BACKGROUND: Penicilliosis is an important opportunistic fungal infection in residents and travelers to Southeast Asia, China and India. Incidence increases during the rainy months and is associated with humidity and soil exposure. Bamboo rats are the only non-human host; however, evidence for zoonotic transmission is lacking, and disease reservoir and transmission risk remain unknown.

METHOD: We conducted a case-control study to evaluate the exposure, behavioral, and geospatial risk factors for penicilliosis in 205 HIV-infected patients with incident penicilliosis and 406 control patients with AIDS but without pencilliosis. Cases and controls were matched for host susceptibility, which included age, sex, CD4 count or stage IV disease. Patients were recruited from the two largest referral centers for HIV care in northern and southern Vietnam. Conditional logistic regression analyses were used to evaluate the following risk categories for disease: injection drug use, antiretroviral therapy (ART), antifungal prophylaxis, cigarette smoking, outdoor occupation, proximity/exposure to bamboo rats, water, soil, tropical plants, highland plants, farming animals, domestic animals, and raw animal products. Geospatial risk was evaluated using global positioning mapping of patients’ residence.

RESULTS: 75% were male. Median age was 34 (IQR: 31 – 38) years. Median CD4 count was 16 (IQR: 7.0- 36.0) cells/µL. In the multivariate analysis, patients with proximity or occupational exposure to tropical plants (bamboo, sugar cane, and/or rice) and patients with occupational exposure to farming animals were at increased risk for penicilliosis, OR 1.84 (95% CI: 1.17-2.90), p=0.00841 and OR 2.03 (95% CI: 1.18-3.49), P=0.01007, respectively. In the univariate analysis, not being on ART, outdoor occupation, proximity/exposure to tropical plants, and exposure to farming animals were statistically significant risk factors for disease. Cases were geospatially distributed in southern Vietnam at provincial level. Comparing to controls, cases appeared to concentrate in the central highlands and its adjacent provinces north of Ho Chi Minh City.

CONCLUSIONS: Our data provided the first evidence for geospatial risk of penicilliosis in the endemic region. The identification of the highlands as disease hot spots suggested an ecological relationship between bamboo rats as an animal reservoir and a potential environmental reservoir in tropical plants and animal farming.

The Exposure and Geospatial Risk Factors for AIDS-Associated Penicilliosis in Vietnam

Abstract Seasonality and environmental predictors

Conclusions

1. Direct exposure to tropical plants or farm animals doubles the risk of disseminated

penicilliosis in patients with HIV/AIDS.

2. Penicilliosis cases cluster in the Central Highland and its surrounding regions of

southern Vietnam, corresponding to the ecological niche region of bamboo rats.

3. Our data confirm the previous findings from Chiang Mai of the plant and farm

animal exposure risk correlation. We show for the first time that there is geospatial

risk factor even in an endemic country, giving further clues to disease natural

reservoir.

Acknowledgements

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Thuy Le1, 5, Brian Jonat2, Ngo T Kim Cuc3, Nguyen Tat Thanh1, Pham Si Lam1, Pham Thi Khuong4, Dang Thi Bich4, Corrine Thompson1, Heiman Wertheim1, Jeremy Farrar1, Nguyen Van Vinh Chau2, Jeremy Day1, Cecilia Shikuma5, Marcel Wolbers1, Guy Thwaites1

1. Oxford University Clinical Research Unit, Ho Chi Minh City 2. New York-Presbyterian Morgan Stanley Children’s Hospital 3. Hospital for Tropical Diseases, Ho Chi Minh City 4.National Hospital for Tropical Diseases, Hanoi 5. Hawaii Center for AIDS, University of Hawaii, Honolulu, USA

Bamboo rats, HIV and penicilliosis in SE Asia

- - - : AIDS admissions ___: Cryptococcosis admissions ___: Penicilliosis admissions

1. Seasonality of penicilliosis in Ho Chi Minh City, 2004-2009 [Le T, CID 2011]

2. Humidity as driver of penicilliosis [Bulterys P, CID 2013]

Research questions

A matched case control study design

Results

What are the exposure and behavioral risk factors for penicilliosis in equally susceptible HIV-infected people in Vietnam?

Are there geographical risk factors for penicilliosis in endemic regions of Vietnam?

Patients were recruited from the 2 largest HIV referral centers in Ho Chi Minh City and Hanoi. Cases and controls were matched by age (+/-5), sex, CD4 (≤ or >50) or WHO disease stage.

Patient characteristics

Cases (N=205)

Controls (N=406)

Age 33 (30 – 38) 34 (31 – 39)

Sex Male

154 (75%) 304 (75%)

CD4 (cells/µL) n=66 9.0 (5.0 – 18.8)

n=128 25.5 (9.0 – 54.3)

Absolute Lymphocyte (cells/µL)

n=197 410 (230 – 600)

n=388 570 (380 – 810)

WHO stage 1 2 3 4

n=204 0 (0%) 0 (0%) 0 (0%) 204 (100%)

n=402 3 (0.7%) 16 (4%) 146 (36%) 237 (59%)

Inpatient Outpatient

205 (100%) 0 (0%)

369 (91%) 37 (9%)

Exposure Risk Factors

Cases (N=205)

Controls (N=406)

Univariate effect: OR (95% CI)

Multivariate effect OR(95% CI)

IVDU 71/205 (35%) 161/406 (40%) 0.79 (0.54 to 1.15), P=0.213

0.85 (0.54 to 1.35), p =0.502

On ARV 72/205(35%) 178/406(44%) 0.68 (0.47 to 0.97), p=0.0348*

0.75 (0.50 to 1.13), p=0.168

On Fluconazole 15/198 (8%) 46/398 (12%) 0.59 (0.31 to 1.11), p =0·099

0.68 (0.35 to 1.34), p =0.269

Cigarette smoking 130/205(63%) 283/406 (80%) 0.65 (0.42 to 1.01), p =0.0561

0.71 (0.43 to 1.18), 0.189

Outdoor occupation 100/205 (49%) 163/406 (40%) 1.47 (1.03 to 2.09), p=0.0349*

1.23 (0.81 to 1.87), p=0.336

Proximity/exposure Water

90/205 (44%) 195/406 (48%) 0.83 (0.58 to 1.19), p=0.311

0.76 (0.51 to 1.13), p=0.175

Proximity/exposure Soil

143/205 (70%) 266/406 (66%) 1.22 (0.85 to 1.75), p=0.288

1.06 (0.69 to 1.63), p=0.799

Proximity/exposure Tropical plants

90/205 (44%) 128/406 (32%) 1.75 (1.22 to 2.56), P=0.00235**

1.84 (1.17 to 2.90), p=0.00841**

Exposure Highland plants

25/205 (12%) 24/406 (6%) 2.25 (1.24 to 4.01), p=0.00753**

1.71 (0.86 to 3.41), p=0.126

Exposure Bamboo rat

3/205 (1.5%) 3/406 (0.7%) 2.00 (0.40 to 9.91), p=0.396

1.71 (0.33 to 8.87), p=0.525

Exposure Domestic animal

57/205 (28%) 113/406 (28%) 1.01(0.67 to 1.51), P=0.973

1.39 (0.87 to 2.22) P=0.166

Exposure Farm animals

40/205 (20%) 53/406 (13%) 1.60 (1.02 to 2.51), p=0.042*

2.03 (1.18 to 3.49) p=0.01007*

Exposure Raw meat

132/205 (64%) 279/406 (69%) 0.82 (0.57 to 1.18), p=0.283

0.91 (0.60 to 1.37) p=0.640

Results (cont.)

(A) (B) (C) (D)

Regions of Vietnam and distribution of subjects: (A) Regions of Vietnam. (B) Number of cases by region and (C) Number of controls by region. Darker colors indicate higher number of cases or controls. D) Ratio of cases to controls by region, with darker color representing a higher number of cases relative to controls. A case/control ratio of 0.5 is expected as 2 controls were recruited for every case. A ratio <0.5 indicates a lower-than-expected number of cases relative to controls. A ratio >0.5 indicates a greater-than-expected number of cases relative to controls. Data for northern regions of Vietnam is excluded from map D, as study subject enrollment was insufficient to draw meaningful conclusions . The ratios of cases to controls are higher in the regions north of Ho Chi Minh City (Southeast, Central Highlands, South Central Coast) than in the Mekong Delta with the highest ratio being the Central Highlands.

3. Exposure to plants or animals are risk factors [Chariyalertsak S, CID 1997]

Chiang Mai, Thailand

1. Patient characteristics 3. Geographic risk factors for penicilliosis

2. Conditional logistic regression analysis of risk factors

Email: thuyl@oucru.org