Have Diagnostics, Therapies, and Vaccines Made the Difference in the Pandemic Evolution of COVID-19 in Comparison with "Spanish Flu"?

In 1918 many countries, but not Spain, were fighting World War I. Spanish press could report about the diffusion and severity of a new infection without censorship for the first-time, so that this pandemic is commonly defined as "Spanish flu", even though Spain was not its place of origin. "Spanish flu" was one of the deadliest pandemics in history and has been frequently compared with the coronavirus disease (COVID)-19 pandemic. These pandemics share similarities, being both caused by highly variable and transmissible respiratory RNA viruses, and diversity, represented by diagnostics, therapies, and especially vaccines, which were made rapidly available for COVID-19, but not for "Spanish flu". Most comparison studies have been carried out in the first period of COVID-19, when these resources were either not yet available or their use had not long started. Conversely, we wanted to analyze the role that the advanced diagnostics, anti-viral agents, including monoclonal antibodies, and innovative COVID-19 vaccines, may have had in the pandemic containment. Early diagnosis, therapies, and anti-COVID-19 vaccines have markedly reduced the pandemic severity and mortality, thus preventing the collapse of the public health services. However, their influence on the reduction of infections and re-infections, thus on the transition from pandemic to endemic condition, appears to be of minor relevance. The high viral variability of influenza and coronavirus may probably be contained by the development of universal vaccines, which are not easy to be obtained. The only effective weapon still remains the disease prevention, to be achieved with the reduction of promiscuity between the animal reservoirs of these zoonotic diseases and humans.

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.

Prevalence of Hepatitis B Virus Markers in Patients with Autoimmune Inflammatory Rheumatic Diseases in Italy.

Chronic hepatitis B virus (HBV) infection may be reactivated by immunosuppressive drugs in patients with autoimmune inflammatory rheumatic diseases. This study evaluates HBV serum markers' prevalence in rheumatic outpatients belonging to Spondyloarthritis, Chronic Arthritis and Connective Tissue Disease diagnostic groups in Italy. The study enrolled 302 subjects, sex ratio (M/F) 0.6, mean age ± standard deviation 57 ± 15 years, 167 (55%) of whom were candidates for immunosuppressive therapy. The Spondyloarthritis group included 146 subjects, Chronic Arthritis 75 and Connective Tissue Disease 83 (two patients had two rheumatic diseases; thus, the sum is 304 instead of 302). Ten subjects (3%) reported previous anti-HBV vaccination and tested positive for anti-HBs alone with a titer still protective (>10 IU/mL). Among the remaining 292 subjects, the prevalence of positivity for HBsAg, isolated anti-HBc, anti-HBc/anti-HBs, and any HBV marker was 2%, 4%, 18%, and 24%, respectively. A total of 26/302 (9%) patients with γ-globulin levels ≤0.7 g/dL were more frequently (p = 0.03455) prescribed immunosuppressive therapy, suggesting a more severe rheumatic disease. A not negligible percentage of rheumatic patients in Italy are at potential risk of HBV reactivation related to immunosuppressive therapy. Before starting treatment, subjects should be tested for HBV markers. Those resulting positive should receive treatment or prophylaxis with Nucleos (t) ides analogue (NUCs) at high barrier of resistance, or pre-emptive therapy, according to the pattern of positive markers. HB vaccination is recommended for those who were never exposed to the virus.

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.

Risk of malignancy in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under immunosuppressive therapy: a single-center experience.

Systemic inflammatory rheumatic diseases are associated with an increased risk of malignancy, in particular of lymphoproliferative disorders. Chronic inflammation, due to the disease itself, generates a microenvironment able to promote cancer development, but it is still controversial whether immunosuppressive therapy may contribute to carcinogenesis. The aim of the study was to evaluate the risk of malignancy in 399 patients affected by rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, all treated with either tumor necrosis factor α-inhibitors plus disease-modifying anti-rheumatic drugs (DMARDs) or DMARDs alone. The risk of malignancy in this cohort of patients, observed in the period between 2005 and 2011 at S. Andrea Hospital-Sapienza University of Rome, was compared with that of the general Italian population, matched for age, sex, and area of residence. Fourteen (3.5%) malignancies, five of which were hematologic, have been observed. The overall cancer risk was not significantly increased in comparison to the general population, whereas the risk of hematologic malignancies appeared significantly higher in RA patients (SIR 4.94, 95% CI 1.35-12.64), particularly in female gender (SIR 6.9, 0.95% CI 1.88-17.66). No significant association between therapy and malignancy was demonstrated in RA patients.

[Cancer incidence in the military: an update]. / Condizione militare e morbosità per cancro: il punto della situazione.

An abnormally elevated rate of Hodgkin's lymphoma was reported in 2001 among Italian soldiers in Bosnia and Kosovo since 1995: a surveillance system was therefore set up for the military community. Preliminary results for a longer period (1996-2007) have shown incidence rates lower than expected for all malignancies. No significant difference was registered between observed and expected cases of Hodkin's lymphoma: the excess of reported cases for this malignancy in 2001-2002 was probably due to a peak occurred in 2000 among the whole military; it is therefore unrelated to deployment in the Balkans, and probably represents a chance event. Moreover, a significant excess of thyroid cancer was reported among the whole military.The estimated number of incident cases, including those missed by the surveillance system, was not significantly higher than expected for all cancers; conversely, the estimated incidence rate of thyroid cancer was significantly increased; this excess, however, is probably due to a selection bias.These data concerning cancer surveillance in the Italian military are consistent with lacking evidence of an increased cancer incidence among troops of other countries deployed in the areas of Iraq, Bosnia, and Kosovo, where armour penetrating depleted uranium shells have been used. However, a comprehensive assessment of cancer morbidity in the military requires a revision of the privacy regulations, in order to link individual records of military personnel and data bases of the National Health Service.

Evaluation of cancer surveillance completeness among the Italian army personnel, by capture-recapture methodology.

OBJECTIVE: This study provides an assessment of completeness of cancer surveillance and incidence estimates for all malignancies, Hodgkin's lymphoma and thyroid cancer in the Italian army, for the years 2001-2007. METHODS: The two-source capture-recapture method was employed, using both Chapman's and Chao's formulae, on the basis of cancer notifications from military hospitals and unit infirmaries. The estimated incident cases were then confronted with the corresponding expected cases; the standardized incidence ratios and 95% confidence intervals (SIR [95% CI]) were then calculated. RESULTS: A total of 442 cancer notifications, concerning 371 cases, were reported (311 from army hospitals and 131 from unit infirmaries; of these, 71 were overlapping). The estimated total number of cases, by Chapman's and Chao's formulae, was 571 and 688, respectively. Overall, sensitivity of the surveillance system was 65% by Chapman's and 54% by Chao's estimators. Completeness of notification was significantly higher in younger patients, in those previously deployed in Bosnia or Kosovo, and for cases of Hodgkin's lymphoma. Estimated SIRs, using both formulae, were not significant for all malignancies and Hodgkin's lymphoma, but significant for thyroid cancer (SIR: 2.25 [1.61-2.89] by Chapman's formula, and 3.12 [1.81-4.43] by Chao's estimator). CONCLUSION: Completeness of cancer registry of the Italian military is low, and methods to improve its sensitivity are discussed. Overall, the estimated number of incident cancer cases, including Hodgkin's lymphoma, is not significantly higher than expected, except thyroid cancer. The increased incidence of this malignancy requires further investigation; however, in the military, as well as in the general population, this may be partly due to the growing availability of diagnostic opportunities in the last decades. Moreover, detection of thyroid cancer may be further facilitated by a selection bias generated by the annual and pre-/post-deployment medical examinations and blood tests routinely performed on all military personnel.

Cancer surveillance in Italian army peacekeeping troops deployed in Bosnia and Kosovo, 1996-2007: preliminary results.

OBJECTIVE: An excess of cancer cases was reported in 2000 among Italian troops involved in peacekeeping operations in Bosnia and Kosovo. A preliminary assessment of cancer risk in this cohort was done for the period 1996-2007, based on cancer surveillance activity, which was started in 2001. METHODS: A retrospective cohort study was done among 27361 Italian Army soldiers deployed in Bosnia, 31052 deployed in Kosovo, and a control group of non-deployed soldiers, whose number varies from 130275 in 1996 to 40967 in 2007. Standardized incidence ratio and 95% confidence intervals (SIR [95% CI]) of the main types of tumours were computed as the ratio of the observed and expected cases. RESULTS: 98 incident cancers were reported among soldiers deployed in Bosnia, 66 in those stationed in Kosovo and 388 in non-deployed personnel. Overall, cancer incidence was lower than expected in all groups. Annual SIR was significantly higher than expected in 2000 for Hodgkin's lymphoma only among troops deployed in Bosnia (4.34 [1.18-11.12]) and non-deployed personnel (3.48 [1.67-6.39]); and in 2001 for thyroid cancer only among troops deployed in Bosnia (5.28 [1.44-13.51]). CONCLUSION: Although further investigation is needed, these preliminary results give no indication of an increased risk of cancer for Italian soldiers who were stationed in Bosnia and Kosovo. The cluster of Hodgkin's lymphoma in 2000 and of thyroid cancer in 2001 were sporadic events, they did not specifically affect deployed personnel and are unlikely to be related to environmental exposures in the Balkans.

Probable dengue virus infection among Italian troops, East Timor, 1999-2000.

To investigate the attack rate and risk factors for probable dengue fever, a cross-sectional study was conducted of an Italian military unit after its deployment to East Timor. Probable dengue was contracted by 16 (6.6%) of 241 army troops and caused half of all medical evacuations (12/24); no cases were detected among navy and air force personnel.

Vaccination policies in the military: an insight on influenza.

Influenza, despite its generally benign clinical course, is accompanied by absenteeism from work, acute suffering and even mortality, mainly in the elderly and in subjects who have high-risk medical conditions. Its prevention consists of strain specific vaccination, which must be repeated annually due to the high antigenic variability of the influenza virus. Influenza may represent an important obstacle to military readiness, particularly when considering its infectivity within closed communities. Despite such epidemiological situations, influenza vaccination is seldom included in the compulsory vaccination programme of the military on a global level. This may be due to several reasons, namely, a lack of confidence in the vaccine's effectiveness, the need for annual administrations (with expansion of economic and organisational efforts), false assumption that influenza is a disease with a minor impact, contradictory results of cost-effectiveness analyses (examples of which have yet to be made specifically for the military environment). The availability of more effective, economic and easy to administer vaccines, together with detailed and tailored cost-effectiveness analyses, may have a beneficial effect on the role the military plays in the fight against influenza across the globe.