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U.S. Army Medical Research Unit Kenya Avian and Pandemic Influenza Activities

In 1969 the U.S. Army Medical Research Unit Kenya (USAMRU-K), a special foreign activity of the Walter Reed Army Institute of Research in Washington, D.C., was activated on a temporary basis at the request of the government of Kenya to study trypanosomiasis (DoD-GEIS, 2007a). USAMRU-K’s operations were originally dedicated to and supported by applied medical research, and its invitation to operate in Kenya was based on that research mission (IOM, 2001). Its operations became permanent in 1973, and since that time research has been conducted on malaria, leishmaniasis, and arboviruses (DoD-GEIS, 2007a). More recently, USAMRU-K has been involved with both avian and pandemic influenza surveillance (Schnabel, 2007).

Support for USAMRU-K influenza surveillance and response projects from the Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS) totaled approximately $3.5 million in fiscal year 2006 (2.6 million in AI/PI funds and $800 thousand in non-influenza DoD-GEIS funds) (USAMRU-K, 2007a). Using these funds, USAMRU-K built laboratory capacity at the Kenya Medical Research Institute (KEMRI) and other sites, established human surveillance projects in Kenya to detect influenza disease and gather much-needed information on the disease in sub-Saharan Africa, and began the processes of establishing similar influenza surveillance projects in Uganda and Cameroon1 (Schnabel,

1

At the time of the IOM team’s visit the planning for the development of a DoD-GEIS influenza surveillance program in Cameroon was just beginning. For this reason no further details on this project are included in the chapter.



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6 U.S. Army Medical Research Unit Kenya Avian and Pandemic Influenza Activities I n 1969 the U.S. Army Medical Research Unit Kenya (USAMRU-K), a special foreign activity of the Walter Reed Army Institute of Research in Washington, D.C., was activated on a temporary basis at the request of the government of Kenya to study trypanosomiasis (DoD-GEIS, 2007a). USAMRU-K’s operations were originally dedicated to and supported by applied medical research, and its invitation to operate in Kenya was based on that research mission (IOM, 2001). Its operations became permanent in 1973, and since that time research has been conducted on malaria, leish- maniasis, and arboviruses (DoD-GEIS, 2007a). More recently, USAMRU-K has been involved with both avian and pandemic influenza surveillance (Schnabel, 2007). Support for USAMRU-K influenza surveillance and response projects from the Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS) totaled approximately $3.5 million in fiscal year 2006 (2.6 million in AI/PI funds and $800 thousand in non- influenza DoD-GEIS funds) (USAMRU-K, 2007a). Using these funds, USAMRU-K built laboratory capacity at the Kenya Medical Research In- stitute (KEMRI) and other sites, established human surveillance projects in Kenya to detect influenza disease and gather much-needed information on the disease in sub-Saharan Africa, and began the processes of establishing similar influenza surveillance projects in Uganda and Cameroon1 (Schnabel, 1 At the time of the IOM team’s visit the planning for the development of a DoD-GEIS influ- enza surveillance program in Cameroon was just beginning. For this reason no further details on this project are included in the chapter. 

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS FIGURE 6-1 DoD’s regional presence in influenza surveillance (Africa), 2007. SOURCE: DoD-GEIS, 2007b. 2007) (see Figure 6-1). Migratory bird surveillance is also being conducted using DoD-GEIS avian influenza (AI) funds in conjunction with the Naval Medical Research Unit No. 3 (NAMRU-3) in Egypt. A site visit team of the Institute of Medicine (IOM) Committee for the Assessment of DoD-GEIS Influenza figure 5-1 and 6-1 Surveillance and Response Programs visited USAMRU-K from March 11-17, 2007.2 A list of the people with whom the site visit team met and the itinerary that was followed can be Revised found at the end of this chapter. 2 Prior to the committee’s visit to USAMRU-K, the laboratory staff provided the commit- tee with detailed background information on USAMRU-K and the pandemic/avian influenza activities they were supporting. These materials are available from the IOM in the Public Access File.

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA INFLUENZA IN KENYA Because of a lack of surveillance activities, little information is avail- able about the disease characteristics of influenza in sub-Saharan Africa. At the time of the IOM visit, for example, it is unclear if there are seasonal outbreaks or what viruses are circulating in countries such as Kenya. Avian influenza has not yet been diagnosed in Kenya’s wild birds or domestic poultry, but because of its situation and location the country has received considerable attention. Kenya lies along the migratory route of birds from Europe to southern Africa. In addition, it has water points that serve as stopovers for a variety of bird species. Kenya’s poultry population is con- siderable—an estimated 30 million, 80 percent of which are indigenous backyard chickens (Kenya Red Cross Society, 2006). Though there have been no outbreaks of avian influenza in the coun- tries neighboring Kenya, both Nigeria and Egypt have reported human cases of avian influenza. In February 2006, Nigeria confirmed H5N1 in poultry, and a month later Niger, a country bordering Nigeria, also con- firmed H5N1 in its domestic poultry. The first and so far only human case in Nigeria was confirmed in late January 2007. Egypt, having reported its first case of human influenza in March 2006, has since had a total of 35, the highest number of bird flu cases among humans outside of Asia (WHO, 2007a; WHO 2007b). MANAGEMENT AND PLANNING In developing avian influenza/pandemic influenza (AI/PI) projects, USAMRU-K staff drew on existing management tools. For example, pre- existing mechanisms to manage the relationship between the staffs of USAMRU-K and the KEMRI lab, including a memorandum of understand- ing that covered laboratory staff’s salaries, allowed USAMRU-K to quickly utilize AI/PI funding. USAMRU-K also signed a contract with the Henry M. Jackson Foundation, which included approximately $1.7 million of 2006 AI/PI funds, to develop and maintain influenza surveillance in Uganda and Cameroon and, potentially, other countries in the region. Current progress in developing the Uganda project is described in a separate section in this chapter. Traditionally the DoD-GEIS coordinator was the principal investiga- tor on all DoD-GEIS-related protocols. More recently, protocols have been amended to give primary scientific and management leadership to others, with the DoD-GEIS coordinator’s position becoming more one of coordina- tion and facilitation. Using the supplemental funding, USAMRU-K has established a cred- ible and highly professional biosafety level 2 (BSL-2) laboratory, which will

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS be used for influenza surveillance activities well into the future. Once all planned surveillance sites are opened and the program is at full capacity, the Kenya flu program will require $800,000 per year, but this future expendi- ture has not been programmed into the USAMRU-K DoD-GEIS program outyear funding. Thus the DoD-GEIS core program at USAMRU-K would suffer drastic cuts if the supplementary flu program had to be absorbed into it. Staffing At the time of the IOM site visit team’s visit, the USAMRU-K staff included nine Americans, a British immunologist, and a National Research Council Fellow, as well as two Kenyan physicians assigned temporarily from KEMRI. In addition there are usually several local and foreign gradu- ate and postdoctoral students working there. The Kenyan technical staff numbers approximately 100. The commander of the Walter Reed Project (WRP) Kenya/USAMRU-K has 11 years experience in Kenya in 3 tours of duty. His relationships with the Ministry of Health (MoH) and KEMRI al- low USAMRU-K to coordinate its work in Kenya and its interactions with the MoH and KEMRI seamlessly. There were a number of dedicated members of USAMRU-K working on the DoD-GEIS AI/PI projects. Despite the DoD-GEIS coordinator’s short time on the job (six months), the IOM site visit team was impressed with his grasp of the DoD-GEIS programmatic situation in Kenya. The virolo- gist responsible for day-to-day DoD-GEIS influenza laboratory activities had considerable postdoctoral experience in animal virology in the United Kingdom prior to his return to Kenya. The WRP veterinarian who oversees surveillance for influenza virus in wild birds works closely with collabora- tors at NAMRU-3. Overall the USAMRU-K staff has administered the AI/PI program well. USAMRU-K would greatly benefit from additional administrative help for DOD-GEIS protocols. Because the AI/PI funds are so constrained with re- spect to when they arrive, how they are to be used, and the limited time in which they must be committed, an important function of the administrator would be to help USAMRU-K project officers allocate AI/PI funding more efficiently to appropriate activities within the allotted calendar interval. Many of USAMRU-K’s AI/PI projects have Kenyan principal investiga- tors. Furthermore, all of the project and laboratory staff are Kenyan, ensur- ing that Kenya will retain the technical capacity to continue the surveillance in the future. In addition, the USAMRU-K staff working in the National Influenza Center (NIC) on influenza surveillance receive the same salaries as their counterparts being paid by KEMRI. This parity in salaries ensures

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA that KEMRI can afford to take up the salaries of these staff if control of the laboratory is turned over to Kenya. Technology and Information Management Technology and information management for the USAMRU-K/ DoD-GEIS influenza project are in their formative stages. The specimen recording is currently done all by hand. Fortunately, the influenza program can draw on existing expertise in this area from other WRP/DoD-GEIS protocols to improve its data management and to fast track the neces- sary improvements. In addition, there are plans for the WRP to obtain a $30,000 sophisticated freezer-management software and bar-coding system, which will help manage the storage and tracking of influenza (as well as all other) specimens. Conclusions The supplemental AI/PI funding received in fiscal year 2006 was suc- cessfully utilized to establish functional influenza surveillance despite a significant delay in receiving the funds. This success demonstrates the flex- ibility and robustness of the administrative infrastructure at USAMRU-K. To maximize AI/PI funds, USAMRU-K would benefit from an additional administrator to help manage the finances of the AI/PI projects. The current USAMRU-K staff appears to be adequate for the current influenza protocols but may be inadequate if the program is to expand. To do longer-term surveillance USAMRU-K would need a mechanism to pay people for longer periods. The annual funding cycles challenge USAMRU-K staff in their ability to plan protocols and staffing beyond one to two years. This challenge of middle-term planning is exacerbated by the short tours of the Army leadership, which often limit Army personnel to tours of two to three years. The basic technological capabilities at USAMRU-K are sufficient, but there is a great need to expand the information systems for sample han- dling. USAMRU-K has already identified this as a need and is currently researching various options. The IOM site visit team considered the invest- ment in a specimen cataloguing and tracking system to be a wise use of DoD-GEIS money as it will benefit all of WRP’s activities, improving the handling of specimens generated there as well as those from DoD-GEIS influenza surveillance.

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS SURVEILLANCE In Kenya, there are ongoing (or soon-to-commence) surveillance ac- tivities supported by DoD-GEIS supplemental funding to detect influenza disease, to perform virologic confirmation, and to isolate influenza viruses in wild bird populations and in human populations. Human Surveillance The DoD-GEIS influenza surveillance in Kenya aims to isolate and characterize influenza viruses circulating among human populations, to estimate the burden of influenza disease among Kenyan children and adults, and to identify other viral and bacterial agents causing acute respiratory illnesses (USAMRU-K, 2007c). The DoD-GEIS-supported national surveil- lance system complements influenza surveillance activities being carried out by the Emerging Infections Program of the Centers for Disease Prevention and Control (CDC) in conjunction with KEMRI. CDC surveillance is aimed at detecting more severe clinical forms of influenza among hospitalized pa- tients, while the WRP surveillance is directed at detecting influenza among less severely ill ambulatory patients seen as outpatients. At the time of the IOM site visit, the surveillance protocol was designed to collect specimens from a maximum of five patients a day ranging in age from 2 months to adult who present at one of five designated outpatient facilities with fever of at least 38oC plus sore throat or cough, and with the onset of illness having occurred within the previous 72 hours (Bulimo, 2007). A questionnaire is administered to collect demographic information along with data on whether other household members have had respiratory illness, if the patient has recently traveled, and if the patient has a history of contact with chickens or other birds. Informed consent is obtained be- fore collecting the demographic and clinical data and the specimens. Two duplicate nasopharyngeal swabs are obtained and put into a transport medium and cultured on Madin-Darby canine kidney (MDCK) cells. From July 2006 through February 2007, a total of 806 specimens were collected. Presently, DoD-GEIS surveillance sites are located throughout the country, clustered according to population densities, and the number of surveillance sites is planned to be expanded (USAMRU-K, 2007c). Since little is known about the seasonality of influenza in tropical popu- lations or about the importance of influenza as a cause of acute respiratory disease in relation to other viral and bacterial respiratory agents in children and adults, epidemiologists at the Kenyan MoH have been urging DoD- GEIS investigators to use the influenza surveillance as an opportunity to investigate in the same patients the co-occurrence of other viral and bacte- rial pathogens hours (Bulimo, 2007). Given the keen interest of the MoH

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA in obtaining such etiologic data, the IOM team was supportive of nesting a study to detect an array of other viral and bacterial etiologies within the influenza surveillance activities. Should such a modification to the protocol proceed, it would be advisable to also collect respiratory specimens from age-matched healthy controls without acute respiratory illness, as a number of known respiratory pathogens can be present in non-ill individuals who have subclinical infection. Quantifying the background of such subclinical infection for various pathogens would be invaluable in allowing the most comprehensive analysis and interpretation of the surveillance data for in- fluenza as well as for other etiologies. Conclusions Overall, the IOM Committee found that USAMRU-K’s human surveil- lance projects in Kenya were well planned and executed. However, the site visit team suggested several areas in which the designs of the projects could be improved. One suggestion was to collect two sets of specimens each day at each site: one set of five specimens from children less than 60 months of age and the other set from children older than 60 months and adults. The significance of this is that acute respiratory illness from a variety of differ- ent respiratory agents is common in young children. Thus, for example, a circulating respiratory syncytial virus (RSV) epidemic occurring at the same time as circulation of influenza viruses could mask detection of the latter if mostly young children were sampled to the exclusion of older children and adults. Having independent collections of specimens from young children as well as from older children and adults would make such problems less likely. In these young pediatric patients the site visit team also suggested using reverse transcription polymerase chain reaction (RT-PCR) to test stool specimens from patients with gastroenteritis in order to detect H5 influenza virus. Several of the current surveillance sites provide opportunities to test specimens from pediatric and adult patients with acute respiratory illness for other viruses (e.g., RSV A and B, parainfluenza viruses 1, 2, and 3, adenovirus, and human metapneumovirus) and bacterial pathogens (e.g., Haemophilus influenzae type b, Streptococcus pneumoniae—which should be serotyped—and Bordetella pertussis) in addition to H5, H3, H1, B, and other influenza viruses. If a broader search for etiologic agents is undertaken, the study should also include collection of specimens from age-matched healthy controls. Such data would elucidate the relative im- portance of influenza viruses at different times of the year in different age groups in comparison with other pathogens. Having data from controls would also allow an estimate of the relative pathogenicity of the different agents by comparing detection of agents in cases versus controls.

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0 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS Because of an outbreak of influenza detected in western Kenya that caused the closure of schools due to a high absentee rate, the team suggested that a surveillance system be established in schools located near the current clinical surveillance sites in order to monitor absenteeism. If cooperation from the local school headmasters, headmistresses, and teachers can be ob- tained, a threshold of absenteeism could be set. If the threshold is surpassed, this would be an indication for a small team from the nearby clinical facility to visit schools and collect upper respiratory specimens from ill children (at school and at their homes). This form of surveillance would also build capacity in conducting outbreak investigation and in the collection of speci- mens during outbreaks. Beyond the improvements to existing surveillance activities, USAMRU-K should explore linkages with school surveillance and expansion into respiratory surveillance in the Kenyan military population. Kenyan military populations have many young adults housed under crowded conditions, so that stringent surveillance for respiratory infections can usually be maintained. In the United States, there have been multiple instances where the onset of epidemic influenza was first detected (and the virus type identified) through detection of outbreaks among military per- sonnel on installations or in military academies. RECOMMENDATION 6-1. The total number of adults and children each day who present to the clinics with acute respiratory illness for specimen collection under the current protocol should be logged, even though only five young children and five older children or adults will be sampled. By recording the total number of such patients and having the proportion of the five-patient samples that are positive, an estimate can be made of the burden of disease leading persons to seek attention at the sentinel health care facilities. Without collecting the number of syndromic eligible cases, burden cannot be estimated. RECOMMENDATION 6-2. To foster collaboration and illustrate the value of the surveillance activities to stakeholders, USAMRU-K should consider supporting a weekly or biweekly summary of the number of cases of acute respiratory illness and of influenza virus isolations, by age group, to be sent to all the surveillance sites to provide feedback to the clinicians involved in the surveillance system. Animal Surveillance Kenya contains part of three flyways for birds migrating from Europe and Asia (Limbaso, 2007). The routes are the western flyway (west of the Rift Valley), the eastern flyway (east of the Rift Valley), and the Rift Valley flyway. In Egypt, scientists at NAMRU-3 were trapping migrating birds

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA and collecting cloacal swabs to detect influenza viruses. The NAMRU-3 scientists contacted Walter Reed and Kenyan scientists to elicit their interest in collaborating to extend that surveillance to the flyways in Kenya. A col- laborative protocol was prepared by a local Kenyan principal investigator. A specific focus of the surveillance project, conceived in early 2004 and ini- tiated in October 2005, is to detect highly pathogenic H5 and H7 (or other highly pathogenic) influenza viruses. The main ornithine targets of this surveillance are ducks and other waders as they migrate from Europe and Asia. It is anticipated that this surveillance can identify sites and situations where spillover can occur to local bird populations (including domestic chickens) and to human populations (Limbaso, 2007). The epidemiologic concern is that migratory birds carrying highly pathogenic influenza viruses can transmit the avian viruses to domestic waterfowl or domestic chickens. Infections in domestic chickens could, in turn, lead to cross-species infec- tion of humans. Migratory bird study sites were selected based on the frequency of the targets (wild ducks and waders). The migration season typically extends from October through March. The 10 sites sampled include (Limbaso, 2007) • sewage ponds in Nairobi, Nakuru (near Lake Nakuru in the Rift Valley, northwest of Nairobi, halfway to Lake Victoria), and Thika (Central Kenya, about 100 kilometers north of Nairobi); • lakes along the Rift Valley; • swamps around Nairobi; and • dams in the central highlands. Birds are trapped and handled by qualified ornithologists; the traps used include wader mist nets, modified Balchiari traps, and door traps. Birds are ringed and classified by species, and various biometric measure- ments are made. Duplicate cloacal samples are collected by the DoD-GEIS veterinarian, preserved in transport medium in liquid nitrogen (-80oC), and transported to the laboratory for virologic processing. All samples are screened for influenza A viruses by RT-PCR in the BSL-3 laboratory on the KEMRI campus, maintained by the CDC Emerging Infections Program in conjunction with KEMRI (Limbaso, 2007). Any H5 isolates are forwarded to NAMRU-3 in Cairo for further characterization. At NAMRU-3 the RT-PCR is confirmed, and, once confirmation is obtained, the samples are cultured in eggs. Subtyping is carried out using kits supplied by the CDC influenza branch. During the last migration season, 438 birds representing 38 different species were sampled. Of these specimens, 24 (5.5 percent) yielded influ- enza A viruses, including one H5N3 isolate of low pathogenicity (Limbaso,

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS 2007). The IOM site visit team discussed with the WRP veterinarian the possibility of performing tracheal cultures as well as cloacal cultures on the larger species of birds. The USAMRU-K-supported team did not have experience with tracheal cultures of birds and was somewhat hesitant to perform these because of concerns that they might inadvertently injure the birds. Accordingly, the IOM site visit team mentioned to the Kenyan sci- entists that NAMRU-2 scientists in Indonesia were carrying out a similar surveillance of wild birds in which tracheal cultures and blood from a wing vein were being obtained in addition to cloacal cultures. The IOM site visit team discussed with WRP Kenya staff the possibility of visiting NAMRU-2 to learn how scientists there perform tracheal cultures. At the present time, there is no systematic surveillance for influenza viruses among either domestic chickens or industrial poultry farm chickens in Kenya. However, there is the intent and capability to perform outbreak investigations, including collection of specimens for diagnostic tests, should there occur a die-off of chickens, either among backyard poultry or indus- trial farm birds. Conclusions While animal influenza surveillance conducted by USAMRU-K in con- junction with NAMRU-3 represents a solid start, the committee concluded that USAMRU-K would benefit from additional guidance from other DoD OCONUS (outside the continental United States) laboratories in order to increase the value of the activities currently being performed and to expand the relative expertise of the USAMRU-K staff on the ground. RECOMMENDATION 6-3. USAMRU-K should draw on the ex- perience of other DoD OCONUS laboratories in animal influenza surveillance. For example, the USAMRU-K veterinarian could be sent to NAMRU-2 in Indonesia to gain experience in performing tracheal cultures on trapped wild birds. LABORATORY Influenza surveillance in Kenya is a collaborative effort between USAMRU-K, KEMRI, the Kenyan MoH, CDC’s International Emerging Infectious Disease Program-Kenya, and the World Health Organization (WHO). The WHO-designated National Influenza Center (NIC) labora- tory is located on the KEMRI campus in Nairobi and is operated jointly by USAMRU-K and KEMRI. Each of the collaborators has a very clearly de- fined role so as to avoid overlapping and duplicating activities. USAMRU- K provides the laboratory director and support for eight technical staff, while KEMRI provides the facilities and two additional technicians. CDC

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA provides two technicians for operation of real-time PCR. Both the KEMRI and CDC staff may be pulled out of the laboratory for emergencies, such as the recent Rift Valley Fever outbreak. USAMRU-K conducts outpatient influenza virus surveillance at five sites. CDC operates the BSL-3 laboratory in the KEMRI facility and conducts hospital-based surveillance at five sites. All respiratory samples collected in both the CDC and USAMRU-K surveil- lance programs are received and processed by the NIC. The MoH is the regulatory authority and ultimate recipient of the data generated by NIC. The IOM site visit team was unable to visit the laboratory in Nairobi because of a temporary security-related travel restriction at the time of the visit but was informed that the existing NIC facilities had been completely stripped and refurbished and new equipment installed. The laboratory resumed operation in 2006, and testing of surveillance samples began in July 2006. The anticipated workload is approximately 200 samples per week, which is a large volume for a complete tissue culture workup on all samples. The laboratory operates under BSL-2 conditions with two Class 2 biosafety cabinets. Laboratory diagnosis is currently performed using tis- sue culture systems with isolates identified by conventional serologic tech- niques. Diagnostic capabilities exist for influenza viruses, adenoviruses, enteroviruses, parainfluenza viruses, human metapneumovirus, and RSV. Real-time PCR is expected to be fully operational in the NIC before the end of March. Thus it is expected that by April 2007 all samples collected under the outpatient surveillance program supported by USAMRU-K, as well as samples collected under the inpatient program supported by CDC, will be screened by RT-PCR for influenza A and B and H5 using specific primers. Samples positive for A or B from the outpatient project will be further se- rotyped from cultures. Influenza-positive samples from the inpatient study will be forwarded to CDC for further workup. Any sample positive for H5 from any human source will be immediately forwarded to the BSL-3 facility without further NIC workup. Influenza viruses isolated to date by the NIC have been sent with original samples to the Air Force Institute for Operational Health (AFIOH) facility in San Antonio for confirmation and virus sequencing. However, shipments to the United States are reportedly expensive (approximately $2,000). Sending isolates to NAMRU-3 was proposed as an alternative. NIC provides weekly and monthly reports to USAMRU-K and to KEMRI, which in turn reports to the MoH. This reporting mechanism is organizationally appropriate but may lead to delays in relaying informa- tion. A mechanism for real-time feedback to the site-collaborating physi- cians has yet to be decided upon. Relationships with KEMRI are good, but the reporting process leaves little opportunity for the NIC to interact with the MoH. The reporting channels to WHO were unclear to the IOM site visit

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS to process such high samples loads. A stockpile of reagents and laboratory consumables has been budgeted using fiscal year 2007 funds (USAMRU-K, 2007b). In the event of a large-scale epidemic, CDC-Kenya would probably take the U.S. government agencies’ lead. CDC’s laboratory and supply capability would probably double surge capacity in Kenya. The Wellcome Trust labo- ratory would also probably participate in outbreak response on the coast. The National Plan of Action for Preparedness and Response to Avian Influenza in Uganda (April 2006) describes the steps necessary to achieve national response readiness. Uganda participated with Kenya in the com- bined WHO/Food and Agricultural Organization (FAO)/CDC training-of- trainers program, but the country lacks the necessary resources to continue in-country training at the same rate as Kenya. Spokespersons for the MoH estimated that the goals of the national plan are roughly 10 percent com- plete. The national plan is currently under review to document progress, identify major program gaps, revise funding needs, and assign priorities for implementation. The major challenges are still the limited financial and human resources (USAMRU-K, 2007b). Conclusions While there have not been any cases of avian influenza in Kenya, USAMRU-K has a history of participating in infectious disease outbreak investigations alongside the MoH and CDC representatives and has a well developed surge capacity plan in the event that an avian outbreak does occur. CAPACITY BUILDING In fiscal year 2006, the supplemental funding was used to strengthen the NIC’s BSL-2 laboratory at KEMRI, including the purchase of a PCR machine (Bulimo, 2007). In addition to the development of the NIC laboratory, USAMRU-K conducted an influenza training course held May 3-11, 2006, at the Walter Reed DoD-GEIS laboratories at KEMRI. This was the first training course conducted by the flu program, and classes covered basic science and prac- tical topics. The USAMRU-K flu staff attended as well as representatives from Cameroon, Uganda, Burundi, and Kenya. In total, 21 participants were given training that consisted of two components, a theoretical element and a practical element. The theoretical aspect included the historical con- text of influenza, the epidemiology of influenza, good laboratory practice, laboratory safety, personal protective equipment, specimen collection and

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA handling, polymerase chain reactions as a diagnostic tool for influenza, and outbreak management. The practical aspect covered cell culture practicum, specimen collection practicum, inoculation of virus samples (including known positives) into MDCK cells, identification of cytopathic effect (CPE) in influenza virus-infected cells, harvest of influenza viruses from infected cell cultures, cryopreservation of MDCK cells as well as virus isolates, and hemagglutinin/human avian influenza practicum. A field trip to a bird breeding and feeding location at the Ruai sewage plant in Nairobi was organized in conjunction with personnel from the National Museums of Kenya to trap birds and collect cloacal swabs. A sacred ibis caught by this team at the Jomo Kenyatta International Airport was brought to KEMRI. All procedures ranging from tagging of the bird to biometric measurements and the collection of cloacal swabs were dem- onstrated by the veterinarian attached to USAMRU-K together with staff from the National Museums of Kenya. At the end of the training course, certificates of participation were presented to all involved. The training course participants were selected because they plan to have direct involvement with USAMRU-K influenza surveillance programs. In addition, the training course incorporated pretests and posttests to evalu- ate the participants’ comprehension of the course. The participants who work within the USAMRU-K flu program have demonstrated understand- ing and knowledge of influenza, but otherwise there has been no mechanism to evaluate how beneficial the training has been. Conclusions In collaboration with KERMI and CDC, USAMRU-K has increased the laboratory capacity of the Kenyan NIC by training staff, strengthening BSL- 2 performance, and adding PCR capabilities. USAMRU-K has contributed to building laboratory capacity elsewhere in sub-Saharan Africa by partici- pating in training laboratory technicians from a variety of countries. COLLABORATION AND COORDINATION Influenza surveillance in Kenya is a collaborative effort between USAMRU-K (DoD), KEMRI, the Kenyan MoH, CDC’s International Emerging Infections Program-Kenya (IEIP), and WHO. USAMRU-K also participates on the Kenyan influenza taskforce with the Ministry of Live- stock and Fisheries, represented by the Central Investigation Laboratories; the Ministry of Health, represented by the Director of Medical Services; research institutes and bodies (KEMRI, USAMRU-K, CDC-Kenya); the ornithology department of the National Museums of Kenya; the Kenya Wildlife Service; and funding bodies such as WHO, the U.S. Agency for

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS International Development, the German Agency for Technical Cooperation, and the FAO. Committees have been formed within this task force, and each is responsible for different aspects such as surveillance, prevention, laboratory support, infection control, and control and eradication. Collaborative operation of the WHO-designated NIC laboratory al- lows for extremely close coordination between USAMRU-K and KEMRI. To facilitate information sharing, the NIC provides weekly and monthly reports to USAMRU-K and to KEMRI, which is responsible for reporting to the MoH. This reporting mechanism is organizationally appropriate but may lead to delays in relaying information. A mechanism for real-time feedback to the site-collaborating physicians has yet to be decided upon. Relationships with KEMRI are good, but the reporting process leaves little opportunity for the NIC to interact with the MoH. USAMRU-K collaborates with CDC-IEIP in Kenya, with Kenya’s MoH and Ministry of Livestock and Fisheries, and with NAMRU-3 in Cairo in conducting a migratory bird surveillance program. In addition to current collaborations, USAMRU-K is exploring the development of an influenza-related protocol with the Kenya Department of Defense. The designation of the laboratory as a National Influenza Center carries with it the obligation to participate fully in the global influenza network on a timely basis. This means the national government is expected to promptly report isolation of influenza viruses to WHO and promptly forward repre- sentative isolates to WHO-designated reference laboratories. Conclusions USAMRU-K is working closely with relevant partners in Kenya to implement avian influenza activities. These relationships have benefited both USAMRU-K and the host country. However, the site visit team was unclear about the sharing of USAMRU-K findings and isolates with the global influenza information network and the communication channels to any WHO entity in terms of planned expan- sion of the African influenza surveillance network. This becomes a larger concern as USAMRU-K expands into other countries in the region. RECOMMENDATION 6-5. Based on the close proximity of labora- tory space at KEMRI and the potential overlap in influenza activities, USAMRU-K should increase its efforts to facilitate communications between principal investigators at the USAMRU-K/NIC and CDC and the staff of the two laboratories, including joint seminars, data sharing, and cross training on equipment and BSL-3 principles and practices. As part of this communication, USAMRU-K and the NIC should develop

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA a written understanding among all partners concerning WHO expecta- tions about the reporting of influenza virus isolations and appropriate communication channels. The site visit team saw a number of examples of close collaborations between USAMRU-K and CDC during the site visit. However, there seemed also to be a number of disconnects between the two U.S. entities, which may represent lost opportunities for efficiency. UGANDA The proposed Uganda program would involve surveillance for H5 and other influenza viruses, including obtaining cloacal cultures from captured migrating waterfowl and assaying for influenza viruses; epidemiological and virologic investigation of chicken die-offs; and detection of influenza virus infections among a systematic sample of pediatric and adult ambula- tory patients who present with acute respiratory illnesses to the outpatient department of Mulago Hospital in Kampala or to rural Kayunga District Hospital (Wabwire-Mangen, 2007). The proposed USAMRU-K project in Uganda is to be administered through the Makerere University Walter Reed Project (MUWRP). Several Walter Reed Project staff members are on the ground facilitating the planning and coordination with Ugandan govern- ment officials (Wabwire-Mangen, 2007). Proposed Human Influenza Surveillance Project in Uganda A professor from Makerere University is the nominated principal in- vestigator of the proposed DoD-GEIS-supported human influenza surveil- lance project. The surveillance plan is to enroll eligible pediatric subjects (age 2 months to 12 years) and adult subjects at two health care facilities, the urban Mulago National Referral and Teaching Hospital in Kampala and the rural Kayunga District Hospital. At Mulago the plan is to seek out pediatric patients with acute respiratory illness from among ambula- tory patients seeking health care at the assessment center (i.e., the triage facility in the outpatient department) or at the pediatric acute care unit, an adjacent unit where more seriously ill children who are not directly admit- ted to the hospital can stay under clinical observation for up to 24 hours (after which they are either admitted to the inpatient pediatric service or discharged to home) (Wabwire-Mangen, 2007). Similarly, adult outpatients with more severe acute respiratory illness are diverted from the triage area of the outpatient department and kept under observation in the accident and emergency unit. After a period of observation, the adult patients are either admitted to the hospital or discharged to home. At Kayunga Hospital

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0 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS specimens will be obtained from eligible pediatric and adult patients with acute respiratory illness seen either in the outpatient department or admit- ted to the hospital (Wabwire-Mangen, 2007). Eligible patients include children (age 2 months to 12 years) and adults who present with fever greater than 38oC, oral or axillary, with cough or sore throat, and with an onset of illness within the previous 72 hours (Wabwire-Mangen, 2007). The IOM site visit team was informed that the protocol intended to exclude pregnant women and patients with exudative tonsillitis or pharyngitis. The IOM team was told that a total of up to five specimens per day would be obtained from patients both at Mulago and at Kayunga. As part of the surveillance protocol, demographic data, clinical in- formation, and a history of travel or animal contact (particularly with chickens) will be collected from each patient. Clinical specimens will be processed in the refurbished microbiology laboratory of the Veterinary School of Makerere University to detect the presence of influenza viruses. Data entry will be performed at MUWRP. Migrating Waterfowl Surveillance in Uganda Nature Uganda, a nongovernmental agency that is the local affiliate of Bird International, has been monitoring the numbers and species of mi- grating waterfowl that land in various regions of Uganda including (1) the western Rift Valley lakes (Queen Elizabeth Conservation Area, Kyambura Wildlife Reserve, Murchison Falls National Park); (2) the Lake Victoria region (eastern, central, and southwestern shorelines, Lake Mburo, and Sango Bay): and (3) the eastern Uganda wetlands (Lake Kyoga, Lake Opeta, Lake Bisina, and two Uganda rice schemes, Kibimda and Doho) (Wabwire- Mangen, 2007). At these sites Nature Uganda workers have found migrat- ing waterfowl in close proximity to indigenous birds, including ducks. USAMRU-K intends to partner with Nature Uganda and to expand the activities to include the collection of cloacal swabs. These swabs will be tested for influenza viruses including H5N1. Any influenza virus isolates will be sent to the WHO International Influenza Virus Reference Labora- tory for viruses of animal origin (Wabwire-Mangen, 2007). Although USAMRU-K does not currently have plans to conduct sur- veillance on domestic birds, the government of Uganda does have a proto- col in place for die-offs. If information reaches the Ministry of Agriculture of a die-off of chickens or of other birds, an investigative team will be sent to obtain specimens and gather information. The specimens will be tested to determine if highly pathogenic influenza viruses are responsible for the severe and fatal disease.

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA Proposed USAMRU-K Laboratory in Uganda The IOM team visited one of the potential sites under consideration by USAMRU-K for assisting Uganda in developing laboratory surveillance capacity. The site is located on the campus of Makerere University in the School of Veterinary Medicine. Proposed space in the 30-year-old building is poorly designed and ill equipped, but it could be adequately renovated to meet requirements for a BSL-2 laboratory. Laboratory staff would need to be hired and trained; no virology professionals are currently associated with the laboratory. Achieving a fully functioning laboratory to support the proposed human and avian surveillance studies will require consider- able investment. Uganda officials fully support the expansion of influenza surveillance capabilities as proposed by USAMRU-K and agree in principle on the pro- posed surveillance protocol and possible sites for sample collection. Details of the laboratory arrangement remain to be resolved. Resolution depends, in part, on an extended visit to the Uganda Virus Research Institute (UVRI) to assess its current activities and capabilities, national and global obliga- tions, interest in expanding influenza virus surveillance, and possible role in the proposed USAMRU-K project. Currently, the Ministry of Agriculture, Animal Industry, and Fisher- ies (MAAIF) is assigned responsibility, in collaboration with the Ugandan Wildlife Authority, for surveillance, situation monitoring, and assessment activities in animals. (The MoH is assigned responsibility for establishing and implementing systems for prevention and containment of influenza in humans.) MAAIF currently monitors the occurrence of important disease threats in wild and domestic animal populations, but it will require con- siderable strengthening in order to meet its responsibilities for AI. MAAIF has no avian influenza diagnostic capabilities itself and in the case of avian influenza relies on the UVRI, which is designated the WHO National Influenza Center. The UVRI is responsible for rapid analysis and sharing of specimens or isolates for (influenza) virus characterization and develop- ment of diagnostics and vaccines. The team was unable to visit UVRI. Both the United Kingdom and the CDC operate laboratories on site, primarily related to the human immunodeficiency virus. A BSL-3 laboratory is on site with funding and training provided by CDC. The team was unable to determine unequivocally whether the laboratory had received final certifi- cation and was fully functioning. Information was unavailable on UVRI laboratory diagnostic capacity, NIC activities, or triage procedures for suspected human or avian influenza virus specimens and samples. In a later discussion with the Commissioner of Health, human resources were said to be the greatest UVRI need.

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS Conclusions The site visit team felt that there were significant and appropriate op- portunities in Uganda for the expansion of influenza surveillance activities by USAMRU-K. At the time of the site visit USAMRU-K staff members were working with Makarere University and the Uganda Walter Reed Project to identify and assess laboratory facilities to manage samples from the projects under proposal. It is crucial for in-country relationships that USAMRU-K ensure that Uganda’s principal partners (WHO, FAO, CDC) are fully informed of discussions with the MoH. RECOMMENDATION 6-6. In order to maximize the AI/PI funds in Uganda, USAMRU-K should explore all options, including UVRI, in developing influenza virus diagnostic capacity within Uganda to ensure optimal use of national and external resources, promote collaboration among all sectors, and maximize potential for sustainability. USAMRU-K Collaborations in Uganda The National Plan of Action for Preparedness and Response to Avian Influenza in Uganda was released in April 2006. The Plan was developed by the Avian Influenza National Task Force (NTF), which was co-chaired by the commissioners of the MoH and the MAAIF and whose membership in- cluded an additional 14 members representing other relevant ministries and development partners. FAO and WHO provided technical support. The plan assesses readiness, assigns responsibilities, guides response preparations, and includes timelines and estimated costs. The major challenges to full implementation of the plan are limited financial and human resources. Conclusions The existence of a well-documented national plan, the inclusion of the Ugandan Ministry of Health and Environment, the sharing of personnel between the MoH and Makerere University, and the established programs of both MUWRP and CDC provide a unique opportunity for collaborative influenza surveillance activities in Uganda. Details of such collaborative activities remain to be worked out. REFERENCES Bulimo, W. 2007. The influenza surveillance program at USAMRU-Kenya. PowerPoint pre- sentation given during site visit on March 13, 2007. Kisumu, Kenya.

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA DoD-GEIS (Department of Defense Global Emerging Infections System). 2007a. U.S. Army Medical Research Unit-Kenya. http://www.geis.fhp.osd.mil/GEIS/Training/USAMRU- K.asp (accessed June 12, 2007). DoD-GEIS. 2007b. Department of Defense influenza surveillance sites worldwide, 00 (unpublished). IOM (Institute of Medicine). 2001. Perspectives on the Department of Defense Global Emerg- ing Infections Surveillance and Response System: A program review. Washington, DC: National Academy Press. Kenya Red Cross Society. 2006. Kenya: Avian influenza. http://www.kenyaredcross.org/User- Files/File/avian_influenza06.pdf (accessed September 5, 2007). Limbaso, S. 2007. Avian influenza: Kenya migratory bird study overview. PowerPoint presen- tation given during site visit on March 13, 2007. Kisumu, Kenya. Schnabel, D. 2007. The Global Emerging Infectious Disease Surveillance and Response System at USAMRU-Kenya. PowerPoint presentation given during site visit on March 12, 2007. Kisumu, Kenya. USAMRU-K. 2007a. Flu budget (unpublished). USAMRU-K. 2007b. Sample surge capacity plan at USAMRU-K (unpublished). USAMRU-K. 2007c. Lab summary report (unpublished). Wabwire-Mangen, F. 2007. Proposed influenza surveillance project (Uganda). PowerPoint presentation given during site visit on March 15, 2007. Kampala, Uganda. WHO (World Health Organization). 2007a. HN avian influenza: Timeline of major events. http://www.who.int/csr/disease/avian_influenza/Timeline_2007_03_20.pdf (accessed July 30, 2007). WHO. 2007b. Cumulative number of confirmed human cases of avian influenza A/(HN) reported to WHO. http://www.who.int/csr/disease/avian_influenza/country/cases_table_ 2007_07_25/en/index.html (accessed July 30, 2007).

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS LIST OF CONTACTS DoD-GEIS USAMRU-K Assessment: Kenya and Uganda Kenya Wallace Bulimo, U.S. Army Medical Research Unit Kenya/National Influenza Center Margaret Koech, U.S. Army Medical Research Unit Kenya Dr. Samson Limbaso, U.S. Army Medical Research Unit Kenya COL Sam Martin, U.S. Army Medical Research Unit Kenya Bernhards Ogutu, U.S. Army Medical Research Unit Kenya /Kenya Medical Research Institute Duke Omariba, U.S. Army Medical Research Unit Kenya Dr. Mark Polhemus, U.S. Army Medical Research Unit Kenya Fred Sawe, U.S. Army Medical Research Unit Kenya Capt. David Schnabel, U.S. Army Medical Research Unit Kenya John Waitumbi, U.S. Army Medical Research Unit Kenya Dr. Doug Walsh, U.S. Army Medical Research Unit Kenya Samuel Sinei, Walter Reed Project, Kericho, Kenya Dr. Phillip Muthoka, Kenyan Ministry of Health Uganda Leigh Anne Eller, Makerere University/Walter Reed Project David Guwatudde, Makerere University/Walter Reed Project Monica Millard, Makerere University/Walter Reed Project Arthur Natwijuka, Makerere University/Walter Reed Project Dr. Denis Byarugaba, Makerere University Dr. Fred Wabwire-Mangen, Makerere University Osman Lukwago-Luswa, Makerere University, Institute of Public Health Lukwago Luswa, Makerere University, Institute of Public Health Merlin Robb, Henry M. Jackson Foundation Winyi Kaboyo, Ugandan Ministry of Health Sam Okware, Ugandan Ministry of Health Edison Mworozi, Mulago Hospital Achilles Byaruhanga, Nature Uganda

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 U.S. ARMY MEDICAL RESEARCH UNIT KENYA SCHEDULE OF EVENTS DoD-GEIS USAMRU-K Assessment Kisumu, Kenya, and Kampala, Uganda Participants: Dr. Walter R. Dowdle Dr. Myron M. Levine J. Alice Nixon March 12-16, 2007 Monday, March , 00 Introduction and Initial Briefing 0915-0930 Overview of USAMRU-K 0930-1000 Col. Sam Martin Overview of USAMRU-K GEIS program 1045-1045 Capt. David Schnabel 1100-1100 Tea Overview of USAMRU-K Kisumu 1130-1130 Col. Doug Walsh Acute Febrile Illness protocol 1130-1200 Lt. Col. Mark Polhemus Tour Kondele facilities 1200-1300 1300-1345 Travel to Kombewa Overview of Flu program and CDC-International 1345-1500 Emerging Infections Program (IEIP) Briefing on Influenza outbreak in Kombewa 1530-1530 Tour Kombewa town or district hospital 1600-1600 1800-1800 Return to hotel Tuesday, March , 00 Tour Kericho District Hospital and overview of 0900-1000 USAMU-K Kericho program Dr. Fred Sawe Overview of USAMRU-K GEIS flu program 1200-1200 Dr. Wallace Bulimo 1315-1315 Overview of Migratory Bird Surveillance Project Dr. Samson Limbaso Tour Clinical Trial Center 1315-1400 Tour factory 1400-1530 1730-1730 Return to hotel

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS Wednesday, March , 00 0900-1600 Travel to Kampala, Uganda Thursday, March , 00 Introductions and presentation of Uganda Influenza 0900-1030 Work Plan Courtesy visits 1030-1200 Chairman of AI/PI Task Force Makarere University School of Veterinary Medicine Mulago Hospital Outpatient Clinic Makarere University Walter Reed Project (MUWRP) facilities Field site visit to Kayunga District Hospital 1630-1630 Summary of day’s events 1700-1700 1700- Return to hotel Friday, March , 00 Informal discussions and site visit wrap-up 0930-1130 Final out-brief 1130-1230 1230-1700 Lunch and free time 1700- Departure