Pediatric Infectious Diseases: 60 Years of
Contributions by Military Pediatricians
To describe the many contributions that uniformed pediatricians have made to thefield of pediatric infectious diseases is a complicated task. Part of the difficulty is that for the decades after the end of World War II, a number of talented and brilliant physicians spent short periods of time in the military to fulfill their service obligations. Investigators such as Floyd Denny and Lew Wannamaker published their seminal works on group A b-hemolytic streptococci and rheumatic fever while on active duty in the US Air Force.1Some of the early work on vaccines for common childhood infections was done by investigators who, at least for a portion of time, wore a military uniform. In addition, many of the contributions of military physicians were often made alongside and in concert with their civilian col-leagues.
In an attempt to illustrate some of the more significant contributions of military pediatricians to the field of pediatric infectious disease, however, a good starting point would be the work of Colonel Ogden Bruton. His early work performed over 60 years ago in many ways began the military legacy of clinical research in a variety of important areas of pediatric infectious disease but in particular those areas where the disciplines of clinical immunology and infectious disease have overlapped.
SERENDIPITY AND THE BEGINNING OF A LEGACY
While evaluating children at what was then known as Walter Reed General Hospital in 1951, Colonel Ogden Bruton observed an 8-year-old boy with recurrent pneumonia. Dr Bruton noted the unusual pattern of this child’s pneumonias, and while analyzing the child’s immune system, noted a lack of serum immunoglobulin. Dr Bruton’s observations eventually led to his reporting of thefirst primary immunodeficiency disease ever to be described, Bruton’s agammaglobulinemia. Both Dr Bruton’s discovery of the disease as well as his attempts at treating it with specific immunotherapy in the form of intramuscular immune globulin would herald the dawn of modern clinical immunology.2,3 Al-though Dr Bruton was a brilliant clinician and researcher, he also was a visionary leader who established the pediatric residency program at Walter Reed and who also served as department chairperson there for over a decade. His clinical discoveries and the leadership that he provided to military medicine in the following decades led to his be-coming one of the most beloved pediatricians to serve in this capacity. Over the past half century, many other prominent military pediatricians have built upon Dr Bruton’s legacy in thefield of pediatric infectious disease and immunology and have also been exceptional leaders and educators in their own right.
AUTHORS:Michael Rajnik, MD, FAAP, Martin Ottolini, MD, FAAP, and Martin Weisse, MD, FAAP
Department of Pediatrics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
ABBREVIATIONS
AAP—American Academy of Pediatrics CSD—cat-scratch disease
ETEC—enterotoxigenicEscherichia coli
NAMRU-3—Naval Medical Research Unit 3 RSV—respiratory syncytial virus
USUHS—Uniformed Services University of the Health Sciences www.pediatrics.org/cgi/doi/10.1542/peds.2010-3797f
doi:10.1542/peds.2010-3797f Accepted for publication Oct 7, 2011
Address correspondence to Michael Rajnik, MD, Department of Pediatrics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814. E-mail: mrajnik@usuhs.mil
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE:The authors have indicated they have nofinancial relationships relevant to this article to disclose.
OUTBREAKS BRING OPPORTUNITY Military infectious disease physicians are often at the forefront of emerging diseases and the study of new patho-gens due to the global reach of the military health care system. The study of cat-scratch disease (CSD) is a micro-cosm of such endeavors. CSD wasfirst reported in the medical literature in 1951, and thefirst pediatric description was published in 1953. Captain Andrew Margileth, who spent 24 years on active duty in the US Navy, concentrated a great deal of his scholarly work on the recognition, diagnosis, and treatment of clinical manifestations of CSD. In 1957, Dr Margileth was thefirst clinician to describe Parinaud oculoglandular syn-drome due to CSD.4An additional clinical observation attributed to Dr Margileth was his recognition of a constellation of systemic symptoms and feverfirst associating CSD as an etiology of“fever of unknown origin.”5 His fascination with this disease led him to try to de-cipher the etiology of these clinical syndromes. In 1984, Dr Margileth et al6 first reported the identification of organisms within the cat scratch pap-ule at the site of inoculation. Ironically, the military was thefirst to isolate an organism from a patient with CSD, and the organism was named for the Armed Forces Institute of Pathology,
Afipia felis.7In the ensuing years, sev-eral investigators, including clinicians from the army and air force, demon-strated that Bartonella henselae, not
Afipia, is the primary etiology of CSD. All told, Dr Margileth published 25 articles concerning various aspects of CSD in the peer-reviewed medical literature over 5 decades.
Colonel James W. Bass began his medical and army careers simultaneously, and he had a profound effect on pediatric medicine as well as military pediatrics. His scholarly work began while in his first tour as a general pediatrician at
of thefirst clinical trials on the use of ampicillin for the treatment of otitis media.8,9 Shortly thereafter, Dr Bass began formal fellowship training under Dr Margaret H.D. Smith at Tulane Uni-versity. A pertussis outbreak in New Orleans during his time there afforded the opportunity for breakthrough work on the carrier state10 and antibiotic treatment11,12 of pertussis. He contin-ued his interest in pertussis over the next 3 decades with a dozen more re-ports and articles. Dr Bass was eclectic in his infectious disease interests, con-tributing advances in penicillin therapy of streptococcal disease, evaluation and management of occult bacteremia, as well as cutaneous manifestations of in-fectious diseases. The military pedia-tricians’interest in CSD was continued by Dr Bass, with the only placebo-controlled antibiotic trial for the treatment of CSD13ever published. Al-though this litany would lead one to believe that Dr Bass was primarily in-volved in clinical research, his greater calling was as a teacher and leader of military pediatrics. His role as thefirst chairman of the Department of Pedi-atrics at the Uniformed Services Uni-versity of the Health Sciences (USUHS), his service on the American Academy of Pediatrics (AAP) “Redbook” Commit-tee, and his long-time service training scores of pediatricians in the legacy of Dr Bruton at Walter Reed in Washington, DC, and Tripler in Hawaii left a great legacy for all those that follow.
NEW UNIVERSITY, NEW FELLOWSHIP, NEW CHALLENGE Upon the charter of what was then the new USUHS in 1972, Dr James Bass was chosen as the chair of the fledgling Department of Pediatrics. One of his first executive decisions was to bring then Army Lieutenant Colonel Gerald W. Fischer on board to lead the division of
fellowship in pediatric infectious dis-eases that would be jointly sponsored by the USUHS and Walter Reed Army Medical Center. The fellowship is now part of the National Capital Consortium for military graduate medical education and has trained over 30 pediatric in-fectious disease specialists in 25 years. The members of the fellowship were some of the earliest clinicians involved in pediatric HIV care and discovery. One of Dr Fischer’s early fellows, then Army Major Dennis Shanks, saw an unusual case of an infant with Toxoplasma en-cephalitis.14 The group began to see additional patients who had a spec-trum of opportunistic infections very similar to adults who were afflicted with AIDS. It was suspected that these patients too must have had an immu-nologic basis for their susceptibility to unusual infections. Ultimately, they be-came one of the early groups to recog-nize the spectrum of disease associated with pediatric HIV infection.
This early work also led to the in-volvement of the Military Pediatric HIV Consortium in many early collaborative efforts. In particular, Dr Fischer re-members working very closely with the National Institutes of Health group led by Dr Phillip Pizzo. In this arrangement, military dependents were some of thefirst children enrolled in studies to examine the use and efficacy of trimethoprim-sulfamethoxazole and zidovudine in children (personal com-munication with Dr Fischer). Pediatric infectious disease physicians continue to have a prominent role in the military research efforts directed at under-standing the immunologic phenomena and the development of treatments for HIV. Dr Robb is now retired from the US Army but presently is a key investigator in military efforts with industry to de-velop novel vaccines tofight HIV.
WORKING TO HELP CHILDREN WORLDWIDE
The military has worked on many projects in its overseas research lab-oratories where great strides in the treatment of “orphan” diseases have been made. The work at Naval Medical Research Unit 3 (NAMRU-3) in Cairo is an excellent example of such work. One of the greatest accomplishments of this institute was the invention of oral rehydration solution for the treatment of cholera in Egypt.18Oral rehydration solution is now used as the mainstay of diarrhea treatment worldwide. For this accomplishment, Navy Captain Robert Phillips was awarded the Lasker Award, considered the American corollary to the Nobel Prize.
More recently, pediatricians have played a large role in the research performed at NAMRU-3. One of the major missions of NAMRU-3 was to study the evaluation and treatment of“enteric” or typhoid fever. Under the direction of Navy Captain Robert Frenck, multiple stud-ies were conducted on the treatment of
typhoid fever with azithromycin.19,20 Ul-timately, this treatment has become the therapy of choice in most situations. An additional focus of research at this institute involved the study of enter-otoxigenic Escherichia coli (ETEC). Vaccinology has been a particular em-phasis in an attempt to understand and prevent diseases due to ETEC. Navy pe-diatric infectious disease specialist Ste-phen Savarino headed a team that established a diarrheal diseasefield site in Abu Homos, Egypt, an agrarian com-munity in the Nile River. Dr Savarino conducted 4 studies of the ETEC vaccine culminating in a large-scale efficacy trial of the vaccine in Egyptian infants and young children.21–23As part of the prep-aration work for the vaccine trials, Dr Savarino established diarrhea surveil-lance in the community and was able to describe the epidemiology of the major pathogens including ETEC, shigella,
Campylobacter, rotavirus, and norovirus. At this time, Dr Savarino continues to work as the military’s head of enteric disease research and continues to search for improved ETEC vaccines.
FROM THE BEDSIDE TO THE BENCH AND BACK
The role of the military in the devel-opment of products, in particular vac-cines, that would end up in commercial production has been well documented. Most of these products were developed with the concept that they would di-rectly benefit the active duty pop-ulations serving the United States. Military pediatricians played key roles in laying the ground work leading to many of these discoveries. One recent series of product development strayed somewhat from the usual path taken. The products leading to the respiratory syncytial virus (RSV) prophylaxis of high-risk neonates were developed through the efforts of the previously mentioned Dr Fischer and Air Force Colonel Val Hemming at USUHS.
Both Drs Fischer and Hemming had research interests centering on the use of passive immunotherapy to prevent childhood diseases such as group B
Streptococcusin neonates. Drs Fischer and Hemming ran a laboratory at USUHS studying passive immunization with the help of Mr Samuel Wilson and Ms Sally Hansen. The observations re-garding RSV were the result of a clini-cal trial where a colleague, Army Colonel Leonard Weisman, noted un-expectedly rapid improvement of a child with presumed group B Strepto-coccus disease after the administra-tion of intravenous immunoglobulin. In the end, this child was found to have RSV. From these findings, the re-searchers postulated that immuno-globulin may have a therapeutic benefit to children with RSV diseases (G.W. Fischer, V. Hemming, MD personal communications, 2010).
The search for further development of this theory led to work with Dr Gregory Prince, a civilian pathologist and dentist with experience studying paramyxo-viruses. Dr Hemming worked with Dr Prince to use an animal model,Sigmodon hispidus, the cotton rat, to further study this disease. Their work resulted in the discovery that passive antibody treat-ment prevented pneumonia in this ani-mal model.24
arrangement facilitated by the Henry M. Jackson Foundation for the Advance-ment of Military Medicine in collabo-ration with MedImmune, Inc, thefirst major clinical trial was completed and published in 1993.25 This initial study demonstrated a significant reduction in the number of hospitalizations, hos-pital days, and ICU days for high-risk infants who received prophylactic in-travenous immunoglobulin with a high titer of RSV neutralizing antibody. After a second study, the PREVENT study, which showed similar results, Respi-Gam, the polyclonal anti-RSV immuno-globulin product was released.26Further work and the development of mono-clonal antibody technology led to the development of a second-generation product, Synagis, which could be de-livered more effectively as a monthly intramuscular injection.27
CONTINUING TO LEAD THE WAY Many military pediatric infectious dis-ease experts have continued to further the field of scientific discovery. Dr Martin Ottolini, a retired US Air Force Colonel, was the long-time pediatric infectious diseases fellowship director at the Uniformed Services University. He trained more than 15 specialists in all 3 services in this role, one of the largest contingents nationally during that period. Additionally, he worked closely with the RSV group and helped develop multiple small animal viral models utilizing the cotton rat,S his-pidus.28,29 He presently serves as an integral program manager in a unique National Institute of Allergy and In-fectious Diseases-sponsored research endeavor, the Infectious Disease Clini-cal Research Program. This program sponsors multicenter prospective clini-cal research utilizing the robust mil-itary medical center conglomeration. In this role, Dr Ottolini is presently
gens such as H1N1 influenza. Navy Captain Judith Epstein has been work-ing extensively in the search for possible immunizations to fight the malaria plague confronting much of the developing world. In her role as US Military Malaria Vaccine Program Director, she is presently overseeing thefirst human trials of an irradiated sporozoite immunization that has been developed in collaboration with Dr Stephen Hoffman and Sanaria In-corporated.30,31 Army Colonel Julia Lynch served as Director, Division of Viral Diseases at the Walter Reed Army Institute of Research. In this role, she has overseen the US Army’s efforts to understand the immunologic re-sponse associated with dengue fever and to ultimately develop a safe and effective vaccine. Additionally, these laboratories have been integral in the development of new oral adenovirus type 4 and 7 vaccines to help protect active duty troops. The adenovirus vaccines are presently under consid-eration for approval by the Food and Drug Administration. Most recently, Dr Lynch has been named the Director of the Military Infectious Disease Re-search Program. In this position, she manages all efforts to protect the US military against naturally occurring infectious diseases.
In addition to the many pediatricians who have made significant contribu-tions to the field of infectious disease during their careers in the military, there are many examples of renowned physicians who continue to lead and educate as they transition into civilian life. Dr Russell Steele did his residency at Tripler under Dr Bass and subse-quently served in many roles as a US Army pediatrician. To the present day, he is highly regarded as one of the leaders in the field of pediatric infec-tious diseases, having published over
Clinical Pediatrics, and having served on the Redbook Committee for many years. Another one of Dr Bass’ key pupils, retired Colonel James Brien, is also a well-recognizedfigure to many pediatricians. Dr Brien’s career in the military included active duty tours at Brooke Army Medical Center and Wal-ter Reed Army Medical CenWal-ter. Dr Brien has mastered the art of teaching through instructive cases. He is a fre-quent speaker at many pediatric con-ferences and reaches tens of thousands of pediatricians with his publications of cases that pose a diagnostic or therapeutic quandary. Another con-temporary of these physicians is re-tired Colonel Richard Lampe. Dr Lampe was the chief of pediatrics at mul-tiple army medical centers and pedi-atric residency director at Walter Reed Army Medical Center. Since re-tiring in 1992, he has led the pedi-atrics department at Texas Tech University Health Sciences Center. He has chaired the AAP’s Uniformed Services Section Executive Committee and now serves as the President of the Texas Pediatric Society. It should be noted that Drs Steele, Brien, and Lampe all served their countries and deployed to the Middle East in support of either the First Persian Gulf War, Operation Enduring Freedom or Operation Iraqi Freedom.
SECTION RECOGNIZES THE LEGACY OF THEIR COLLEAGUES
speaker are presented the Ogden C. Bruton Award and Lectureship, re-spectively. In recognition of his con-tributions to CSD research as well as his work on the interpretation of tuberculin skin testing and cutaneous manifestations of diseases in chil-dren, the top clinical researcher is presented with the Andrew Margileth Award. Given Dr Hemming’s contri-butions to both infectious disease research as well as education and academic leadership as both Chair-man of the Department of Pediatrics at USUHS and then dean of the medical school, the top uniformed services medical student researcher is awar-ded the Val Hemming Award, and fi -nally, in recognition of the legendary
teaching exploits of Dr. Bass, the James Bass Challenge Bowl is a college bowl medical trivia contest pitting pediatricians from the army, air force, and navy against each other at the annual Uniformed Services Pediatric Seminar meeting.
CONCLUSIONS
The Medical Corps of all 3 branches of the military have a proud tradition of service and excellence in pediatrics and pediatric infectious disease. In fact, the study and treatment of in-fectious diseases within the military in general can be traced back to some of the earliest investigators in the field such as army physicians Bailey
K. Ashford and Walter Reed for their studies of hookworm and yellow fever, respectively. Military pediatricians and pediatric infectious disease spe-cialists presently work and practice in an environment that has been nur-tured by the careful hands of many of the leaders presented in this article; however, it would be impossible to enumerate the many other contribu-tions made by those not listed. With this tradition in mind, military pediatric infectious disease physicians continue not only to proudly treat the children of military service members wherever they may reside but continue to make advances to the science of medicine for the benefit of children both locally and globally.
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