1. Update on Q Fever Epidemic in the Netherlands and US Public Health Response Hira Nakhasi, Ph.D. CBER/FDA Blood Product Advisory Committee Meeting Rockville, MD, USA July 26, 2010

2. Background-I- Causative agent The causative agent of Q fever is a gram-negative coccobacillus Coxiella burnetii, an obligate intracellular bacterium that lives in macrophages. The causative agent of Q fever is a gram-negative coccobacillus Coxiella burnetii, an obligate intracellular bacterium that lives in macrophages. – ~40 species of ticks involved in Tx in animals. Tx to humans through ticks is rare Q fever was first described in Australia in 1935 and since then cases have been reported worldwide including in the US. Q fever was first described in Australia in 1935 and since then cases have been reported worldwide including in the US. C. burnetii is resistant to heat and drying, osmotic shock, UV and common disinfectants because of the presence of a spore-like stage. C. burnetii is resistant to heat and drying, osmotic shock, UV and common disinfectants because of the presence of a spore-like stage. The microorganisms exists in two antigenic forms: The microorganisms exists in two antigenic forms: – Phase I- highly infectious; found in nature – Phase II- attenuated and avirulent. Can be easily spread in humans through inhalation Can be easily spread in humans through inhalation As few as 10 organism of Cb in humans can be infectious As few as 10 organism of Cb in humans can be infectious Bacteria are shed in milk, urine, and feces of infected animals, amniotic fluid, placenta during birthing, and contaminated wool. Bacteria are shed in milk, urine, and feces of infected animals, amniotic fluid, placenta during birthing, and contaminated wool.

3. Background-II- Clinical outcome On average, incubation period prior to development of clinical symptoms is ~14 days (7-28 days) On average, incubation period prior to development of clinical symptoms is ~14 days (7-28 days) Approximately 60% of bactermic cases are asymptomatic Approximately 60% of bactermic cases are asymptomatic Infection may lead to acute or chronic disease Infection may lead to acute or chronic disease The clinical symptoms in acute cases are: The clinical symptoms in acute cases are: – Often non-specific – Self-limiting flu like syndrome – Pneumonia – Hepatitis Approximately 5% of infected individuals may develop chronic infection Approximately 5% of infected individuals may develop chronic infection – More severe, CFR 15%; Endocarditis + chronic hepatitis The Standard treatment is doxycycline (daily two doses of 100mg for 14-21 days) The Standard treatment is doxycycline (daily two doses of 100mg for 14-21 days) Infection in children is milder and less symptomatic compared to adults Infection in children is milder and less symptomatic compared to adults Farmers, veterinarians and animal handlers are at risk for infection Farmers, veterinarians and animal handlers are at risk for infection

4. Background-III- Transmission Transmission can occur through: Transmission can occur through: – Inhalation of aerosols or contaminated dusts from infected ruminants or their products – Ingestion of contaminated meat or unpasteurized milk – Direct contact with infected animals, contaminated materials (wool, straw, fertilizer and laundry) – Interdermal inoculation – Bone marrow transplantation – Transplacental route – Sexual (Cb DNA in semen) – Blood transfusion (one reported case in the US in 1977)

5. Background-IV - Tests There is no FDA licensed blood donor screening test for C. burnetii There is no FDA licensed blood donor screening test for C. burnetii In house developed IFA, complement fixation, microagglutination or ELISA are commonly used for diagnosis In house developed IFA, complement fixation, microagglutination or ELISA are commonly used for diagnosis In research setting PCR based tests and cultures are also used to detect C. burnetii. In research setting PCR based tests and cultures are also used to detect C. burnetii.

6. Q Fever Epidemiology in the US Q fever first described in 1938 by Cox and Davis Q fever first described in 1938 by Cox and Davis Cases reported during World war II and in Gulf war among military personnel Cases reported during World war II and in Gulf war among military personnel < 200 cases reported in US/year < 200 cases reported in US/year Q fever is considered enzootic in ruminants (sheep, goats, and cattle) throughout the country Q fever is considered enzootic in ruminants (sheep, goats, and cattle) throughout the country Disease is believed to be substantially underreported because of its nonspecific presentation and the subsequent failure to suspect infection Disease is believed to be substantially underreported because of its nonspecific presentation and the subsequent failure to suspect infection Recent nation wide sero-survey in the US suggested ~3.1% seroprevelance among adults aged 20 years and older. Recent nation wide sero-survey in the US suggested ~3.1% seroprevelance among adults aged 20 years and older.

7. Q Fever Epidemic in the Netherlands In the past, about 17 cases/yr on average In the past, about 17 cases/yr on average 168 cases in 2007 168 cases in 2007 1000 cases in 2008 1000 cases in 2008 2357 cases in 2009- 6 deaths 2357 cases in 2009- 6 deaths Considered a major public health problem Considered a major public health problem Pneumonia predominant clinical presentation Pneumonia predominant clinical presentation ~20% of cases admitted to hospital ~20% of cases admitted to hospital

8. The origin of Q fever in NL: 3 years of airborne spread of Coxiella burnetii spores from infected dairy goat farms Close proximity of goat farms to human habitations Factory farming- high density of goats “Deep Litter” animal husbandary Abortion “waves”

9. Netherlands 2009: largest outbreak of Q fever ever Netherlands 2009: largest outbreak of Q fever ever (Prof. Hans L. Zaaijer, Sanquin - The Netherlands)

10. Notified cases of Q fever in NL, 2007-2009 (Prof. Hans L. Zaaijer, Sanquin - The Netherlands) !?

11. Q fever and Dutch blood donors: A retrospective sero-survey in 2009: A retrospective sero-survey in 2009: – PCR testing of 1000 donations: 6 reactive (weak signal, high Ct value) 6 reactive (weak signal, high Ct value) 3/6 confirmed by serology in index-and F/U samples 3/6 confirmed by serology in index-and F/U samples 3/6 F/P PCR, sero-negative in F/U samples 3/6 F/P PCR, sero-negative in F/U samples 2/3 PCR + donations transfused 2/3 PCR + donations transfused – 1 recipient tested (IgG +++, IgM borderline 10 m after transfusion) – Possible /probable case of T-T Cb – Serological testing (IgM &IgG): 545 (serial F/U) samples revealed 13% seroprevelance and a seroconversion rate of 2%. 545 (serial F/U) samples revealed 13% seroprevelance and a seroconversion rate of 2%. – Look back on 8 donors (notified their BB Q fever within 3 wk) 1/8 PCR positive (recipient terminally ill, not tested) 1/8 PCR positive (recipient terminally ill, not tested) 6 recipients of PCR negative donations 6 recipients of PCR negative donations – 2/6 IgG positive (1 diagnosed Q fever before Tx ; and another living in endemic area)

12. Current Control Measures in the Netherlands Mandatory animal vaccination Mandatory animal vaccination Culling of 10s of thousands of pregnant goats Culling of 10s of thousands of pregnant goats Testing of milk tanks Testing of milk tanks Life time deferral with history of Q fever compared to 2 year deferral in rest of Europe Life time deferral with history of Q fever compared to 2 year deferral in rest of Europe In 2010 started screening donations for Cb DNA in high incidence areas In 2010 started screening donations for Cb DNA in high incidence areas

13. Q fever Status in the NL as of July 2010 Measures instituted seem to have resulted in the control of Q fever epidemic Measures instituted seem to have resulted in the control of Q fever epidemic So far no outbreak reported So far no outbreak reported No wave of abortions occurred in the goat farms No wave of abortions occurred in the goat farms Testing of donations from at risk areas, since March 15 th 2010 for Coxiella DNA found no positives (0/3000) Testing of donations from at risk areas, since March 15 th 2010 for Coxiella DNA found no positives (0/3000) According to Dutch Health Council “Q fever is not a threat to safety of blood” in the NL According to Dutch Health Council “Q fever is not a threat to safety of blood” in the NL Dutch Agriculture Ministry has lifted restriction on breeding and transporting milk goats and milk sheep Dutch Agriculture Ministry has lifted restriction on breeding and transporting milk goats and milk sheep

14. US Public Health Concern - US Public Health Concern - based on the epidemic in the NL for the last three years Epidemic in the NL raised a public health concern as to whether there is risk of Coxiella burnetii transmission through transfusion from US donors who travelled to the NL. – – Visiting an affected farm is highly correlated with rate of infection

15. US Public Health Response Starting Jan 2010, monthly meetings held among the PHS agencies to monitor the epidemic in the NL Starting Jan 2010, monthly meetings held among the PHS agencies to monitor the epidemic in the NL FDA and DHHS participated in a meeting organized by European Center for Diseases Prevention and Control (ECDC) on April 9, 2010 to take stock of the factors responsible for Q fever Epidemic in the NL FDA and DHHS participated in a meeting organized by European Center for Diseases Prevention and Control (ECDC) on April 9, 2010 to take stock of the factors responsible for Q fever Epidemic in the NL Based on Q fever risk models developed in the NL and France by ECDC, FDA and CDC determined there is low risk to blood safety from US travelers to NL (~6-15 imported cases/year) Based on Q fever risk models developed in the NL and France by ECDC, FDA and CDC determined there is low risk to blood safety from US travelers to NL (~6-15 imported cases/year) No US sero surveys are needed at this time No US sero surveys are needed at this time If the circumstances warrant FDA will consider issuing guidance for donor deferral for travel to the NL If the circumstances warrant FDA will consider issuing guidance for donor deferral for travel to the NL

16. US Public Health Response CDC issued a Health Alert Network Notification (HAN) for “Potential for Q fever infection among Travelers returning from Iraq and the NL”. May 12, 2010. CDC issued a Health Alert Network Notification (HAN) for “Potential for Q fever infection among Travelers returning from Iraq and the NL”. May 12, 2010. Both AABB and DOD continue to enforce the Leishmania deferral policy for civilians and military personnel returning from Q fever endemic countries such as Iraq and Afghanistan Both AABB and DOD continue to enforce the Leishmania deferral policy for civilians and military personnel returning from Q fever endemic countries such as Iraq and Afghanistan Given the current status of the Q fever epidemic in the NL, it is likely that the risk to US blood safety is low, however FDA will continue to monitor the situation. Given the current status of the Q fever epidemic in the NL, it is likely that the risk to US blood safety is low, however FDA will continue to monitor the situation.