Wells were coated with ng PGL-1 dissolved in iso-propanol and dried. ELISA was then performed[ 52 ]. Plates were incubated at room temperature for 10 min. Grzegorz Telega began following a 9-year-old boy who was diagnosed with CD in June He initially presented in with persistent diarrhea, weight loss and unexplained fever. His linear growth had slowed considerably. At the time of the initial diagnosis, the patient was 4 feet 8. Prior to the onset of illness, his weight had previously reached 80 pounds 90 th percentile. Initially, in August , the patient received azathioprine and steroids with concurrent antibiotic therapy including clarithromycin and rifabutin, in low doses similar to those used in the Australian trial[ 23 ].
Telega, the pediatric gastroenterologist, prescribed the antibiotics and received consultative advice initially from Dr. Hermon-Taylor and later additionally from Drs. Chamberlin and Borody. The patient also took daily probiotics, which were administered at mid-day. After 7 d of antibiotic therapy, as predicted by Dr. John Hermon-Taylor the patient developed a mild fever that lasted for several days, which Dr. Hermon-Taylor had previously observed in other patients and compared to a Jarish Herxheimer reaction. The patient responded favorably to the antibiotics for about 8 mo, but by June , he became symptomatic and relapsed a finding similar to that of the Australian trial.
The period of relapse lasted from June to March and during this time he remained on low dose antibiotics. A colonoscopy on January 11, showed multiple aphthous ulcers in the colon and his weight on that day was By February 11 th , his weight was 90 pounds 41 kg. Summary of Mycobacterium avium subsp.
In late , in addition to receiving antibiotics, over the course of a three-month period, the patient received a total of 11 once weekly ultraviolet blood irradiation UVBI treatments which were performed by Dr. In addition to UVBI therapy, on advice from experts, the doses of clarithromycin and rifabutin were increased and ciprofloxacin was added to the regimen.
In May , after the patient was in clinical remission, clofazimine an antibiotic with restricted use in the United States which is used for the treatment of leprosy and Mycobacterium avium complex was added at a dose of 50 mg taken once daily. The clofazimine was obtained from a source in Australia. The patient had a history of seasonal triggered by pollen asthma beginning at age 3 years and the last episode of asthma he has experienced was in April These antibiotics have been used in many prior studies to treat MAP in humans.
The doses in this patient were adjusted over time. He received over 4 years of continuous antibiotic therapy until January From January , he was on cycled therapy of rifabutin, ciprofloxacin and clarithromycin until May The patient has been in complete remission since April Since May , he has received no medications of any type and he has been without any signs or symptoms of CD and is now 5 feet A colonoscopy and upper gastrointestinal endoscopy in August, were normal.
There are many reports in the literature of patients with CD who have responded favorably to antibiotic therapy[ 28 , 53 - 55 ]. She had a several year history of hypothyroidism and was on thyroid hormone replacement.
The symptoms of neuralgia and paresthesia progressively advanced and involved her bilateral hands, elbows, shoulders, neck, legs and feet. The PGL-1 assay was negative. The initial diagnosis at the Cleveland Clinic was hypersensitivity syndrome and the patient was referred to the Cleveland Clinic Neurological Center for Pain where she received the diagnosis of thoracic outlet syndrome with probable evolving complex regional pain syndrome CRPS.
Recommendations for therapy included physical therapy, muscle relaxants and gabapentin. Gabapentin at the lowest recommended dose made her very dizzy and therefore, she discontinued this medication. The patient obtained multiple sessions of physical therapy which were beneficial and engaged in gradually increasing regular exercise including walking and swimming as tolerated. In December , she could only walk feet or tread water wearing a floatation device for 5 min.
The cause of this condition is unknown. Due to suspicion that CRPS could be a manifestation of a MAP infection, blood samples were tested for evidence of MAP infection; the first blood sample was obtained November 6, and the second on November 20, MAP was detected by culture from the second blood sample. There was rapid progression of clinical disease between November 6, when her MAP antibody titer was 1. During this two week period she developed generalized extreme hypersensitivity to minor tactile stimuli. MAP experts were consulted and appropriate antibiotics were prescribed.
Cryoglobulins [ 57 - 59 ] and ACE[ 60 , 61 ] are elevated in other mycobacterial infections including tuberculosis and leprosy. Prior to the onset of disease and the initiation of therapy, the patient had persistent relative lymphocytosis and eosinophilia which was present as early as Relative lymphocytosis has been described in tuberculosis[ 62 ]. Neurologic findings are not uncommon in CD[ 63 ]. In addition, siblings of patients with CD are at much higher risk of developing CD than the general population[ 64 ]. In mid December , the patient was placed on anti-MAP therapy and supplementary Vitamin A and Vitamin D similar to that administered to her brother.
Her height and weight are 5 feet 9. Four days after the initiation of therapy she experienced a mild fever which lasted two days. Previously, Weg speculated that CRPS is due to an infection caused by a cell wall deficient bacterium[ 65 ]. David Haas of the University of Charleston Chemistry Department, confirmed by gas chromatography, mass spectroscopy, ultraviolet absorption spectroscopy and infrared spectroscopy that the clofazimine, which was imported from India, was not a counterfeit drug.
Following the initiation of therapy, she developed monocytosis and the relative lymphocytosis persisted. By the fall of , she could swim one mile or walk five miles per day. Although her general condition has greatly improved including absence of the generalized extreme hypersensitivity, she still experiences episodes of migratory pain. With treatment of leprosy, reversal reactions and prolonged neuralgia have been observed[ 66 ]. Six weeks after beginning the anti-MAP therapy, while still taking supplemental thyroxine, she began experiencing palpitations and it was noted that her TSH had dropped to the low normal range.
On the presumption that the palpitations indicated that her thyroid function was recovering, in January , she stopped supplemental thyroxine, has not experienced symptoms of hypothyroidism, and her TSH is now in the normal range. A TSH from May 7, was 4. By October 14, , a complete blood count and differential were normal. A follow-up cryoglobulin study obtained from April 17, was negative after 4 h and positive after 72 h.
In early January , the patient consulted Dr. Kuruvilla John who has since that time followed her case. The patient has declined treatment for MAP.
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The nephew of the mother of cases 1 and 2 has lymphangiomatosis, a disease of unknown etiology. The father of cases 1 and 2 was tested for MAP infection. After 6 mo of incubation, MAP was grown from his blood. He is healthy but suffered from seasonal asthma triggered by pollen at age 12 years and also while living in Germany from to In addition, he has rosacea, which was diagnosed by clinical signs and a skin biopsy showing non-caseating granulomas.
This condition is treated with a topical ointment containing azelaic acid. In , his blood was found positive for antibodies to p35 and p36 MAP antigens. Because of the devastating nature of the diseases in case 1 and case 2 and the poor record of efficacy, standard therapies were eschewed. IRB approval is generally not required in the care of individual patients. Additional family members were tested for evidence of MAP infection as well.
The families of both parents of case 1 and case 2 have a history of susceptibility to mycobacterial infection. Family pedigree summarizing history of mycobacterial infection and other diseases of cases 1 through 5 and additional family members. The presence of viable MAP in the blood of a majority of CD patients is an important finding which has been previously reported by Naser[ 20 , 22 ].
In case 1, the recovery of the viable organism in the setting of two diseases and the failure to recover the viable organism in the absence of these two diseases argues in favor of a pathogenic role of MAP in these patients. Similarly, in case 2, the recovery of the viable organism in the setting of two other diseases and the failure to recover the organism in the absence of these two other diseases also argues in favor of a pathogenic role of MAP. Furthermore, the recovery of the viable organism in case 2 in which the patient suffered from CRPS cannot be explained by the leaky bowel hypothesis since this patient has not experienced bowel related symptoms.
In addition, a pathogenic role of MAP in the human host is likely, considering the zoonotic capacity of slow-growing mycobacteria and because this organism is an obligate pathogen, i. A second possible interpretation of the findings in these case reports is that the diseases were not caused by MAP and went into remission spontaneously. With the assumption that case 1 and case 2 resolved spontaneously, the outcome follows the likelihood function. The probability of spontaneous resolution in case 1 is 0. Controlled clinical trials of anti-MAP therapy are necessary to determine whether these case reports are reproducible.
Clinical trials have been designed and funding is being sought. A third possible interpretation of the recovery of MAP from the blood samples in case 1 and in case 2, is that the MAP organism is a contaminant from specimen processing.
This interpretation is unlikely since in both cases there are increased antibodies directed against MAP indicating a host response to the organism. The presence of elevated serologic markers which are associated with mycobacterial infection, including CRP in case 1 and ACE in case 2, also weighs against this possibility. We believe that the profound long lasting remission in case 1 resulted from anti-MAP therapy and is unlikely due to steroid administration, since such remissions rarely result from steroid administration alone.
However, at this time, the optimal antibiotic combination is unknown. The presence of the viable bacterium in the blood of an apparently healthy host case 5 is an interesting finding. Apparently healthy individuals may have less virulent forms of disease such as transient childhood asthma or rosacea as noted in case 5. In addition, if MAP-infected people are followed over a long enough period of time, some may eventually develop one of the diseases traditionally considered autoimmune.
It would not be surprising if there is a population of individuals who are MAP-infected but never develop disease. A similar situation probably pertains to human paratuberculosis, i. Clinically normal cattle with known MAP infection are common suggesting a parallel in the human population[ 75 ]. Any theory of causation of the autoimmune diseases must explain two consistent observations for most of these diseases: Future work may shed light on the immunology of gender differences with these diseases. Because of the known risk of disease progression in CD from birth control medication, women who have been diagnosed and treated for a MAP infection should consider non-hormonal birth control methods.
The optimal hosts for MAP are ruminants; cattle, sheep, and deer, in which, a higher burden of bacteria are generally found than in humans. These animals have a higher body temperature than humans ranging from These differences in body temperature suggests that the growth of MAP in laboratory culture may be accelerated by raising the incubation temperature to F.
Further investigation of this issue is warranted. If controlled trials of MAP related illnesses confirm the findings of these case reports and the autoimmune diseases can be cured, because the bacterium is present in the food supply, will treated patients redevelop disease on re-exposure to the organism? The precautionary principle should apply and improved food safety and public health measures are necessary to limit human exposure to MAP. Until improved measures are in place, treated and cured patients should probably avoid known sources of MAP which include pasteurized milk and milk products such as yoghurt, cheese and ice cream and undercooked beef.
Open label trials of long-term antibiotic therapy in CD have a significant relapse rate. Adjunctive therapy such as UVBI combined with appropriate antibiotics may be a way to improve therapeutic outcomes.
UVBI was developed by Knott[ 86 ]. Knott was most likely aware of the work of Finsen who received the Nobel Prize in , for his work showing the beneficial effects of ultraviolet treatments of the skin in patients with lupus vulgaris, i. The Knott device was used for the treatment of many infections[ 88 - 90 ]. Several studies[ 91 , 92 ] as well as three controlled trials from Russia have shown beneficial effects in the treatment of tuberculosis[ 93 - 95 ].
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Various studies on UVBI that may explain the benefit of this therapy include the following. Ultraviolet light in the C region UVC inactivates bacterial and viral pathogens, present in the blood, which is irradiated. In the case of bacteria and DNA viruses, UVC induces the formation of thymine-thymine dimers, which prevents replication[ 96 ]. Bacteria including Mycobacterium tuberculosis have UV repair mechanisms and normal lymphocytes also have UV repair mechanisms[ 98 , 99 ]. Ultraviolet light shined on murine fibroblasts results in the formation of hydrogen peroxide and hydroxyl radicals which are also bactericidal and virucidal[ ].
Ultraviolet light in the A region and at higher doses and exposure durations causes immune suppression, but ultraviolet light in the B UVB region and UVC have been shown to stimulate dendritic cells[ - ]. Hemoglobin which has been irradiated with UVB and UVC wavelengths exhibits fluorescence[ ] and the wavelength of light which is emitted, nm, causes the formation of DNA or RNA adducts in riboflavin and other chromophores and these adducts are bactericidal and virucidal[ ].
It is now known that in spite of long term treatment of tuberculosis by antibiotics, there are persisters, which are not killed by the drugs[ , ]. Also Mycobacterium avium complex organisms can resist the bactericidal activity of clarithromycin within the phagosomes of macrophages[ ]. Viable MAP organisms which have survived the antibiotics by either of these routes and which are within macrophages may not survive ultraviolet irradiation[ 68 ].
An in-vitro study showed that monocytes which are irradiated with UVB and then infected with Mycobacterium avium intracellulare MAI organisms, efficiently inhibit the intracellular replication of MAI[ ]. The authors in this work speculated that the intracellular inhibition of MAI replication in the UV treated macrophages may be due to the induction of intracellular vitamin D production by the UVB.
Vitamin D has been shown to play an important role in the host immune response to mycobacterial infection[ ]. Vitamin D has also been shown to reduce the proliferation of M. Activated dendritic cells are known to produce Vitamin D[ ] and Vitamin D induces the intracellular production of cathelicidin, which is an antimicrobial protein[ ]. High levels of Vitamin D have been correlated with a reduced risk of developing multiple sclerosis, and Vitamin D intake is inversely associated with rheumatoid arthritis another autoimmune condition and the severity of this latter disease also correlates with Vitamin D levels[ ].
Finally, many types of cells including leukocytes and, in particular, monocytes, exposed to ultraviolet light secrete heat shock proteins and these proteins play an important role in the response to infection[ - ]. These case reports support a pathogenic role of MAP in humans. RedHill Biopharma Ltd. Researchers who explore the role of MAP in the autoimmune diseases should be aware that our current diagnostic tests are crude. The suboptimal sensitivity and the variation between current serologic assays for MAP make the diagnosis of MAP infection difficult.
However, in the presence of otherwise unexplained autoimmune disease, the occurrence of positive blood cultures for MAP should be a significant finding. Furthermore, pre-existing therapies for these conditions may hinder culture recovery methods. Many of the currently used immunomodulators have demonstrated bacteriostatic effects on MAP in-vitro [ , ]. When possible, MAP diagnostic testing should be conducted on newly diagnosed patients prior to instituting immunosuppressive therapies which can inhibit the growth of MAP in cultures.
Concurrent detection of antibodies directed at MAP will probably be helpful in this regard[ 50 ]. MAP cultures should be performed in laboratories with expertise. Parrish et al[ ] failed to replicate the blood culture study of Naser et al, but their method did not include egg yolk in the medium regarded by many as vital for MAP growth and the cultures were only held for 18 wk MAP cultures for humans are usually held for at least 6 mo and up to one year.
Modifying the assay into its isotype components, i. Further research is necessary in this area. Should MAP be proven to cause many of the autoimmune diseases, a potential role in carcinogenesis should be explored. Helicobacter pylori is now recognized as playing a major role in the pathogenesis of primary gastric MALT lymphoma and gastric carcinoma[ ]. CD patients are known to have increased risk of bowel cancer and lymphoma. Whether this increased risk is due to the immunosuppressive therapies used in this disease or due to infection by MAP is unknown and should be investigated further[ ].
In summary, much more must be learned about this elusive and enigmatic organism and about the human diseases with which it is associated. Please summarize main symptoms in one sentence. Please summarize main clinical findings in one sentence. Please summarize thoughts and methods for differential diagnosis in one sentence. The differential diagnosis in case 1 included celiac disease and food allergy while the differential diagnosis in case 2 included multiple sclerosis.
Please summarize laboratory testing methods and major findings in one sentence. Case 1 had anemia, elevated erythrocyte sedimentation rate, CRP and WBC while case 2 had elevated angiotensin converting enzyme, cryoglobulins, lymphocyte and eosinophil count and TSH and initially, both patients had blood cultures positive for Mycobacterium avium subsp. Please summarize imaging methods and major findings in one sentence. Case 1 had multiple aphthous ulcers on upper gastrointestinal endoscopy and on colonoscopy while case 2 had an unremarkable EMG study.
Please summarize pathological methods and major findings in one sentence. Case 1 had granulomas in the gastric and colonic biopsies while case 2 had no biopsies. Please summarize treatments and drugs used in one sentence. Both case 1 and case 2 received a combination of periodic ultraviolet blood irradiation UVBI and antibiotics which included clarithromycin, rifampin and ciprofloxacin for at least 2 years. Please provide other contents related to the case report to help readers better understand the present case.
Please explain uncommon terms present in the case report. UVBI is ultraviolet blood irradiation which consists of periodic irradiation of approximately cc of patient blood using ultraviolet light in the B and C regions. Please summarize experiences and lessons learnt from the case in one sentence.
This study is anecdotal and it will be necessary to study large numbers of patients in a controlled trial setting to determine whether these results are reproducible.
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Ethics approval: Institutional review board approval was not sought since the law allows off label use of FDA approved drugs and also allows the administration of UVBI in New York; IRB approval is generally not required in the care of individual patients. Informed consent: Informed consent was not sought from each of the patients in this series of case reports since each patient was treated individually and did not enroll in a formal study.
Unless an operative procedure or blood transfusion is intended, physicians caring for individual patients who are not part of a formal study, do not routinely seek informed consent from their patients. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. Peer-review started: October 27, First decision: November 14, Article in press: January 8, P- Reviewer: Qi Y L- Editor: A E- Editor: Wang CH. National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. World J Gastroenterol.
Published online Apr 7. Author information Article notes Copyright and License information Disclaimer.
Connell Ave. Author contributions: Kuenstner JT conceived of the combined UVBI and antibiotic treatment protocol and discovered the MAP infections in all of the cases; Chamberlin W and Telega G were the treating physicians for patient 1 and Chamberlin W, Weg S and John K were the treating physicians for patient 2; Naser SA, Collins MT and Aitken JM performed MAP cultures and MAP serologic assays on patients 1 through 5; Eckstein TM performed a serologic assay for leprosy on patient 2 and provided guidance on the presentation of the case reports and interpretation of the MAP literature; Haas D performed extensive analytic spectroscopic tests to confirm the chemical composition of a medication taken by patient 2; Dow CT conceived some of the theoretical basis of the study and contributed some of the references relating to human infection by MAP; Kali M and Welch C performed the statistical analysis which is a key part of the discussion; Petrie T designed and built the UVBI machine which was used to treat patients 1 and 2.
Published by Baishideng Publishing Group Inc. All rights reserved. This article has been cited by other articles in PMC. Open in a separate window. Figure 1. Assay for evidence of leprosy One assay was performed to detect antibodies to M. Figure 2. Figure 3. Table 1 Summary of Mycobacterium avium subsp.
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Case 4 The nephew of the mother of cases 1 and 2 has lymphangiomatosis, a disease of unknown etiology. Case 5 The father of cases 1 and 2 was tested for MAP infection. Figure 4. Clinical diagnosis Please summarize main clinical findings in one sentence. Differential diagnosis Please summarize thoughts and methods for differential diagnosis in one sentence. Laboratory diagnosis Please summarize laboratory testing methods and major findings in one sentence.
Imaging diagnosis Please summarize imaging methods and major findings in one sentence. Pathological diagnosis Please summarize pathological methods and major findings in one sentence. Treatment Please summarize treatments and drugs used in one sentence. Related reports Please provide other contents related to the case report to help readers better understand the present case. Term explanation Please explain uncommon terms present in the case report. Experiences and lessons Please summarize experiences and lessons learnt from the case in one sentence.
Footnotes Ethics approval: October 27, First decision: November 14, Article in press: January 8, P- Reviewer: This information can be viewed online, downloaded or printed. Download materials. KCI offers educational forums for healthcare professionals at the local, regional and national levels. Attend in person or online. Register now. Discover how our innovative approach to healing and unrivalled portfolio help patients heal. Our commitment is to deliver proven end-to end solutions that reduce costs and create economic values. Helping patients become whole through proven technologies and solutions.
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