A 25-year-old woman presented with fever of unknown origin, exhibiting malaise and low-grade fevers in evenings. These fevers exhibited a pattern of starting mid-menstrual cycle with resolution around the onset of menses, matching a pattern of "habitual hyperthermia" reported by H. Reimann in the 1930s. Extensive workup was unremarkable, and the fevers improved on oral synthetic estrogen and progesterone therapy

Currier, Judith S

Yang, Otto O

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UCLAUCLA Previously Published WorksTitleReimann's “Habitual Hyperthermia” Responding to Hormone TherapyPermalinkhttps://escholarship.org/uc/item/149181hhJournalOpen Forum Infectious Diseases, 3(3)ISSN2328-8957AuthorsYang, Otto OCurrier, Judith SPublication Date2016-05-01DOI10.1093/ofid/ofw127 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaOpen Forum Infectious DiseasesB R I E F R E P O R TReimann’s “Habitual Hyperthermia”Responding to Hormone TherapyOtto O. Yang1,2,3 and Judith S. Currier11Division of Infectious Diseases, Department of Medicine, and 2Department of Microbiology,Immunology, and Molecular Genetics, David Geffen School of Medicine, University of CaliforniaLos Angeles, and 3AIDS Healthcare Foundation, Los Angeles, CaliforniaA 25-year-old woman presented with fever of unknown origin,exhibiting malaise and low-grade fevers in evenings. These fe-vers exhibited a pattern of starting mid-menstrual cycle withresolution around the onset of menses, matching a pattern of“habitual hyperthermia” reported by H. Reimann in the1930s. Extensive workup was unremarkable, and the fevers im-proved on oral synthetic estrogen and progesterone therapy.Keywords. fever unknown origin; habitual hyperthermia.CASE REPORTA 25-year-old woman had approximately 1 year of intermittentlow-grade fevers (antipyretic unresponsive), with fatigue, mal-aise, proximal muscular aches, sweats, poor appetite, and 20pounds weight loss. Her history was significant for birth by ce-sarean section at 38 weeks for fetal distress, unspecified upperairway surgery in infancy, intermittent fevers that spontaneous-ly resolved in early childhood, mild childhood asthma, frequentotitis media requiring tympanostomy tubes into adulthood, en-vironmental allergies with sinus congestion, eczema, and hives,and frequent viral upper respiratory infections and pharyngitis.In addition, she had self-limited “chronic lymphocytic thyroid-itis,” irritable bowel syndrome, and pneumonia as a youngadult, but she had no diabetes mellitus or known immunodefi-ciency. Her ethnicity was Arab and European for her paternaland maternal lineages, respectively, and her family history in-cluded a paternal aunt and uncle with unclear fevers in child-hood that spontaneously resolved.Physical examination, routine blood tests (including com-plete blood count [CBC]), and chest x-ray were unrevealing.A detailed body temperature log (digital oral readings 8:00 AM,noon, and 8:00 PM) displayed exaggerated diurnal temperaturevariation, with relatively normal morning temperatures and in-termittent evening elevations (Figure 1A).Additional blood tests returned normal/negative: erythrocytesedimentation rate (ESR), C-reactive protein, ferritin, comple-ment, D-dimer, interleukin (IL)-1β and IL-6, serum proteinelectrophoresis, immunoglobulins,Mycobacterium tuberculosis,dihydrorhodamine 123 oxidation, human immunodeficiencyvirus, hepatitis B virus, hepatitis C virus, Coccidioides immitis,rheumatoid factors, Sjögren’s syndrome (SS)A/SSB, Jo 1, andantinuclear antibodies (borderline at 1:40). Periodic fever syn-drome genetic screening (Gene Dx) for ELANE (ELA2), LPIN2,MEFV, MVK, NLRP3 (CIAS1), PSTPIP1, and TNFRSF1A re-vealed only MEFV E148Q heterozygosity. Mitochondrialdeoxyribonucleic acid genetic screening (Pro Genetic) forA3243G, T3271C, A8344G, G8363A, T8993C, T8993G,T9176C, G13513A, and T14709C was negative. Computed to-mography scan of the sinuses was normal as were magnetic res-onance imaging scans of the chest, abdomen, and pelvis.DISCUSSIONEmpiric diagnostic and therapeutic trials of prednisone and col-chicine had no discernable effects (Figure 1B). Follow-up re-vealed a consistent pattern of rising evening temperaturesafter menses, abruptly dropping just before onset (Figure 1C).To evaluate hormonal involvement, oral combination levonor-gestrel/ethinyl estradiol (Jolessa) was initiated. The cyclical pat-tern of fever (and associated fatigue, malaise, anorexia, sweats,and muscle aches) immediately dampened, although inci-dentally she developed acute otitis media, mastoiditis, and con-sistent fevers, which improved after mastoidectomy andtympanostomy tube placement (Figure 1E). Interruption of le-vonorgestrel/ethinyl estradiol after 3 months was accompaniedby recurrent symptoms that were unresponsive to anakinra.Restarting hormonal treatment yielded a long-term response(Figure 1F), although the patient continues to have fevers dur-ing frequent episodes of seasonal upper respiratory infections.“Habitual hyperthermia” is poorly defined, apparently firstcoined in 1917 as persistently elevated basal body temperatureup to 38.0°C without pathology [1]. In 1932 and 1935, Dr. H. A.Reimann [2, 3]described a more specific syndrome in women asexaggeration of diurnal temperature variation in the latter halfof the menstrual cycle that was unresponsive to antipyretics.White blood cell count with differential, ESR, and “metabolictests” were normal. He offered no diagnostic criteria, statingthat such observations are “helpful in establishing a diagno-sis . . . but the picture must be regarded as a whole” [2], andno further definitions followed after 1935.Received 2 April 2016; accepted 14 June 2016.Correspondence: O. O. Yang, BSRB 173, 615 Charles E Young Drive S, Los Angeles, CA 90095(oyang@mednet.ucla.edu).Open Forum Infectious Diseases®© The Author 2016. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. This is an Open Access article distributed under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in anymedium, provided the original work is not altered or transformed in any way, and that the workis properly cited. For commercial re-use, please contact journals.permissions@oup.com.DOI: 10.1093/ofid/ofw127BRIEF REPORT • OFID • 1However, habitual hyperthermia has been diagnosed in multi-ple case series of fever of unknown origin (FUO), assigned to 5 of199 patients (2.5%) by Knockaert et al [4] in 1992, 11 of 290 pa-tients (3.8%) by Vanderschueren et al [5] in 2003, and 8 of 144patients (5.5%) by Zenone [6] in 2006, yet these reports lack di-agnostic criteria (eg, gender) and/or citations defining the syn-drome. Moreover, Vanderschueren et al [5] stated that thestandard Petersdorf [7] FUO criteria exclude habitual hyperther-mia despite offering it as an etiology for 3.8% of their cohort.Our case closely matches Reimann’s: a woman with exagger-ated diurnal temperature variation temporally related to themenstrual cycle, normal CBC, and ESR, and lack of responseto antipyretics, although she had associated symptoms and ahistory of childhood fevers that he did not describe in hiscases. It is unclear why she had symptoms associated with herfevers that are more consistent with an inflammatory cause,reflecting either a variant of the syndrome or a superimposedprocess. Blood IL-1β and IL-6 were normal and anakinra hadno effect, supporting his hypothesis of central dysregulation.Although our patient also had superimposed frequent upper re-spiratory tract infections, the underlying pattern of tempera-tures absent these infections closely mirrors his reports.Responsiveness to levonorgestrel/ethinyl estradiol additionallysuggests a menstrual-related hormonal effect that is responsiveto suppression by synthetic estrogen/progesterone. Althoughvariation related to the menstrual cycle has been known since1868 [8] or earlier, the mechanism of hormonal effects remainsunclear [9].CONCLUSIONSTo our knowledge, this is the first detailed report of habitual hy-perthermia since 1935, and it is the only successful therapeuticFigure 1. Pattern of fevers. (A) Ten days of representative body temperatures measured orally at approximately 8:00 AM, noon, and 8:00 PM are plotted, showing changingamounts of diurnal variation over time. (B) The 8:00 PM temperatures over 300 days are plotted against trials of prednisone and colchicine, as well as onset of menstrual cycles.(C) The median temperatures across 10 menstrual cycles are plotted in relationship to start of menses. (D) The 8:00 AM and 8:00 PM temperatures in the 3 months precedingtreatment with oral levonorgestrel/ethinyl estradiol are plotted. (E) Temperatures in the 3 months after starting oral levonorgestrel/ethinyl estradiol are plotted. The shaded areaindicates the timing of acute otitis media and mastoiditis culminating in mastoidectomy and tympanostomy tube placement. (F) Temperatures are plotted after several monthsreceiving oral levonorgestrel/ethinyl estradiol.2 • OFID • Yang and Currierintervention. How long to treat and the natural history of thissyndrome are unclear. When Reimann [10] re-evaluated hisfirst case from 1932 in 1946 after “six pregnancies . . ., an attackof typhus, several bouts of malaria,” the temperature pattern re-mained, and he concluded “it will be of interest to see what ef-fect the menopause will have,” although that outcome for thispatient and the others he described in the second report appearsto be lost to the annals of medical history.AcknowledgmentsWe thank the patient for her diligent temperature record-keeping andgenerous willingness to share her case. We also thank and Dr. Paul Krogstadfor manuscript review.Potential conflicts of interest. All authors: No reported conflicts. Allauthors have submitted the ICMJE Form for Disclosure of Potential Con-flicts of Interest.References1. Moro E. [Habituelle Hyperthermie]. Sonderdruck aus: Monatsschrift für Kinder-heilkunde XIV Bd 1917; 4:S. 214–23.2. Reimann HA. Habitual hyperthermia. J Am Med Assoc 1932; 99:1860–2.3. Reimann HA. Habitual hyperthermia: a clinical study of four cases with long con-tinued low grade fever. Arch Intern Med 1935; 55:792–808.4. Knockaert DC, Vanneste LJ, Vanneste SB, Bobbaers HJ. Fever of unknown origin inthe 1980s. An update of the diagnostic spectrum. Arch Intern Med 1992; 152:51–5.5. Vanderschueren S, Knockaert D, Adriaenssens T, et al. From prolonged febrile ill-ness to fever of unknown origin: the challenge continues. Arch Intern Med 2003;163:1033–41.6. Zenone T. Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital. Scand J Infect Dis 2006; 38:632–8.7. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Med-icine 1961; 40:1–30.8. Squire W. Puerperal temperatures. Trans Obstet Soc Lond 1868; 9:129–44.9. Forman RG, Chapman MC, Steptoe PC. The effect of endogenous progesterone onbasal body temperature in stimulated ovarian cycles. Human Reprod 1987; 2:631–4.10. Reimann HA. Habitual hyperthermia; premenstrual fever. J Am Med Assoc 1946;132:144.BRIEF REPORT • OFID • 3

Reimann's “Habitual Hyperthermia” Responding to Hormone Therapy

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Reimann's "Habitual Hyperthermia" Responding to Hormone Therapy.

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