Outbreak of Histoplasmosis in a School Party That Visited a Cave in Belize: Role of Antigen Testing in Diagnosis
Jane A. Buxton, Meenakshi Dawar, L. Joseph Wheat,William A. Black, Nelson G.Ames, Marcella Mugford, and David M. Patrick
Histoplasmosis is endemic in parts of South and Central America and the role of bat guano is widely recognized in promoting the growth of the organism.1,2 Previous outbreaks have been reported among cavers in the United States3,4 and South America,5 often in travelers upon return to their home country. The illness may be quite severe, as the exposure is often extensive, emphasizing the importance of recognition of the risk for histoplasmosis in cavers and understanding the approach to diagnosis. Thirteen students (aged 16 to18 years) and 2 teachers from a school in Trail, British Columbia, Canada, traveled in Belize with 2 guides (1 Canadian, 1 from Belize) from March 16 to 26, 2000. Local BC physicians reported complaints of fever and chills in returning travelers to the BC Centre for Disease Control (BCCDC).
Jane A. Buxton, MBBS, MHSc, FRCPC: Federal Field Epidemiology Training Program, Laboratory Centre for Disease Control, Health Canada, Ottawa, ON, Canada; Meenakshi Dawar, MD MHSc, FRCPC: Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC, Canada; L. Joseph Wheat, MD: Histoplasmosis Reference Laboratory, Indiana University School of Medicine, Indianapolis, IN, USA; William A. Black, MBChB, FRCPC:The Provincial Laboratory, British Columbia Centre for Disease Control Society, Vancouver, BC, Canada; Nelson G. Ames, MD, MHSc, and Marcella Mugford, RN: Kootney Boundary Health Services, BC, Canada; David M. Patrick, MD, MHSc, FRCPC: Epidemiology Services, British Columbia Centre for Disease Control Society, Vancouver, BC, Canada. The histoplasma antigen testing was supported by a Merit Review Grant from the Department of Veterans Affairs. The authors had no financial or other conflicts of interest to disclose. Reprint requests: David M. Patrick, MD, MHSc, FRCPC, Epidemiology Services, British Columbia Centre for Disease Control Society, 655 West 12th Avenue, Vancouver, BC, Canada V5Z 4R4. J Travel Med 2002; 9:48–50.

Method Two physicians from BCCDC flew to Trail on April 12, 2000 to investigate the outbreak. Information collected by local public health staff, available chest x-rays, and laboratory results were reviewed. Trip and symptom details were obtained from one of the teachers. A standard questionnaire, aimed to identify potential risk factors and symptoms, was developed. The questionnaire was administered, and blood and urine samples were obtained, at the high school on April 13. An enzyme-linked immunoassay (EIA) was used to detect histoplasma antigen in serum and urine; and has been previously described.6 Results, expressed as enzyme immunoassay units, of 1 unit or higher are regarded as positive. On May 25, a second questionnaire to determine symptom duration was administered at the school and convalescent serology and urine samples obtained. Telephone follow up of those reporting persisting symptoms was attempted. Results Sixteen initial questionnaires were completed; all 13 students (one by telephone); both teachers and the Canadian guide who faxed his response. No contact was possible with the guide from Belize. The prime focus of the trip involved salt water kayaking between islands and camping on the beaches. On March 18, all students, staff, and both guides had a 3-hour excursion into a cave where bats were present. At times, headroom was limited so the party crawled on the dry cave floor in bat guano.
Illness Profile

Fourteen individuals reported being ill following their return to Canada (attack rate of 87.5%); one student and the Canadian guide remained well. The symptom onset dates were April 2–9 (days 15–22 post bat cave exposure); Figure 1. All who were unwell complained of headaches, chills, sweats, and muscle aches (mainly of the

Chest X-ray Results Figure 1 Reported date of histoplasmosis illness onset by students. and 8 had a cough. and 4 reported symptoms were worse. abdominal pain (6).B u x t o n e t a l . Fever persisting for >3 weeks may indicate development of progressive disseminated disease. Although not noted as a major complaint at the initial public health nurse interviews. 4 (29%) were ill for more than 50 days.6. Ten (71%) of those who fell ill. however. unlike birds. a fourth demonstrated a faint nodule in the right upper lobe. 2 were negative (1 of these was from the asymptomatic student). no rashes or other skin complaints were reported or seen. The acute and convalescent urine antigen tests of the student with a well-defined nodule were negative (unfortunately no convalescent serum was available for antibody testing). 7 reported improvement in their symptoms. the only sign of a past exposure being a positive intradermal histoplasmin test. 8 a sore throat. dengue serology. Of the 14 questionnaire respondents who had been ill. Follow up of these 4 was attempted. and 4 were improving. 10 had chest pains. Most patients who acquire histoplasmosis remain asymptomatic. overall 7 of the 15 student/teacher-group tested positive for histoplasma antigen (4). Other symptoms reported were nausea (5 persons). (2 asymptomatic. this student reported debilitating symptoms continuing for 3 months after exposure so was given an oral antifungal regimen (itraconazole 200 mg bid for 6 weeks) with marked improvement in symptoms. Therapy may be helpful in symptomatic patients whose conditions have not improved during the first month of infection. 1 showed a well-defined nodule of the left upper lobe. back and neck). antibody (2). and 9 reported joint symptoms. for a sensitivity of 71% in acute histoplasmosis. swollen lymph nodes (2). Treatment is not usually indicated because the illness is self limited and associated with minimal morbidity.7 Only one of the students who visited Belize required an oral antifungal regimen with marked improvement of their symptoms. Inapparent infections are very common in endemic areas and usually result in increased resistance to infection. which were generally worse later in the day. The severity of illness after inhalation exposure to H. capsulatum depends on the intensity of exposure and the immunity of the host. may themselves become infected with H. or both (1). spirochetes and trypanosomes.Thus. a spore producing dimorphic fungus. . which accelerate spore formation. experienced symptoms attributed to histoplasmosis lasting 18–27 days. the third had patchy basal infiltrate but no pulmonary nodularity. which may be aborted by therapy. which had resolved on a follow-up chest x-ray. and guide who visited a cave in Belize. Fifteen follow-up questionnaires. 14 convalescent urine. Similar findings were observed in a study by one of the authors (LJW) during an outbreak in a Thick and thin smears for malaria. Laboratory Results Four cases had chest x-rays performed:1 was reported as normal. Discussion Histoplasma capsulatum. 10 reported feeling completely better. reported respiratory symptoms were common: 11 had shortness of breath.2 Bats.8 Antigen was detected in the urine of 5 of 7 subjects tested within the first month of exposure. most felt unusually tired and light-headed. Twelve persons reported a fever. The role of bird and bat guano is widely recognized in promoting the growth of the organism in soil by providing a source of nitrates. teachers. capsulatum. H i s t o p l a s m o s i s i n a S ch o o l Pa r t y C a v i n g i n B e l i z e 49 additional individual (who was positive for urine antigen in April) had both M and H antibody to histoplasma. n = 14). also obtained within a month of exposure. Urinary antigen was not detected in follow-up urine specimens from 14 travelers. histoplasma antibody and antigen tests on all 10 serum samples obtained on day 26 post bat cave exposure were negative. This study shows the potential role of antigen testing for diagnosis of acute histoplasmosis. 9 individuals had seen a physician since their return to Canada. No specimens were available from the Canadian guide.1. Heavy exposure can cause severe diffuse pulmonary infection. Seven urine samples. 1 . 1 reported symptoms lasting 60 days but contact with the other 3 has not been possible. 3 reported no improvement. By April 13. Convalescent serum specimens (> 2 months postexposure) were available for 10 travelers: 2 were positive for M antibody to histoplasma (both students had not provided urine samples in April). were tested for histoplasmsa antigen: 5 were positive. is endemic through much of the world including the United States and Central and South America. and 10 convalescent serum specimens were obtained.

Wheat LJ. Vo l u m e 9 . 24:313–327. Larrabee WF. School District 57. Connolly PA. and entering a confined crawl space have been found to be risk factors for histoplasmosis illness. this report emphasizes the risk for histoplasmosis among cavers. 10.8 Thus urine antigen testing is most useful for patients with acute presentations following exposure to a site suspected to be contaminated with H. Urine testing also should be performed in persons presenting within a month of presumed exposure to identify cases before the development of antibodies. Am J Trop Med Hyg 1978. Illness Survey. None of those who caved in Belize exhibited antigenemia. University of Northern BC. 9. 14. We have also demonstrated the potential usefulness of urine antigen testing and the limitations of serologic testing for diagnosis of acute histoplasmosis. Davies SF. Bigler WJ. Practice guidelines for the management of patients with histoplasmosis.13 The high attack rate of the Belize travelers may possibly be attributed to a number of factors: the young age of the travelers. Durkin MM. Outbreak of histoplasmosis among cavers attending the National Speleological Society Annual Convention. Comparison of radioimmunoassay and enzyme-linked immunoassay methods for detection of Histoplasma capsulatum var. Possible explanations for this discrepancy include differences in sensitivity of the testing methods (complement fixation tests are more sensitive than the immunodiffusion technique used in this study). et al.50 J o u r n a l o f Tr a v e l M e d i c i n e . but it is not a reportable disease. Johnson J. 37:312–313. 118:1205–1208. lack of previous exposure. Williams B. Public Health Rep 1970. BC. 37:312–313. Cave-associated histoplasmosis: Costa Rica. Texas. Ajello L. Kaufman L. 13. Fojtasek M. 3. 30:688–695. Crockett LK. 5.9 The sensitivity of antigen detection is lower in patients with subacute pulmonary histoplasmosis (about 30%) or chronic pulmonary histoplasmosis (15%). and the large inoculum of spores to which they were exposed crawling in the dry bat guano on the cave floor. Wheat J.9. Sem Resp Infect 1986. 6. Kelley MF. capsulatum or with diffuse pulmonary infiltrates. Palmer J. J Clin Microbiol 1997. Ashford DA. 1995. 27:281–285. Serodiagnosis of histoplasmosis. 60:899–903.12 H. et al. Acknowledgment The authors would like to acknowledge the travelers.5%) is remarkably consistent with that found in a group of university students who entered a cave inhabited by bats in Costa Rica (88%). 7. Report prepared by the Department of Health Care and Epidemiology. 17:191–195. capsulatum has not been known to cause illness in BC. H. MMWR 1988.14 Health care providers should include histoplasmosis in their differential diagnoses of travelers to endemic areas complaining of fever and chills and ask about cave exposure. and The Reference Laboratory in Edmonton for histoplasma antibody testing. The role of bats in the propagation and spread of histoplasmosis: a review. J Wildlife Dis 1981. An epidemic of histoplasmosis on the isthmus of Panama. or intensity of exposure. 12. 31:527–531.3 The high attack rate of histoplamsosis of the Belize travelers (87. capsulatum has been more readily isolated from caves under dry conditions. Am J Trop Med Hyg 1982. staff of The Kootney Boundary Community Health Services Society for their assistance. The risk of acquiring histoplasmosis must be considered by any tour operator or traveler contemplating cave exploration in Central or South America. In summary. Sarosi G. Isolation of Histoplasma capsulatum from Arizona bats.10 However. An outbreak and review of cave-associated histoplasmosis capsulati. Prince George. Kabler MF. outbreaks have occurred among individuals exploring caves in the United States. et al. Ajello L. 11. All 25 histoplasmin skin tests performed as part of an illness survey of students with respiratory symptoms in northern BC were negative. Am J Epidemiol 1968. Contribution of bats to the maintenance of Histoplasma capsulatum in a cave microfocus. antibodies were detected in only 3 of 10 (30%) convalescent sera from the Belize cavers. showing the greater sensitivity of urine testing in acute histoplasmosis. Wheat J. and their physicians for their cooperation and help. J Med Vet Mycol 1986. Ajello L. Russell LH.4. Bat and soil studies for sources of histoplasmosis in Florida. Arch Pathol Lab Med 1994.3 including caves outside the endemic area. 89:606–614. IN. 2. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis. cave associated histoplasmosis – Costa Rica. Vancouver. McKinsey D. supporting the need for convalescent antibody testing. 8. Sacks JJ. Am J Trop Med Hyg 1999. International notes. antigenuria was detected in 20 of 24 (83%) prisoners. Bigler WJ. 75–80% of subjects exhibited an antibody response. N u m b e r 1 prison. Winkler WG. longer time spent in the caves. References 1. Disalvo AF. capsulatum antigen. 35:2252–2255. Connolly-Stringfield P. 1:9–15. McMurray DN. Gourley MF. et al. timing of specimens. In other studies. . Hoff GL. Hajjeh RA. 1994. Antigen testing may permit a rapid (1 day turn-around-time) diagnosis in such cases. their school. 4. MMWR 1988. Other studies have shown the serologic response to be poor in the first month after exposure.11 Fewer years of caving experience. Clin Infect Dis 2000. University of British Columbia and the Faculty of Health and Human Sciences. 85:1063–1069. Ajello L.

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