A Historical Review of Military Medical Strategies for Fighting Infectious Diseases: From Battlefields to Global Health.

The environmental conditions generated by war and characterized by poverty, undernutrition, stress, difficult access to safe water and food as well as lack of environmental and personal hygiene favor the spread of many infectious diseases. Epidemic typhus, plague, malaria, cholera, typhoid fever, hepatitis, tetanus, and smallpox have nearly constantly accompanied wars, frequently deeply conditioning the outcome of battles/wars more than weapons and military strategy. At the end of the nineteenth century, with the birth of bacteriology, military medical researchers in Germany, the United Kingdom, and France were active in discovering the etiological agents of some diseases and in developing preventive vaccines. Emil von Behring, Ronald Ross and Charles Laveran, who were or served as military physicians, won the first, the second, and the seventh Nobel Prize for Physiology or Medicine for discovering passive anti-diphtheria/tetanus immunotherapy and for identifying mosquito Anopheline as a malaria vector and plasmodium as its etiological agent, respectively. Meanwhile, Major Walter Reed in the United States of America discovered the mosquito vector of yellow fever, thus paving the way for its prevention by vector control. In this work, the military relevance of some vaccine-preventable and non-vaccine-preventable infectious diseases, as well as of biological weapons, and the military contributions to their control will be described. Currently, the civil-military medical collaboration is getting closer and becoming interdependent, from research and development for the prevention of infectious diseases to disasters and emergencies management, as recently demonstrated in Ebola and Zika outbreaks and the COVID-19 pandemic, even with the high biocontainment aeromedical evacuation, in a sort of global health diplomacy.

Immunogenicity of Viral Vaccines in the Italian Military.

Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response to the live trivalent measles/mumps/rubella (MMR), the inactivated hepatitis A virus (HAV), the inactivated trivalent polio, and the trivalent subunits influenza vaccines in two cohorts of Italian military personnel. The first cohort was represented by 108 students from military schools and the second by 72 soldiers engaged in a nine-month mission abroad. MMR and HAV vaccines had never been administered before, whereas inactivated polio was administered to adults primed at infancy with a live trivalent oral polio vaccine. Accordingly, nearly all subjects had baseline antibodies to polio types 1 and 3, but unexpectedly, anti-measles/-mumps/-rubella antibodies were present in 82%, 82%, and 73.5% of subjects, respectively (43% for all of the antigens). Finally, anti-HAV antibodies were detectable in 14% and anti-influenza (H1/H3/B) in 18% of the study population. At mine months post-vaccination, 92% of subjects had protective antibody levels for all MMR antigens, 96% for HAV, 69% for the three influenza antigens, and 100% for polio types 1 and 3. An inverse relationship between baseline and post-vaccination antibody levels was noticed with all the vaccines. An excellent vaccine immunogenicity, a calculated long antibody persistence, and apparent lack of vaccine interference were observed.

Safety of Multiple Vaccinations and Durability of Vaccine-Induced Antibodies in an Italian Military Cohort 5 Years after Immunization.

We previously examined the safety and immunogenicity of multiple vaccines administered to a military cohort, divided into two groups, the first composed of students at military schools, thus operating inside the national borders for at least 3 years, and the other formed of soldiers periodically engaged in a 9-month-long mission abroad (Lebanon). In the current study, we analyzed 112 individuals of this cohort, 50 pertaining to the first group and 62 to the second group, in order to examine the possible late appearance of side effects and to calculate the half-life of the induced antibodies. Moreover, the possible involvement of B-cell polyclonal activation as a pathogenetic mechanism for long term antibody persistence has even been explored. No late side effects, as far as autoimmunity and/or lymphoproliferation appearance, have been noticed. The long duration of the vaccine induced anti-HAV antibodies has been confirmed, whereas the antibodies induced by tetravalent meningococcal polysaccharide vaccine have been found to persist above the threshold for putative protection for a longer time, and anti-tetanus, diphtheria, and polio 1 and 3 for a shorter time than previously estimated. No signs of polyclonal B-cell activation have been found, as a possible mechanism to understand the long antibody persistence.

Effects of Hypobaric Hypoxia on Endothelial Function and Adiponectin Levels in Airforce Aviators.

Background: Hypobaric hypoxia (HH) increases the risk of high altitude-related illnesses (HARI). The pathophysiological mechanism(s) involved are still partially unknown. Altered vascular reactivity as consequence of endothelial dysfunction during HH might play a role in this phenomenon. Adiponectin exerts protective effect on cardiovascular system since it modulates NO release, antagonizing endothelial dysfunction. Aims of this study, performed in a selected population of airforce aviators, were (1) to investigate whether exposure to acute HH might be associated with endothelial dysfunction and (2) to evaluate whether adiponectin might be involved in modulating this phenomenon. Methods: Twenty aviators were exposed to acute HH in a hypobaric chamber by simulating altitude of 8000 and then 6000 m for 2 hours. Vascular reactivity was evaluated by the EndoPAT test immediately before and after the HH; salivary and blood adiponectin levels were measured. Results: EndoPAT performed immediately after HH divided pilots in two groups: 12 pilots with preserved vascular reactivity and 8 pilots with reduction of vascular reactivity, indicating that HH exposure might cause endothelial dysfunction. Salivary and blood adiponectin levels increased post-HH in a time-dependent manner in all aviators, but the significant increase was observed only in those with preserved vascular reactivity suggesting that HH stimulated release of adiponectin that, in turn, by exerting a protective effect, might reduce endothelial dysfunction. Conclusions: Acute HH may cause endothelial dysfunction due, at least in part, to reduced release of adiponectin. This phenomenon might be involved in pathophysiology of HARI.

High Altitude Performance of Loudspeakers and Potential Impact on Audiometric Findings.

BACKGROUND: The evaluation of how air rarefaction can affect a loudspeaker performance at altitude implies the need for characterization of earphones during hypobaric conditions. The aim of this study was phonometric analysis at different altitudes of the acoustic output of a widely used earphone model, along with its consequences on audiological investigations conducted under such environmental conditions.METHODS: The transfer function of a TDH-39P earphone was analyzed with an artificial ear under nine different altitude levels, from sea level up to 35,000 ft, inside a hypobaric chamber. A specific phonometric system not sensitive to environmental pressure changes was used. Other potentially confounding factors, such as environmental temperature and humidity, were continuously monitored.RESULTS: No relevant temperature or humidity changes were detected. The sound pressure level generated by the earphone under hypobaric conditions was found considerably affected by air density changes. These data produced a correction table aiming at recalibrating the earphone's output at each audiometric octave test frequency within the 250-8000 Hz range. Quite different characteristics of response were observed at different audiometric frequencies. Such findings were particularly evident for altitudes exceeding 12,000 ft.DISCUSSION: The development of a frequency-selective and altitude-related correction factor for acoustic stimuli is an essential aspect when hearing threshold measurements in hypobaric environments are performed.Lucertini M, Botti T, Sanjust F, Cerini L, Autore A, Lucertini L, Sisto R. High altitude performance of loudspeakers and potential impact on audiometric findings. Aerosp Med Hum Perform. 2019; 90(7):655-659.

Tetanus-diphtheria vaccination in adults: the long-term persistence of antibodies is not dependent on polyclonal B-cell activation and the defective response to diphtheria toxoid re-vaccination is associated to HLADRB1∗01.

Cellular and humoral immune responses to tetanus-diphtheria vaccine (Td) were assessed in human leukocyte antigen (HLA)-typed Italian military personnel who received multiple concomitant vaccines. Td-specific antibodies and T-lymphocytes were measured in individuals with one (group-1) and more than one (group-2) Td boosters. A third group (group-3), who received several vaccines, but not Td, was studied to verify the hypothesis of the polyclonal B-cell activation as mechanism for antibody persistence. The antibody response to Td toxoids was higher in group-1, who showed lower baseline antibody levels, than in group-2 subjects. The antibody response to tetanus was higher than to diphtheria toxoid in both groups. No correlation between antibody and cellular response, and no interference in the response to Td by co-administration of different vaccines were observed. HLA-DRB1∗01 allele was detected at significant higher frequency in subjects unable to double the baseline anti-diphtheria antibody levels after the vaccination. Anti-tetanus and diphtheria antibodies half-lives were assessed and the long-lasting persistence above the threshold for protection (0.1 IU/ml) was estimated in over 65 and 20 years, respectively. No significant increase of anti-diphtheria antibodies was observed in consequence of polyclonal B-cell activation. This study emphasizes the duration of Td vaccination-induced seroprotection, suggesting that re-vaccination should probably be performed at intervals longer than 10 years. No reciprocal interference by concomitantly administered vaccines has been observed. HLA-DRB1∗01 allele was significantly associated with anti-diphtheria defective response. Finally, this study does not confirm that anti-diphtheria antibody levels are maintained by polyclonal B-cell activation. Clinical trial registry: The study was registered with NCT01807780.

Lack of evidence for post-vaccine onset of autoimmune/lymphoproliferative disorders, during a nine-month follow-up in multiply vaccinated Italian military personnel.

Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to ≥4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post-vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up.

Motion Sickness Prediction in Aeromedical Evacuation of Patients with Ebola.

INTRODUCTION: Aeromedical evacuation of patients affected by severe infectious diseases inside an aircraft transit isolator (ATI) system is at potential risk of motion sickness (MS). A test flight was then conducted to quantify this risk during the transfer of an Ebola patient from West Africa to Italy. CASE REPORT: A mannequin was inserted inside an ATI and instrumented to provide acceleration parameters throughout the test flight. The analysis of the data predicted a MS incidence of about 2% for a 6-h flight, so the decision to use anti-MS drugs only in selected cases was taken (i.e., those with positive past history of MS, gastrointestinal disorders, or residual carsickness due to previous ambulance run). On this basis, an actual aeromedical evacuation of an Ebola patient was successfully performed without the use of any anti-MS drugs. DISCUSSION: During aeromedical evacuation with ATI systems, the patient's risk of MS should be evaluated on an individual basis and calibrated according to the specific exposure to motion evoked by the flight platform used. Due to the possible onset of untoward effects, prevention with anti-MS drugs in these patients should be limited to selected cases.

Predictors of ear barotrauma in aircrews exposed to simulated high altitude.

INTRODUCTION: Ear barotrauma is an adverse effect related to hypobaric exposure. Ear, nose, and throat (ENT) diseases are risk factors for barotrauma in aircrews trained in a hypobaric chamber, but excluding affected subjects from exposure does not abolish the risk in asymptomatic trainees. We investigated other possible predictors, including history of ENT diseases, ENT clinical abnormalities, altitude, and subject's age. METHODS: After a complete ENT evaluation including otoscopy and tympanometry, 314 aircrews underwent hypobaric chamber training. Two altitude training profiles up to 35,000 ft (10,668 m) and 25,000 ft (7620 m), respectively, were used. Subjects were grouped according to if they were asymptomatic, had acute barotitis, or reported delayed ear pain the day after the exposure. RESULTS: There were 7 men who had acute barotitis (incidence of 2.3%) and 28 men who had delayed ear pain (incidence of 9.2%). A significant association resulted between history of ENT diseases and delayed ear pain and between abnormal ENT findings and acute barotitis in subjects exposed to the higher profile. Altitude was associated with increased risk of delayed ear pain. Delayed ear pain was associated with older age in subjects exposed to the lower altitude and younger age in subjects exposed to the higher altitude. DISCUSSION: Our data suggest that in subjects exposed to 35,000 ft (10,668 m), the history of previous ENT diseases and younger age may be valid predictors of delayed ear pain, while abnormal ENT findings may predict acute barotitis. At 25,000 ft (7620 m), subjects with older age may have increased risk of delayed ear pain.

Altitude chamber related adverse effects among 1241 airmen.

INTRODUCTION: Altitude chambers are used for training aircrews, but incidents have been reported, including decompression sickness (DCS) and barotrauma. To minimize chamber-related adverse effects we implemented a set of measures, including altitude restriction and a pre-chamber clinical selection (PCS) of subjects before exposure. METHODS: We reviewed our records regarding 1254 individuals who were trained from 2003 to 2009. After the first 3 subjects, the maximum altitude of the highest training profile was limited to 43,000 ft (13,106.4 m) instead of 45,000 ft (13,716 m) and, after the first 327 subjects, a clinical evaluation of each trainee was performed by an otolaryngologist before altitude exposure. The evaluation included otoscopy and tympanometry, and subjects with abnormal results were not cleared for altitude exposure. Subjects were grouped by having undergone the highest profile before (3 subjects) or after altitude restriction (8 subjects) and received clinical selection (PCS group, 927 subjects) or not (control group, 327 subjects). RESULTS: We recorded 32 total adverse effects (overall incidence 2.6%), 21 in the PCS group (2.3%) and 11 in the control group (3.4%). The difference between groups was not significant. Adverse effects included 19 cases of acute barotitis (1.5%), 1 case of DCS (0.08%), and 4 cases of syncope (0.3%). The incidence of barotitis was 1.1% in the PCS group and 2.7% in the control group. The altitude restriction was ineffective in preventing both barotrauma and DCS. CONCLUSIONS: The incidence of adverse effects in our subjects was low and pre-chamber clinical selection appeared to be effective in reducing the risk of barotitis.

Ear pain after breathing oxygen at altitude: prevalence and prevention of delayed barotrauma.

INTRODUCTION: Military pilots frequently report ear pain with onset several hours after altitude exposure while breathing pure oxygen, but the prevalence of this problem is unknown. A similar problem is described in divers after breathing hyperbaric oxygen and it is related to the oxygen contained in the middle ear. METHODS: In order to assess the prevalence of delayed ear pain after altitude exposure and investigate the effectiveness of preventive use of a nasal balloon (NB), we studied 88 healthy military jet pilots who were asymptomatic after altitude chamber exposure which included 100% oxygen breathing. A group of 44 subjects received the NB shortly after the chamber and they were advised to use it every hour before going to sleep. A control group of 44 subjects was requested to perform the Valsalva maneuver alone over the same period. All subjects underwent clinical examination by an otolaryngologist and tympanometry just before the chamber exposure and again the day after. RESULTS: The day after the altitude exposure, 53.4% of subjects reported ear pain. In the treated group, 61.4% of subjects were free of symptoms, compared to 31.8% in the control group (P < 0.01). Tympanogram was abnormal in eight symptomatic subjects and in six asymptomatic. CONCLUSION: Our data suggest that in our subjects there is high prevalence of delayed ear barotrauma after altitude chamber exposure while breathing pure oxygen and the tympanogram may improve the accuracy of the diagnosis in asymptomatic subjects. The nasal balloon appears to be effective for prevention.

Acute otitic barotrauma during hypobaric chamber training: prevalence and prevention.

INTRODUCTION: Barotitis media is known to be an adverse effect of altitude changes, but few studies have investigated this condition with respect to hypobaric chamber training and the resulting estimations of prevalence vary. METHODS: In order to assess the prevalence of hypobaric chamber-related barotitis and evaluate a method of prevention, 335 healthy military pilots undergoing high altitude training were subject to clinical examination and tympanometry before entering the chamber. In order to minimize the risk of barotrauma, only subjects with normal preflight findings were cleared for altitude exposure. Barotitis media was diagnosed on the basis of ear pain and clinical findings according to Teed's classification. RESULTS: Barotitis occurred in eight subjects; seven cases were monolateral and one bilateral, prevalence was 2.4%. CONCLUSION: The prevalence of barotitis after hypobaric chamber training is low in our study, suggesting that a pre-chamber medical check including clinical examination and tympanometry could be effective in identifying subjects at risk.