Update on Q Fever Epidemic in the Update on Q Fever Epidemic in the Netherlands and US Public Health Netherlands and US Public Health

ResponseResponse

Hira Nakhasi, Ph.D.CBER/FDA

Blood Product Advisory Committee Meeting

Rockville, MD, USA

July 26, 2010

Background-I- Causative agentBackground-I- Causative agent

• The causative agent of Q fever is a gram-negative coccobacillus The causative agent of Q fever is a gram-negative coccobacillus Coxiella burnetii, Coxiella burnetii, anan obligate intracellular bacterium that lives in macrophages.obligate intracellular bacterium that lives in macrophages.– ~40 species of ticks involved in Tx in animals. Tx to humans through ticks is rare ~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 Q fever was first described in Australia in 1935 and since then cases have been reported worldwide including in the US.reported worldwide including in the US.

• C. burnetiiC. burnetii is resistant to heat and drying, osmotic shock, UV and common is resistant to heat and drying, osmotic shock, UV and common disinfectants because of the presence of a spore-like stage.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 naturePhase I- highly infectious; found in nature– Phase II- attenuated and avirulent.Phase II- attenuated and avirulent.

• Can be easily spread in humans through inhalationCan be easily spread in humans through inhalation

• As few as 10 organism of As few as 10 organism of CbCb in humans can be infectious in humans can be infectious

• Bacteria are shed in milk, urine, and feces of infected animals, amniotic fluid, Bacteria are shed in milk, urine, and feces of infected animals, amniotic fluid, placenta during birthing, and contaminated wool.placenta during birthing, and contaminated wool.

Background-II- Clinical outcomeBackground-II- Clinical outcome• On average,On average, incubation period prior to development of clinical symptoms is ~14 days incubation period prior to development of clinical symptoms is ~14 days

(7-28 days)(7-28 days)

• Approximately 60% of bactermic cases are asymptomaticApproximately 60% of bactermic cases are asymptomatic

• Infection may lead to acute or chronic diseaseInfection may lead to acute or chronic disease

• The clinical symptoms in acute cases are:The clinical symptoms in acute cases are:– Often non-specificOften non-specific– Self-limiting flu like syndromeSelf-limiting flu like syndrome– PneumoniaPneumonia– HepatitisHepatitis

• Approximately 5% of infected individuals may develop chronic infection Approximately 5% of infected individuals may develop chronic infection – More severe, CFR 15%; Endocarditis + chronic hepatitisMore 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 infectionFarmers, veterinarians and animal handlers are at risk for infection

Background-III- TransmissionBackground-III- Transmission

• Transmission can occur through:Transmission can occur through:

– Inhalation of aerosols or contaminated dusts from Inhalation of aerosols or contaminated dusts from infected ruminants or their productsinfected ruminants or their products

– Ingestion of contaminated meat or unpasteurized milk Ingestion of contaminated meat or unpasteurized milk – Direct contact with infected animals, contaminated Direct contact with infected animals, contaminated

materials (wool, straw, fertilizer and laundry)materials (wool, straw, fertilizer and laundry)– Interdermal inoculationInterdermal inoculation– Bone marrow transplantationBone marrow transplantation– Transplacental routeTransplacental route– Sexual (Sexual (CbCb DNA in semen) DNA in semen)– Blood transfusion (one reported case in the US in 1977)Blood transfusion (one reported case in the US in 1977)

Background-IV - TestsBackground-IV - Tests

• There is no FDA licensed blood donor screening test for There is no FDA licensed blood donor screening test for C. C. burnetiiburnetii

• In house developed IFA, complement fixation, In house developed IFA, complement fixation, microagglutination or ELISA are commonly used for microagglutination or ELISA are commonly used for diagnosisdiagnosis

• In research setting PCR based tests and cultures are also In research setting PCR based tests and cultures are also used to detect used to detect C. burnetiiC. burnetii..

Q Fever Epidemiology in the USQ Fever Epidemiology in the US

• Q fever first described in 1938 by Cox and DavisQ fever first described in 1938 by Cox and Davis• Cases reported during World war II and in Gulf Cases reported during World war II and in Gulf

war among military personnelwar among military personnel• < 200 cases reported in US/year< 200 cases reported in US/year• Q fever is considered enzootic in ruminants Q fever is considered enzootic in ruminants

(sheep, goats, and cattle) throughout the country (sheep, goats, and cattle) throughout the country • Disease is believed to be substantially Disease is believed to be substantially

underreported because of its nonspecific underreported because of its nonspecific presentation and the subsequent failure to presentation and the subsequent failure to suspect infectionsuspect infection

• Recent nation wide sero-survey in the US Recent nation wide sero-survey in the US suggested ~3.1% seroprevelance among adults suggested ~3.1% seroprevelance among adults aged 20 years and older. aged 20 years and older.

Q Fever Epidemic in the Q Fever Epidemic in the NetherlandsNetherlands

• In the past, about 17 cases/yr on averageIn the past, about 17 cases/yr on average

• 168 cases in 2007168 cases in 2007

• 1000 cases in 20081000 cases in 2008

• 2357 cases in 2009- 6 deaths2357 cases in 2009- 6 deaths

• Considered a major public health problemConsidered a major public health problem

• Pneumonia predominant clinical presentationPneumonia predominant clinical presentation

• ~20% of cases admitted to hospital~20% of cases admitted to hospital

The origin of Q fever in NL: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”

Netherlands Netherlands 2009:2009:largest largest outbreak of outbreak of Q fever everQ fever ever (Prof. Hans L. Zaaijer, Sanquin

- The Netherlands)

Notified cases of Q fever in NL, 2007-2009

(Prof. Hans L. Zaaijer, Sanquin - The Netherlands)

!?

Q fever and Dutch blood donors:Q fever and Dutch blood donors:• A retrospective sero-survey in 2009: A retrospective sero-survey in 2009:

– PCR testing of 1000 donations: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 samples3/6 confirmed by serology in index-and F/U samples• 3/6 F/P PCR, sero-negative in F/U samples3/6 F/P PCR, sero-negative in F/U samples• 2/3 PCR + donations transfused2/3 PCR + donations transfused

– 1 recipient tested (IgG +++, IgM borderline 10 m after transfusion)1 recipient tested (IgG +++, IgM borderline 10 m after transfusion)– Possible /probable case of T-T Possible /probable case of T-T CbCb

– Serological testing (IgM &IgG): Serological testing (IgM &IgG): • 545 (serial F/U) samples revealed 13% seroprevelance and a 545 (serial F/U) samples revealed 13% seroprevelance and a

seroconversion rate of 2%.seroconversion rate of 2%.

– Look back on 8 donors (notified their BB Q fever within 3 wk)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 donations6 recipients of PCR negative donations

– 2/6 IgG positive (1 diagnosed Q fever before Tx ; and another living in 2/6 IgG positive (1 diagnosed Q fever before Tx ; and another living in endemic area)endemic area)

Current Control Measures in the Current Control Measures in the NetherlandsNetherlands

• Mandatory animal vaccination Mandatory animal vaccination • Culling of 10s of thousands of pregnant Culling of 10s of thousands of pregnant

goatsgoats• Testing of milk tanksTesting of milk tanks• Life time deferral with history of Q fever Life time deferral with history of Q fever

compared to 2 year deferral in rest of compared to 2 year deferral in rest of EuropeEurope

• In 2010 started screening donations for In 2010 started screening donations for CbCb DNA in high incidence areasDNA in high incidence areas

Q fever Status in the NL as of Q fever Status in the NL as of July 2010July 2010

• Measures instituted seem to have resulted in the control of Q fever Measures instituted seem to have resulted in the control of Q fever epidemicepidemic

• So far no outbreak reportedSo far no outbreak reported

• No wave of abortions occurred in the goat farmsNo wave of abortions occurred in the goat farms

• Testing of donations from at risk areas, since March 15Testing of donations from at risk areas, since March 15 thth 2010 for 2010 for CoxiellaCoxiella DNA found no positives (0/3000) DNA found no positives (0/3000)

• According to Dutch Health Council “Q fever is not a threat to safety of According to Dutch Health Council “Q fever is not a threat to safety of blood” in the NLblood” in the NL

• Dutch Agriculture Ministry has lifted restriction on breeding and Dutch Agriculture Ministry has lifted restriction on breeding and transporting milk goats and milk sheeptransporting milk goats and milk sheep

US Public Health ConcernUS 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

US Public Health ResponseUS Public Health Response• Starting Jan 2010, monthly meetings held among the PHS agencies to Starting Jan 2010, monthly meetings held among the PHS agencies to

monitor the epidemic in the NLmonitor the epidemic in the NL

• FDA and DHHS participated in a meeting organized by European FDA and DHHS participated in a meeting organized by European Center for Diseases Prevention and Control (ECDC) on April 9, 2010 Center for Diseases Prevention and Control (ECDC) on April 9, 2010 to take stock of the factors responsible for Q fever Epidemic in the NLto 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 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 ECDC, FDA and CDC determined there is low risk to blood safety from US travelers to NL (~6-15 imported cases/year)from US travelers to NL (~6-15 imported cases/year)

• No US sero surveys are needed at this timeNo US sero surveys are needed at this time

• If the circumstances warrant FDA will consider issuing guidance for If the circumstances warrant FDA will consider issuing guidance for donor deferral for travel to the NLdonor deferral for travel to the NL

US Public Health ResponseUS Public Health Response

• CDC issued a Health Alert Network Notification (HAN) for CDC issued a Health Alert Network Notification (HAN) for ““Potential for Q fever infection among Travelers returning Potential for Q fever infection among Travelers returning from Iraq and the NLfrom Iraq and the NL”. May 12, 2010.”. May 12, 2010.

• Both AABB and DOD continue to enforce the Both AABB and DOD continue to enforce the LeishmaniaLeishmania deferral policy for civilians and military personnel returning deferral policy for civilians and military personnel returning from Q fever endemic countries such as Iraq and from Q fever endemic countries such as Iraq and Afghanistan Afghanistan

• Given the current status of the Q fever epidemic in the NL, it 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 is likely that the risk to US blood safety is low, however FDA will continue to monitor the situation.will continue to monitor the situation.