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Spontaneous remission of Crohn's disease following a febrile infection: case report and literature review Hoption Cann, Stephen A; van Netten, Johannes P May 19, 2011

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CASE REPORT Open AccessSpontaneous remission of Crohn’s diseasefollowing a febrile infection: case report andliterature reviewStephen A Hoption Cann* and Johannes P van NettenAbstractCrohn’s disease is a chronic illness that may often follow a relapsing-remitting course. Many of the factors that maybe associated with the spontaneous remission of this disease (i.e. not related to specific treatment) remain to bedetermined. In the present report, we review the medical history of a patient with a long history of moderate tosevere Crohn’s whose complete remission immediately followed the development of a febrile infection.The patient first developed symptoms of Crohn’s in her late adolescent years. At the time of diagnosis at age 23,she was placed on mesalamine - without effective control her disease symptoms. Due to progressive deterioration,the patient underwent a bowel resection at age 25. Soon afterwards symptoms recurred, gradually increasing inseverity. In February 2005, at age 36, the patient developed a painful abscess associated with a rectal fistula. Othersymptoms at the time included chronic bone and stomach pain, swollen joints, and debilitating fatigue. Surgicalcorrection was scheduled in mid-March. In late February, the patient developed a respiratory infection associatedwith fevers of 103-104°F. After the onset of fever, the abscess pain disappeared and this was soon followed by adisappearance of all other disease symptoms. By the time the corrective surgery occurred, she had no Crohn’ssymptoms. Her remission lasted 10 weeks when the previous symptoms then reappeared. The patient hassubsequently used a variety of conventional therapies, but still suffers from severe symptoms of her disease.In recent years, a growing body of literature has emphasized the important role that innate immunity plays in theetiology of Crohn’s disease; however, a key component of innate immunity, the febrile response, has beenoverlooked. Other cases of spontaneous remission following febrile infection in inflammatory bowel disease havebeen reported. Moreover, induction of a febrile response was in the past used as a treatment for inflammatorybowel disease, but was later replaced by surgery and corticosteroids. Further exploration of this arm of the innateimmune response may provide new opportunities for patients where conventional therapies fail to secure relief.BackgroundCrohn’s disease is a chronic inflammatory disease of thegastrointestinal tract that often follows a relapsing-remitting course. Current treatment regimens forCrohn’s disease focus on immunosuppressive agentsincluding aminosalicylates, corticosteroids, purine analo-gues such as azathioprine or 6-mercaptopurine, and bio-logic therapies such as tumor necrosis factor alphainhibitors. Along similar lines, surgery is frequentlyemployed to excise regions of immune-mediated inflam-matory activity. Contrasting such approaches, recentstudies have suggested that underlying defects in innateimmunity may play a role in the development of thisdisease [1,2]. Innate immune deficiencies may in turnleave predisposed individuals vulnerable to an infectionor infections that cause the disease. In support of a rolefor infection, various antibiotic [3] and probiotic [4]regimens have been explored in an attempt to eradicateor displace the suspect pathogen(s). Many pathogenshave been implicated with the idea that the disease mayresult from some form of occult infection [5,6] or fromreduced control/decreased biodiversity of commensalbacteria [7,8]. While the probiotic or antibiotic approachmay lead to a lessening of inflammation and symptoms,the ability of such regimens to produce cures is limitedand antibiotic side effects prevent its long term use.* Correspondence: hoption.cann@ubc.ca1School of Population and Public Health, University of British Columbia,Vancouver, BC, V6T 1Z3, CanadaHoption Cann and van Netten BMC Gastroenterology 2011, 11:57http://www.biomedcentral.com/1471-230X/11/57© 2011 Hoption Cann and van Netten; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Although many studies have highlighted defects in theinnate immune response, the febrile response armremains a critical, but often ignored component ofinnate immunity [9,10]. In the present case study, wereport on the temporary remission of severe Crohn’sdisease following an influenza-like illness with repeatedhigh fevers and review the literature associated with thisphenomenon.Case presentationThe patient is a 40 year old female with lengthy historyof moderate to severe Crohn’s disease. The patient’sfamily history included a father who was diagnosed withCrohn’s disease at age 20. He later developed colon ade-nocarcinoma at age 46 years, dying the following yearfrom his cancer.The patient first developed symptoms of her disease incollege at age 18. Symptoms at the time includedabdominal pain, weight loss (15 lbs), and debilitatingfatigue. However, even previous to this time, the patientsuffered for many years from pain in her bones andjoints. During her college years, she continued to loseweight. At age 23, following the onset of severe abdom-inal pain and an inability to eat or drink, a diagnosis ofCrohn’s disease was finally made. The disease was foundto occupy the ileocaecal region. At that time, she begantreatment with mesalamine, although it was not effectivein controlling her symptoms.At age 25, the patient presented with symptoms ofacute bowel obstruction. Surgery revealed volvulus ofthe ileocaecal region and 10 inches of the distal ileumand entire caecum were excised. Symptoms recurredfairly soon afterward, but it was a further 6 to 7 yearsbefore they became severe.In February 2005, at age 36, the patient developed apainful fistula-associated rectal abscess. At this time, thepatient’s ongoing symptoms included chronic bone andabdominal pain, swollen joints, and debilitating fatigue.On February 18th, she was placed on cephalexin to treatthe abscess previous to a scheduled surgery to correctthe fistula. Following a week with no improvement inabscess pain while on the antibiotic, the patient thendeveloped an influenza-like infection (high fevers, chills,headache, cough, and rhinorrhea). After the first onsetof fever, the abscess pain was no longer apparent. Therecurrent fevers (103-104°F) from the infection persistedfor four days and were associated with a complete disap-pearance of all other disease symptoms. This was fol-lowed by an increase in appetite and weight. On March18th, the patient underwent the scheduled surgery tocorrect the fistula. Her energy level had been continuallyimproving and after a month she was running up to 3miles a day and was able to run up hills that she couldnot even walk up prior to her remission. Afterapproximately 10 weeks of this symptom-free remission,her previous disease symptoms began to return. Theinitial symptoms included hugely swollen knees anddiarrhea. The patient was again placed on cephalexin inthe expectation that it might result in another remission,but the intervention had no effect on symptoms.Since that remission, the patient subsequently used:budesonide; triple antibiotic therapy; infliximab withprednisone; and is presently on adalimumab withmethylprednisolone to treat swollen and painful joints.The patient’s current symptoms include bone pain,recurrent painful blisters on her hands, crusting andbleeding of the external nares, oral ulceration, chronicabdominal pain with periodic diarrhea, and swollen andpainful joints with occasional extreme pain and swelling.ConclusionsIn the present case, the patient was diagnosed withCrohn’s 13 years before the infection-associated remis-sion, although she was symptomatic with the disease atleast 17 years before this remission. The patient’s onlypreceding remission was that following small bowel sur-gery; otherwise the patient had never been symptom-free and ever-present were symptoms including chronicfatigue, bone and abdominal pain, painful and swollenjoints, blisters and ulceration and a poor appetite caus-ing her to be chronically underweight. The patient con-tinues to struggle with these many symptoms whichhave not been effectively controlled despite intensivemedical management.Lobel and colleagues reported on an interesting seriesof four Crohn’s disease and one ulcerative colitis remis-sion that followed febrile infections [11]. The patients’fevers, usually high, were of two weeks or greater induration. In four of five cases, no etiology for the fevercould be determined, and in the fifth patient, the infec-tion resulted from a perforation of an ileocolic anasto-mosis and intraabdominal, perihepatic andperipancreatic abscesses. None of the infections wererespiratory in nature. There were four females withCrohn’s disease (age range 24 to 31 years) and one 34year old male with ulcerative colitis. Reported remis-sions were of 2-10 years in duration with no recurrencesat the time of reporting, although three subjectsremained on maintenance therapy subsequent to theirremissions. All patients were taking 6-mercaptopurine(6MP) at the time of remission and the authorshypothesized that fever along with 6MP-induced leuko-penia was an important factor in the remissions.A therapy to stimulate the innate febrile immuneresponse in inflammatory bowel disease dates back toArthur Hurst, who in 1921 [12] experimented with adysenteric bacterial serum therapy for one of hispatients with ulcerative colitis. Hurst would later reportHoption Cann and van Netten BMC Gastroenterology 2011, 11:57http://www.biomedcentral.com/1471-230X/11/57Page 2 of 4that there was no recurrence when he last saw thepatient 15 years later [13]. Hurst, who subsequentlytreated many more ulcerative colitis patients with thistherapy, summarized several of his notable findings [14].First, he found that intramuscular injections were bene-ficial, but less frequently than intravenous injections;although he did raise the concern that an anaphylacticreaction may occur following intravenous injection ofthe vaccine. He further observed that rapid recovery wasmost likely in the early stages of disease, but could occa-sionally be very striking in long standing cases. Finally,he noted that recurrence was much reduced if treatmentwas continued until the sigmoidoscope shows no traceof inflammation, even if symptoms had already disap-peared for some weeks.Based on the preliminary findings of Hurst, in the1920s and 1930s Burrill Crohn (who first characterizedregional ileitis or Crohn’s disease [15]) experimentedusing various intravenous therapies for the treatment ofulcerative colitis. He stated that in approximately 45% ofcases there was a persistent cessation of symptoms andrestitution to a normal state. Crohn made some interest-ing observations on the use of Hurst’s immunotherapy,which he used regardless of whether or not dysenteryorganisms could be detected in a patient’s blood [16]:“A severe febrile reaction was welcomed. A certaindegree of anaphylactic shock was regarded as morebeneficial than deleterious. The most beneficialresults were seen in those patients in whom theintravenous injection of serum resulted in immediateserum shock analogous to a non-specific proteinreaction and in those who showed late serum sick-ness with urticaria and even joint manifestations.The use of polyvalent anti-dysentery serum seemedto give us best results.In order to determine whether the effect of thisserum was a specific or a non-specific one, weattempted, in a number of cases, to duplicate theresults by the intravenous injection of typhoid vac-cine, such representing a convenient and directmethod of nonspecific protein therapy. Some fairlygood results were seen. Other miscellaneous meth-ods of treatment were tried at various times in thecourse of years, these methods including autogenousvaccines of fecal organisms, Bargen’s serum and vac-cine, transfusions, etc., some with good results,many of them without any noticeable effect. Itwould seem that among the various types of intrave-nous therapy, no one item seemed to have a specificeffect upon the disease. It soon became obvious thatany protein agent which would produce a proteinshock and a febrile reaction, could bring about abeneficial change in the chronic course of thisdisease. The change from the slow, lethargic chroni-city into a sudden flare-up induced by the proteintherapy of whatever type, frequently seemed to alterthe long drawn-out course of the malady. After sev-eral severe protein shocks, the temperature wouldfrequently subside, diarrhea gradually and moreslowly diminish until constipation was achieved andthe general health of the patient, appetite, strengthand weight began to show steady improvement.”Following World War II, new treatment optionsbecame available including antibiotics and corticoster-oids. By that time, Crohn had discontinued using bacter-ial vaccines for his patients with inflammatory boweldisease in preference to surgery, which initially seemedto lead to a very high cure rate: “The percentage of sur-gical cures is high, even when reckoned conservatively,and it is grossly well over 80 per cent [17].” Although insubsequent years, it became apparent to Crohn thatrecurrences following surgery were not uncommon, andsimilarly, other promising therapies failed to meet initialexpectations [18].The possibility exists that other factors may have beenresponsible for the patient’s remission. For example, theantibiotic cephalexin could have played a role, althoughsome facts warrant against such a possibility. Thepatient had been on cephalexin for many days withoutany effect on her symptoms, and following diseaserecurrence the rechallenge with cephalexin had noimpact on her symptoms. As to the surgery, by the timethe operation for her fistula had taken place, herCrohn’s symptoms had already abated and therefore itwas an unlikely factor in her remission. In contrast tothe case series by Lobel, the acute infections that wereassociated with remissions were of a longer durationthan in the present case; however, they also correspond-ingly produced remissions of a much longer duration.In the present case, the complete remission was unu-sual for this patient due to a long history of severe andpoorly controlled disease. Moreover, the remission asso-ciated with the patient’s febrile infection is analogous toother reports of spontaneous or induced remissions fol-lowing fever. In fact, the prompt improvement noted inthese reports, and in the present case, provides furthersupport for the hypothesis that the innate immuneresponse plays a key role - an adaptive immuneresponse would require a longer time period to develop.Strategies that try to suppress the immune system orthose that try to eradicate or displace harmful bacteriahave shown limited efficacy. An alternative approachwould be to develop therapies that specifically activatethe innate febrile immune response, and therebyattempt to reassert immune system control over patho-gens or harmful indigenous flora.Hoption Cann and van Netten BMC Gastroenterology 2011, 11:57http://www.biomedcentral.com/1471-230X/11/57Page 3 of 4AcknowledgementsWe wish to thank the patient for agreeing to allow us to report on herremission.Authors’ contributionsSAHC was in direct contact with the patient. SAHC drafted the manuscriptwith the assistance of JPvN. SAHC and JPvN made the final corrections andcomments. Both authors read and approved the final manuscript.Competing interestsSAHC and JPvN have interests in a company that manufactures a sterilebacterial preparation for the treatment of cancer.Received: 10 September 2010 Accepted: 19 May 2011Published: 19 May 2011References1. Coulombe F, Behr MA: Crohn’s disease as an immune deficiency? Lancet2009, 374:769-70.2. Vavricka SR, Rogler G: New insights into the pathogenesis of Crohn’sdisease: are they relevant for therapeutic options? Swiss Med Wkly 2009,139:527-34.3. Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M: Long-termantibiotic treatment for Crohn’s disease: systematic review and meta-analysis of placebo-controlled trials. Clin Infect Dis 2010, 50:473-80.4. Haller D, Antoine JM, Bengmark S, Enck P, Rijkers GT, Lenoir-Wijnkoop I:Guidance for substantiating the evidence for the beneficial effects ofprobiotics: probiotics in chronic inflammatory bowel disease and thefunctional disorder irritable bowel syndrome. J Nutr 2010, 140:690S-7S.5. Scanu AM, Bull TJ, Cannas S, Sanderson JD, Sechi LA, Dettori G, Zanetti S,Herman-Taylor J: Mycobacterium avium subspecies paratuberculosisinfection in cases of irritable bowel syndrome and comparison withCrohn’s disease and Johne’s disease: common neural and immunepathogenicities. J Clin Microbiol 2007, 45:3883-90.6. Hansen R, Thomson JM, El-Omar EM, Hold GL: The role of infection in theaetiology of inflammatory bowel disease. J Gastroenterol 2010, 45:266-76.7. Lidar M, Langevitz P, Shoenfeld Y: The role of infection in inflammatorybowel disease: initiation, exacerbation and protection. Isr Med Assoc J2009, 11:558-63.8. Packey CD, Sartor RB: Commensal bacteria, traditional and opportunisticpathogens, dysbiosis and bacterial killing in inflammatory boweldiseases. Curr Opin Infect Dis 2009, 22:292-301.9. Hoption Cann SA, van Netten JP, van Netten C: Acute infections as ameans of cancer prevention: opposing effects to chronic infections?Cancer Detect Prev 2006, 30:83-93.10. Hoption Cann SA: Peak fever: helpful or harmful? Heart Lung 2011, Epubahead of print.11. Lobel EZ, Korelitz BI, Vakher K, Panagopolous G: Prolonged remission ofsevere Crohn’s disease after fever and leucopenia. Dig Dis Sci 2004,49:336-38.12. Hurst AF: Ulcerative colitis. Guy’s Hospital Reports 1921, 71:26.13. Hurst AF: Discussion on the diagnosis and treatment of colitis. Proc R SocMed 1927, 20:367-75.14. Hurst AF: Treatment of ulcerative colitis. BMJ 1936, 1:320-21.15. Crohn BB, Ginzburg L, Oppenheimer GD: Regional ileitis: a pathologic andclinical entity. JAMA 1932, 99:1323-29.16. Crohn BB, Rosenak BD: A follow-up of ulcerative colitis (non-specific). AmJ Dig Dis Nutr 1935, 2:343-46.17. Crohn BB: Regional ileitis. Grune & Stratton, NY; 1949.18. Crohn BB: Regional ileitis. Grune & Stratton, NY;, 2 1958.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/11/57/prepubdoi:10.1186/1471-230X-11-57Cite this article as: Hoption Cann and van Netten: Spontaneousremission of Crohn’s disease following a febrile infection: case reportand literature review. BMC Gastroenterology 2011 11:57.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitHoption Cann and van Netten BMC Gastroenterology 2011, 11:57http://www.biomedcentral.com/1471-230X/11/57Page 4 of 4


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