisch-Herxheimer Reaction, Stockholm 1972. A summary based on seven publications).

8. Cytokines Involved in Human Septic Shock-the Model of the Jarisch-Herxheimer Reaction. George E. Griffin Division of Infectious Diseases St. George Hospital Medical School, Tooting, London.

9.Herxheimer, K. Krause. “Uber eine bei Syphilitische vorkommende Quecksilerberreaktion. Deutsch. Med. Wschr.28:50, 1902.

10. McGrath DS, Goh N, Foley PJ, du Bois RM: Sarcoidosis - genes and microbes--soil or seed. Sarcoidosis Vasc Diffuse Lung Dis. 2001 Jun;18(2):149-64[Pubmed Abstract]

11. du Bois RM, Goh N, McGrath D, Cullinan P: Is there a role for microorganisms in the pathogenesis of sarcoidosis. J Intern Med. 2003 Jan;253(1):4-17[Pubmed Abstract]

12. Moller DR, Chen ES: What causes sarcoidosis. Curr Opin Pulm Med. 2002 Sep;8(5):429-34[Pubmed Abstract]

13. Cantwell AR Jr: Histologic observations of variably acid-fast pleomorphic bacteria in systemic sarcoidosis - a report of 3 cases. Growth. 1982 Summer;46(2):113-25[Pubmed Abstract]

14. Nilsson K, Pahlson C, Lukinius A, Eriksson L, Nilsson L, Lindquist O: Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis. J Infect Dis. 2002 Apr 15;185(8):1128-38. Epub 2002 Mar 21[Pubmed Abstract]

15. Enhanced production rate of 1,25-dihydroxyvitamin D in sarcoidosis.

16. Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2

17. Alan Cantwell, MD: Bacteria in Sarcoidosis and a Rationale for Antibiotic Therapy in this Disease. JOIMR 2003;1(5):1

18. Marshall TG, Marshall FE: The Science Points to Angiotensin II and 1,25-Dihydroxyvitamin D. [Electronic Letter] Chest 2003; 6 Feb. Available from URL

19. Marshall TG, Marshall FE: Valsartan Dosing Regime Modulates Psychotic Events in Two Sarcoidosis Patients

20. Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus

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