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Human Cryptosporidium (Cr.) transmission has been thought to occur only via fecal-oral, water-, or food-borne routes. We recently found that 35% of Ugandan children with Cr. diarrhea and cough were PCR sputum-positive, suggesting that respiratory tract (RT) infection occurs frequently in children with Cr. infection (R21AI 068474). This suggests that Cr. transmission may occur via aerosols or respiratory droplets ejected during coughing. Using linked hospital and household studies, we will assess the clinical and public health significance of RT infection. We hypothesize that RT infection has clinical sequelae; and that prior exposure to Cr. may limit RT infection, in contrast to malnutrition or HIV which may facilitate or worsen clinical RT infection. Further, we surmise that parasite species affects the propensity for RT infection. Finally, we hypothesize that children with RT infection have increased propensity for transmission of Cr. to others. Aim 1 is a hospital-based study that will assess severity of RT illness and possible modifying factors. We will enroll Ugandan children aged 9-36 months who (Group A) have primary diarrhea and unexplained cough or tachypnea; or (Group B) primary clinical pneumonia with or without diarrhea. The respiratory status of all children will be rigorously assessed, including pulse oximetry. Both groups will be screened for Cr. in the stool, and eligibility for sputum induction after clinical and laboratory testing affirms the procedure can be safely performed. Prior Cr. exposure will be judged via two novel immunological methods, salivary antibody to gp15 and an indirect immunofluorescence assay against replicating Cr. grown in vitro. Nutritional status will be gauged via anthropometrics, hemoglobin, and serum albumin. HIV testing, if consented to, will be performed. Sputum isolates of Cr. will be speciated via RFLP analysis. Concurrent RT infections will be exhaustively assessed by standard microbiology, multiplex PCR, and staining for HIV-related organisms. Children identified in Aim 1 will then serve as index children for household transmission studies under Aim 2A. We will visit households of index children to characterize the clinical history, enteric and RT Cr. status, and exposure history (with salivary antibody to gp 15) of household members, at the time of presentation of the index child and 2 weeks later. We will then compare transmission rates in households of children with and without RT Cr. infection in both a retrospective and prospective fashion. To address the hypothesis that adults with RT Cr. could act as agents of transmission, under Aim 2B we will establish whether there is any evidence of RT Cr. in adults using an inexpensive, efficient approach testing thousands of specimens - by re-screening sputa collected for tuberculosis testing for Cr. This group is enriched with persons with HIV.

Griffiths, Jeffrey
Tufts University
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