Hepatitis B is found in virtually every region of the globe. Of the more than 2 billion people who are or have been infected, 350 to 400 million are carriers of the chronic disease; the remainder undergo spontaneous recovery and production of protective antibodies. Nearly 100% of infected infants (that is, those born to HBV-infected mothers) become chronically infected. The risk of developing a chronic infection decreases with age.

At least 30% of those with chronic HBV infection experience significant morbidity or mortality, including cirrhosis and hepatocellular carcinoma. Most people do not know they are infected until they present with symptoms of advanced liver disease, which means that infected individuals can spread the infection unknowingly, sometimes for many years. Although oral antiviral therapies are effective at stopping HBV replication, they do not cure the disease. Therefore, therapy is usually lifelong. Treatment is also complicated by the development of drug resistance and side effects. A vaccine against HBV is safe and effective in 90 to 95% of people; however, the individuals who are most at risk of becoming infected are often those with limited access to the vaccine, such as marginalized populations or people living in resource-limited countries.

There is substantial evidence that an individual's likelihood of recovering from an acute HBV infection or developing severe sequelae from infection is influenced, in part, by genes [39–45]. Candidate gene and genome-wide association studies have identified variants associated with HBV-related disease progression or hepatocellular carcinoma in various populations [46–52]. Treatment response to interferon (IFN)-α has been associated in some, but not all, studies with IFNλ3 polymorphisms. Finally, specific gene variants (HLA and non-HLA alleles) have been associated with vaccine response and non-response [54–57].

AMR may be primary or secondary. Primary AMR occurs when the infecting microbe is resistant at the outset and secondary AMR is when resistance develops during treatment, which may occur when people do not finish a full course of antibiotics or when antibiotics are used inappropriately. AMR infections may arise in a surgical wound, at the site of an intravenous cannula, or other skin surfaces which have been breached due to a medical procedure. Resistant infections can also arise in the bowel, urine or the lungs (for example, ventilator associated pneumonia) and are a risk in severely ill patients in intensive care. The impact of hospital acquired AMR is serious for the individual patient and can result in severe medical complications, extended hospital length of stay and death. Hospital acquired infections contribute significantly to avoidable illness and death. In the United States (US) over 2 million people acquire an infection from a hospital each year, with around 70% of these hospital-acquired infections caused by AMR strains. Those who are at highest risk for hospital-acquired AMR infections are those in intensive care units (ICUs), chronic care areas, or nursing homes and those who are immunocompromised. Community-acquired resistance is an increasing problem with examples being urinary tract infections and pneumonia. In its endemic state, these are the manifestations of AMR, which contributes to chronic burden of disease.

A 2014 review paper on AMR estimated up to 50,000 deaths in Europe and the US alone are attributed to AMR, and globally, AMR causes around 700,000 deaths annually – these figures consider AMR bacterial infections, malaria, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and TB. The review also predicts that by the year 2050, AMR will cause around 10 million deaths annually. The reliability of these estimates (i.e. of 10 million deaths by 2050) have been questioned as an imprecise over-estimate which draws on biased sources of data from hospital-based surveillance systems, which do not reflect community burden of disease. Further, the scenarios from which these estimates were generated are unrealistic as they assume a rise in resistance levels for all bacteria, and that the rate of people becoming infected will increase while the mortality risk per infection remains the same. Current evidence suggests these scenarios are unlikely because mortality rates associated with bacterial infections are actually decreasing because of increasing capability to provide appropriate hospital care. Furthermore, the methods used in the 2014 review were not been subject to peer review or scientific scrutiny and the report does not acknowledge levels of uncertainties associated with the estimates. Finally, the global burden of disease study does not feature AMR among its leading causes of death and disability, and shows that since 2008 infections have been overtaken by non-communicable diseases globally as the leading cause of disease burden. Respiratory infections, TB, malaria and HIV are the main infectious diseases in the top 10, and there has been a reduction globally in communicable diseases. Whilst multi-drug resistant TB (MDRTB) is increasing, less than 4% of TB is MDRTB globally, and HIV drug resistance is falling in many countries. Many of the respiratory infections which contribute to global burden of disease occur in countries where access to antimicrobials is uncommon.

AMR may cause acute burden of disease in a population during a pandemic, depending on various factors. These include the ability of the microbe to spread rapidly and cause a pandemic or large epidemic (for example, some common types of pneumonia which may complicate influenza are not transmissible between people); the severity of the disease caused by the microbe; the degree of AMR (partial or complete); and the number of drugs to which resistance is present – multidrug resistant strains have a greater impact. In addition, whether there are alternative drugs to use in place of the ineffective drug and the extent which disease control efforts rely on the use of antimicrobials to mitigate a pandemic will also have an impact.

These factors are influenced by inherent characteristics of the pathogens themselves in addition to external contextual factors. For example, the ability of the microbe to spread is determined by epidemiological parameters including R0, incubation period and transmission rates. The burden of AMR during a pandemic will also vary for different regions – for example, low income regions will likely suffer a higher burden due to poorer health care standards in hospitals, greater crowding, limited access to laboratories, widespread purchasing of antimicrobials without prescription and poor regulatory frameworks for antibiotic use.

Acute viral infections such as influenza also have profound impacts on global health. In contrast to the yearly epidemics caused by seasonal influenza, a pandemic can occur when a new virus emerges in a naive population and is readily transmitted from person to person. The US Centers for Disease Control (CDC) estimates that the H1N1 2009 pandemic resulted in 41 to 84 million infections, 183,000 to 378,000 hospitalizations, and nearly 285,000 deaths worldwide. Although the morbidity and mortality of that pandemic were lower than feared, public health professionals continuously monitor for the emergence of more virulent strains.

As an airborne infection, influenza is transmitted easily and quickly, and its effects can be acute, although there is wide variability in response to infection. Much of the heterogeneity in the severity of seasonal influenza infections has been attributed to the degree of acquired immunity in the population affected, patient co-morbidities and the virulence of the strain. Also, influenza epidemics and pandemics are often caused by the introduction of novel viruses for which most people have limited acquired immunity. The emergence of new strains, and the lack of cross-protection by existing vaccines, does not leave much time for vaccine development. In pandemics, including the H1N1 2009 influenza pandemic, healthy young individuals with no co-morbidities have comprised a significant proportion of fatal and severe cases. These pandemics have provided an opportunity to evaluate the host innate immune response among populations without underlying background immunity.

Research has identified genetic factors associated with severity of illness due to influenza [63–65] and death from severe influenza. Genetic information about immune response to influenza could inform vaccine development and distribution, and disease treatment strategies. Several candidate gene studies suggest that variations in HLA class 1 and other genes contribute to differences in antibody response to influenza vaccines. Ongoing experience with vaccine use has provided opportunities to learn about the potential role of genetics in vaccine safety and efficacy.

However, AMR can complicate an epidemic or pandemic. In the case of a pandemic, where large scale infections would affect the population in a short space of time, AMR could contribute adversely to serious illness and death on a mass scale. The mortality impact of AMR on a pandemic of any infection depends on a series of factors. Whilst there are other contributors, the main determinants are whether or not there is a drug available to treat the infection. If this is zero, then the impact of AMR is zero. It also depends on: the degree of AMR – whether it is partial, or complete; the total mortality caused by the infection; and the proportion of deaths preventable by that drug. These factors together, determine the impact of AMR on a pandemic. The equation can also be modified for morbidity. Many emerging infections (such as Ebola and MERS) have no available drug for treatment, so the impact of AMR is zero. The overall mortality impact of AMR can be summarised by Fig. 2. This equation is adapted from the “risk triangle” concept which is widely used in disaster management, whereby ‘risk’ refers to potential lives lost and is proportionally dependent on three components: hazard, exposure and vulnerability.

Influenza is the most likely cause of a pandemic where AMR would be a factor. Influenza morbidity and mortality can be due to the virus itself or to secondary bacterial infections, therefore AMR can doubly impact an influenza pandemic through both antiviral and antibiotic resistance. Based on data from the 2009 influenza A(H1N1) pandemic, the case fatality rate could be anything from 1 to 20% in the absence of substantial AMR. Bacterial infections can contribute to up to 50% of the total deaths, so if bacterial AMR is a factor, then in the worst case scenario up to 50% of deaths could not be prevented.

According to the website of Haz-map data, biological hazards can be classified into six categories: contact with infected living animals (Table 1); contact with contaminated animal products (Table 2); tick, flea, or mite bite (Table 3); contact with human or animal waste (Table 4); contact with infected patient or blood (Table 5); and raising dust containing pathogens (Table 6). This method of classifying occupational infections is commonly used because it provides a means to link diseases and occupations in the Haz-Map database. We deemed that this type of classification can explain effectively the relationship between biological hazards and occupational diseases, and is the most realistic classification to apply at the workplace.

Although described through the results of this review, the possible biological hazards associated with industries and precautions to protect workers' health are also summarized in Table 7.

Common respiratory virus (CRV) infections are frequent causes of upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI) in HSCT patients. CRV infections can also occur during neutropenia and show significant morbidity and mortality. The epidemiology of CRV infection in HSCT patients is likely to reflect that in the community, with seasonal variations. Influenza and respiratory syncytial virus (RSV) infections usually occur in winter, parainfluenza virus (PIV) infections in summer, and rhinovirus throughout the year. In HSCT recipients, CRV infection is not limited to URTIs and is more likely to progress to LRTIs. Respiratory virus multiplex PCR enables rapid diagnosis of CRV infections in clinical practice.

There are little data on CRV infection in HSCT patients in Korea. In a 4-year retrospective study in the authors’ HSCT center from 2007 to 2011, 67 of 1,038 HSCT patients (6.5%) had 71 cases of CRV-LRTI. RSV (43.6%) was the most common pathogen of CRV-LRTI, followed by PIV (26.8%), influenza virus (19.7%), and rhinovirus (9.9%). The overall mortality rate at day 30 after CRV-LRTI was 32.8%, and high-dose steroid usage (> 1 mg/kg/day), severe immunodeficiency, and lymphopenia (absolute lymphocyte count < 200 cells/mm3) were significantly associated with mortality. These findings are similar to the prevalence, mortality rate, and mortality-related risk factors of CRV-LRTI in Europe and the United States.

The average mortality rate of RSV-LRTI is 32% (range, 0% to 70%) in international studies, and the major risk factors for progression to LRTI are lymphopenia, old age, mismatched/unrelated donor, and neutropenia. In cases of PIV-LRTI, the overall mortality rate is 10% to 30%, and high-level corticosteroid exposure, neutropenia, lymphopenia, and early onset after HSCT are the major risk factors for LRTI. The rate of progression of influenza to LRTI is 25% to 28% and the overall mortality rate is 25% to 58%. The risk factors for progression to influenza-LRTI are early onset after HSCT, lymphopenia, old age, neutropenia, and delayed antiviral administration. In cases of rhinovirus, most infections are asymptomatic, less than 10% of patients progress to definite pneumonia, and the mortality rate is < 10%. In addition, human metapneumovirus, adenovirus, coronavirus, and bocavirus can cause URTIs and LRTIs in HSCT patients.

Can all of these disease susceptibility and immune function differences between dogs and cats be explained by their relative genetics? The most important genes regulating immune responsiveness are those of the MHC. Dogs and cats are unusual amongst mamallian species in having this gene complex spread over two chromosomes - a break that occurred before the divergence of these species over 55 million years ago. The cat also appears to lack one of the loci within the MHC class II gene cluster (the DQ gene), the implication of which might be that cats have more restricted possibilities for antigen presentation. We know that inbreeding has led to limited genetic diversity within the different breeds of dog [91–94] and that within breeds there is a high linkage disequilibrium (i.e. non-random association of alleles at different loci on chromosomes) and restricted MHC type. This means that the dog is a particularly valuable model for genetic studies of disease. In contrast, there is much less linkage disequilibrium in cats and feline breeds compared with the dog. Such restricted genetic diversity might help explain the susceptibility of dogs to certain diseases, including potentially, the arthropod-borne infectious diseases.

Work-related accidents involving biological fluids in health care workers (HCWs) are among the most frequent and most serious accidents, which can lead to the development of various diseases. Occupational exposure among these workers, more specifically among nurses, can be attributed to several direct or indirect factors, such as integral and direct care to patients, administering medication and dressing wounds, cleaning and sterilization of surgical materials and diverse instruments, excessive workload, and inappropriate conditions for carrying out the work process.

In Korea, two main groups of biological agents are regarded as occupational hazards: allergenic and/or toxic agents forming bioaerosols, and agents causing zoonoses and other infectious diseases. Bioaerosols occurring in the agricultural work environments comprise bacteria, fungi, high-molecular-weight polymers produced by bacteria (endotoxin) or fungi (β-glucans), and low-molecular-weight secondary metabolites of fungi (mycotoxins and volatile organic compounds). It also includes various particles of plant and animal origins. All these agents can cause allergic and/or immunotoxic occupational diseases of respiratory organs (airways inflammation, rhinitis, toxic pneumonitis, hypersensitivity pneumonitis, and asthma), conjunctivitis, and dermatitis in exposed workers. Very important among zoonotic agents causing occupational diseases are those causing tick-borne diseases. Recently, severe fever with thrombocytopenia syndrome (SFTS) caused by Phlebovirus (SFTS virus) and Tsutsugamushi disease caused by Orientia tsutsugamushi

[8] have become serious social problems. Among other infectious, nonzoonotic agents, bloodborne human hepatitis and immunodeficiency viruses [human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV)] pose the greatest hazard to HCWs. Of interest are also bacteria causing legionellosis in people occupationally exposed to droplet aerosols, mainly from warm water.

Occupational infectious diseases in Korea occur mostly in people associated with industries of construction, forestry, agriculture, sanitation and similar services (i.e., hospital, healthcare services, emergency response, etc.), and food manufacturing. Only a few studies have been conducted on biological factors at work. For example, a study reported regarding bacterial concentration and environmental factors in factories using water-soluble metalworking fluids, and another study reported about dominant microorganisms in waste-handling industries. New methods are being tried to identify biological agents and analyze them, but these technologies are still in their early stages.

The disease is caused by Corynebacterium pseudotuberculosis. There are two basic forms of caseous lymphadenitis, that is, internal form and external form. Most of the affected animals manifest both forms of the disease depending on the multiple factors that are age, physiological conditions, environmental factors, and managemental practices. There is obvious nodule formation under the skin as well as enlargement of peripheral lymph nodes in the external form. The affected lymph nodes along with the subcutaneous tissues are enlarged with thick as well as cheesy pus which may rupture outward spontaneously or during the process of shearing or dipping. The internal form of caseous lymphadenitis (CLA) is manifested by vague signs such as weight loss, poor productivity, and decrease in fertility [3, 148, 149]. For the detection of the causative agent, Corynebacterium pseudotuberculosis, in sheep and goats, a double antibody sandwich ELISA has been developed, which has been further modified for improving the sensitivity. The main objective of developing this test is to detect the presence of antibodies against the bacterial exotoxin. It has been found that six proteins with varying molecular mass ranging from 29 to 68 kilo Dalton (kDa) react with sera from both goats and sheep acquiring infection experimentally or naturally. For classification of the sera with inconclusive results, immunoblot analysis has been found to be valuable [100, 101]. Quantification of interferon gamma (IFN-γ) is essential for accurate diagnosis of the disease for which an ovine IFN-γ ELISA has been developed. The sensitivity of the assay is slightly more for sheep than in goats while the specificity of the assay is higher for goats than for sheep. It can thus be concluded that IFN-γ is a potential marker in order to determine the status of CLA infection in small ruminants. For the diagnosis of CLA, another novel strategy is the employment of PCR for identification of the bacteria isolated from abscesses. The PCR has been found to be both sensitive and specific in addition to its rapidity of detecting C. pseudotuberculosis from sheep that are naturally infected.

Biological response modifiers (BRM) are substances that interact with and modify the host immune system by acting on a therapeutic target considered important in the pathogenic process of the disease. Monoclonal antibodies (mAbs) are now established as therapies for malignancies, transplant rejection, several immune disorders from most organ systems, and even infectious diseases (54). Safety problems related to immunomodulation and infection have been identified in some cases (55). The use of mAb indirectly provides insights into the function of the molecule to combat particular pathogens, increasing our knowledge of the immune system (56). A recent consensus document has reviewed the groups of drugs according to the targeted site of action, the expected impact on susceptibility to infection, the evidence of risk, and the recommendation of prevention strategies. It is also important to mention the influence of previous or concomitant therapies, underlying conditions, and the accumulative exposure to the agent (44). As regards lower RTI, treatment with BRM results in an increased risk is reported for pneumonia, influenza-related complications, TB and NTM, Pneumocystis, and fungal infections, such as histoplasmosis, taking into account the impact of geographical variations on incidence rates (57). The knowledge obtained from experience with the prescription of BRM may be particularly valuable for the understanding of some genetic inborn errors, as the type of infections acquired as a side effect may help to identify which genetic defects favors a similar infectious phenotype. With the current knowledge and because of pleiotropic effects, it is not feasible to show how biological agents actually mimic some inborn errors of immunity, but several parallelisms can be inferred. We provide a Table containing the list of BRM according to their functional classification, and inborn errors categorized according to common infectious phenotypes (Table 1). Data presented are extracted from the respective consensus documents, and lists the main RTI and preventive recommendations.

Current recommendations should be focused on rheumatic diseases because of the greater experience in follow-up time (more than 15 years) and number of patients treated. Biological therapies targeting TNF-α, T cells, B cells, and various cytokines (including IL-6 and IL-1) have become essential for the treatment of rheumatic diseases [mainly rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis], as well as other immune-mediated diseases. Moreover, additional drugs with novel targets, including those that inhibit IL-12–IL-23, IL-17α, or the Janus activating kinase system have been introduced more recently. Immunomodulation offered by biological and non-biological disease-modifying therapies and prednisone contributes greatly to the increased risks of opportunistic infections (OI) (58, 59). In Figure 1 we present the sites of action and associated risks of the most frequently prescribed BRM.

Two recent meta-analysis have calculated the relative risk of infection for rheumatic patients under biological treatment, with an odds ratio (OR) of 1.31–1.41 (60, 61). The absolute increase in the number of serious infections per 1,000 patients treated/year is six times higher than that observed with synthetic disease-modifying anti-rheumatic drugs (DMARDs). Different meta-analyses and national registries have confirmed the increase on the impact of any infections (20%), serious infections (40%), and TB (250%), associated with anti-TNF-α use (60). In addition, the risk of serious infections is highest during the first 6 months of therapy (62) (up to 4.5-fold risk), although, after 1 year this risk is no different from conventional DMARDs. Recurrent infections in RA are common. In a prospective observational cohort study, the baseline annual rate of a first serious infection was 4.6%. Additionally, 14% of this cohort experienced a recurrent episode/year during their follow-up, with the highest risk being within the first year (29%), and with respiratory infections being the most common (44% of all episodes) (63). Factors that have shown to be predictive of infection include, age, functional status, specific comorbidities (chronic renal/lung disease), corticosteroid treatment, number of previous DMARD, treatment failures, previous serious infections, and current treatment with anti-TNF-α inhibitors or non-biological DMARDs (64). Nevertheless, recent data suggest that patients having a serious infection and exposed to biological treatment have a significantly lower risk of sepsis and fatal outcome than patients treated with conventional DMARDs (62, 65). British and French national biological registries have reported OI rates of 200–270/100,000 in patients using anti-TNF-α therapies (66, 67). In particular, there is evidence of an increased risk of M. tuberculosis, herpes zoster, and Listeria infections. The overall incidence of OI is not significantly different considering drug classes; however, the rate of PJP is significantly higher in those patients using rituximab in comparison to anti-TNF-α therapy. The absolute risk of PJP is low, although corticosteroid exposure is a strong predictor. Current data do not support PJP prophylaxis for all rituximab users. However, it may be appropriate in certain high-risk individuals. Furthermore, rituximab-associated neutropenia and impaired antibody response is also well-described.

Pre-clinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept) is associated with a 2- to 4-fold increase in the risk of active tuberculosis and other granulomatous conditions. Risk seems to be lower for etanercept (68). Risk also depends on local TB prevalence: in the year 2000, Spanish investigators reported an estimated TB incidence of 1,893/100,000 person-years in patients with RA treated with infliximab (69). This rate is ~10- to 20-fold higher than the observed rate in naïve patients. These rates have decreased dramatically since the establishment of latent tuberculosis infection (LTBI) screening prior to biological therapy (67, 70). It is essential to rule out LTBI in such individuals in order to reduce the risk of active TB reactivation. Interferon-gamma release assays (IGRAs) are useful tools for LTBI diagnosis. They are more specific than the tuberculin skin test (TST) because they do not show cross-reactivity with BCG-vaccination or NTM sensitization (71–73). Moreover, these in-vitro assays incorporate a mitogen control that can detect the presence of anergy, common in patients on immunosuppressive therapy (74). However, the clinical performance of IGRAs is still controversial due to the variety of concomitant immunosuppressive drug-regimens used at the time of LTBI screening, population heterogeneity, and the severity of the disease itself (75). Therefore, the clinical accuracy of IGRAs seems to be differentially affected depending on the specific type of immune disorder. Crohn's disease and/or its concomitant drug-profile (such as azathioprine or high-dose corticosteroids) could negatively affect the clinical performance of IGRAs when compared with other immune-mediated diseases, such as psoriasis or inflammatory rheumatic diseases (76). Thus, it seems prudent and convenient to perform dual LTBI testing with TST and IGRAs (77). Patients with RA and underlying structural lung diseases are at increased risk of developing NTM infection (78), mostly Mycobacterium avium. In some countries, NTM infections are more common than TB after anti-TNF-α treatment. However, there are still no established recommendations as regards screening and prophylaxis (79). A baseline chest x-ray should be recommended prior to starting therapy, and in patients with chronic unexplained cough, further work-up should include chest computed tomography scans and culture of respiratory specimens.

Immunization strategies are recommended for all cases, regardless of whether the patient has PID or is receiving immunosuppressive treatment, and it is of importance to be vaccinated according to the national immunization routine schedules. For patients with anti-TNF-α treatment, pneumococcal and age-appropriate anti-viral vaccinations (i.e., influenza) should be administered (68). Immunization before and after BRM is well-established as regards inactivated vaccines, and precautions should be taken for live vaccines (57). However, even if response to vaccines is impaired in patients with PID (80), it may have an effect in patients receiving some BRM. This may be partially explained by the concept of trained immunity-based vaccines (81).

In conclusion, RTIs belong to the most common causes of infections in humans worldwide. The genetic contribution to severe RTIs may have been masked by other interventions (82). The inborn errors of innate immunity show us that the absence of a measurable immunological defect does not exclude an immunodeficiency (41). Further functional genetic studies are necessary in order to fully validate the impact of host genetics during lung infections. The knowledge obtained from experience with the prescription of BRM may be particularly valuable, as the infections acquired as a side effect may help to identify genetic defects with a similar infectious phenotype. In the meantime, recommendations based on biological rationale and clinical experience are mandatory in order to prevent re-emerging severe infections.

Depending upon the involvement of etiological agent, the infectious respiratory diseases of small ruminants can be categorized as follows [9, 14]:bacterial: Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, enzootic pneumonia, and caseous lymphadenitis,viral: PPR, parainfluenza, caprine arthritis encephalitis virus, and bluetongue,fungal: fungal pneumonia,parasitic: nasal myiasis and verminous pneumonia,others: enzootic nasal tumors and ovine pulmonary adenomatosis (Jaagsiekte).

Manytimes due to environmental stress, immunosuppression, and deficient managemental practices, secondary invaders more severely affect the diseased individuals; moreover, mixed infections with multiple aetiology are also common phenomena [5, 8, 13, 15].

These conditions involve respiratory tract as primary target and lesions remain confined to either upper or lower respiratory tract [7, 16]. Thus, these diseases can be grouped as follows [5, 8, 14, 17].Diseases of upper respiratory tract, namely, nasal myiasis and enzootic nasal tumors, mainly remain confined to sinus, nostrils, and nasal cavity. Various tumors like nasal polyps (adenopapillomas), squamous cell carcinomas, adenocarcinomas, lymphosarcomas, and adenomas are common in upper respiratory tracts of sheep and goats. However, the incidence rate is very low and only sporadic cases are reported.Diseases of lower respiratory tract, namely, PPR, parainfluenza, Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, caprine arthritis encephalitis virus, caseous lymphadenitis, verminous pneumonia, and many others which involve lungs and lesions, are observed in alveoli and bronchioles.

Depending upon the severity of the diseases and physical status of the infected animals, high morbidity and mortality can be recorded in animals of all age groups. These diseases alone or in combination with other associated conditions may have acute or chronic onset and are a significant cause of losses to the sheep industry [3, 10]. Thus, the respiratory diseases can also be classified on the basis of onset and duration of disease as mentioned below [3, 9, 14, 18]:acute: bluetongue, PPR, Pasteurellosis, and parainfluenza,chronic: mycoplasmosis, verminous pneumonia, nasal myiasis, and enzootic nasal tumors,progressive: Ovine progressive pneumonia, caprine arthritis encephalitis virus, caseous lymphadenitis, and pulmonary adenomatosis.

FeLV can cause severe clinical syndromes, and progressive FeLV infection is associated with a decrease in life expectancy. Still, many owners still elect to provide therapy for their FeLV-infected cats, and with proper treatment, FeLV-infected cats, especially in indoor-only households, may live for many years with good quality of life. Diseases secondary to immunosuppression account for a large portion of the syndromes seen in FeLV-infected cats, and it is important to realize that many of these secondary diseases are treatable. In most naturally infected cats, FIV does not cause a severe clinical syndrome. Most clinical signs in FIV-infected cats reflect secondary diseases, such as infections and neoplasia, to which FIV-infected cats are more susceptible. With proper care, FIV-infected cats can live many years and, in fact, commonly die at an old age from causes unrelated to their FIV infection. While long-term studies describing clinical outcomes of naturally occurring FeLV and FIV infection are lacking, modalities for treatment of secondary infections or other co-incident diseases are available, and by treating these symptomatically, the life expectancy and quality of life of FeLV- and FIV-infected animals can be significantly improved.

As all T. brucei-infected DBA/1 mice die within approximately 45 days post-CIA induction (30 days post-infection), we decided to treat infected mice with the anti-trypanosomal drug, Berenil, before the onset of death round day 35 post-immunization (day 21 post-infection, see arrow) and assess the development of CIA. It is important to note that the uninfected group also received the Berenil treatment in order to avoid any unspecific effects of this drug. Interestingly, T. brucei clearance from the blood circulation induces the restoration of CIA clinical symptoms. Indeed, starting one week after Berenil treatment, a gradual but drastic enhancement of the mean arthritic score per mouse was observed in the group of mice that were infected (Fig 3A). In agreement with these results, a significant increase in the titers of anti-CII Abs belonging to the IgG2a isotype, one the main isotypes implicated in CIA development, was observed between day 38 and 56 post-CIA induction in the CIA-primed and infected group of mice (Fig 3B).

The usual route of infection in the T. brucei mouse model is the intraperitoneal (i.p.) administration. In order to avoid any biases and to strengthen the physiological impact of our results, we decided to monitor the outcome of CIA in mice following infection using T. brucei-infected tsetse flies. It is important to note that the Berenil treatment was administered two weeks post-infection instead of three as the fly infection is more virulent (personal observation). Like the i.p. infection, the natural route of infection is also able to dampen the development of CIA (Fig 3C), as characterized by a slower development of CIA in these mice. The more rapid increase of the CIA score following the natural route of infection might be due to the fact that Berenil treatment was administered two weeks post-infection (day 28 post-immunization, see arrow) instead of three. By day 47 post-CII priming, the mean arthritic score per mouse of the infected group tended to catch up with the one of the uninfected group as the average of both scores are well above 10. As shown previously, we observed that a physiological infection also mediates a drastic decrease in anti-CII specific IgG2a and IgG2b antibodies (Fig 3D) by day 28 post-immunization (14 days post-infection), which coincided with a delay in the onset of CIA. Following tsetse fly infection, the drug treatment restored anti-CII specific IgG2a and, to some extent, IgG2b antibody titers, which correlates with the drastic increase of the mean arthritic score per mouse.

Surprisingly, 47 days post-CIA induction, we observed a decline in the mean arthritic score per mouse in mice that were “physiologically” infected and treated with Berenil (box Fig 3C). The most obvious explanation was that the drug could not sterilize the host from the parasite. Indeed, we demonstrated a relapse of T. brucei parasites in the blood of treated mice (data not shown). Similar results were observed in one independent experiment following intraperitoneal infection with T. brucei.

Together, these results highly suggest the correlation between the presence of the parasite, the absence of CIA development and the lower titers of anti-CII specific IgG Abs.

A total of 88,956 HALYs (729 per 100,000 population) were estimated to have been lost annually due to the 51 infectious agents and associated syndromes studied; 74,297 (83.5%) years of life were lost due to premature mortality (YLL) and 14,668 (16.5%) were due to YERF (table 1). There was modest correlation between YLL and YERF (Pearson correlation coefficient = 0.56). The ten highest burden pathogens were HCV, S. pneumoniae, Escherichia coli, HPV, HBV, HIV, Staphylococcus aureus, influenza virus, Clostridium difficile, and rhinovirus. YLL exceeded YERF for most pathogens. Nearly 50% of the burden was attributed to five pathogens. The top ten pathogens accounted for approximately 67% of total HALYs and the top 20 pathogens accounted for 75%.

We estimated that these infectious diseases accounted for 5390 deaths (44.2 per 100,000) and 7,196,349 incident cases (58,987 per 100,000) annually in Ontario (table 2). E. coli, S. pneumoniae, HCV, HBV, and C. difficile accounted for the greatest numbers of deaths, while rhinovirus, influenza virus, S. pneumoniae, coronavirus, and E. coli accounted for the greatest number of incident cases.

Among the 20 leading pathogens, the overall burden was comparable between the sexes. However, we observed a number of sex-specific differences (figure 1); HCV, HBV, and HIV had a greater impact on males, while HPV, E. coli, gonorrhea, and chlamydia had a greater impact on females.

The top three selected infectious disease syndromes (pneumonia, septicaemia, and urinary tract infections) accounted for 74% of the total syndrome HALYs lost. Among these syndromes, pneumonia accounted for the greatest proportion of total HALYs (figure 2). For most syndromes, YLL accounted for a greater burden than YERF. The exceptions were acute bronchitis, upper respiratory tract infection, otitis media, pharyngitis, and conjunctivitis.

The ranking of infectious diseases using the GBD methodology was generally similar (Spearman rank correlation coefficient = 0.88), but the GBD methodology indicated a greater proportion of the burden attributable to premature morbidity (51.2%) versus mortality (48.8%; table 3).

Of 4,128 patients who were screened in the FRIDU, 114 patients were admitted to the resuscitation area due to clinical instability during FRIDU screening; three of these patients died in the ED. One of the 3 underwent cardiac arrest in the FRIDU and was moved to the resuscitation zone in the ED while cardiopulmonary resuscitation was performed. Twenty-nine of the 114 patients were discharged or referred elsewhere in the resuscitation area (Fig. 1) and were excluded from the analysis due to limited clinical and laboratory data. The 85 hospitalized patients who deteriorated during FRIDU screening are described in Table 5.

Of the 85 patients, 17 (20%) had contagious diseases and 37 (44%) were male. Most patients had fever (n = 64, 75%) and/or dyspnea (n = 66, 78%). Twenty-seven patients (32%) had septic shock, 33 (38%) had respiratory failure, 10 (12%) had heart failure, and 15 (18%) had an illness with an unknown cause.

Numerous pathogenic infections can potentially impact the outcome of ADs. Until recently, the majority of them were shown to promote autoimmunity, whereas a minority of infections demonstrated a protective function. In this study, we demonstrated that infection of DBA/1 prone mice with African trypanosome parasites substantially delayed the onset of a B cell-mediated autoimmune disease, namely CIA, and, therefore also plays a beneficial role. This observation is in agreement with more general and recent epidemiological data that demonstrated a reversed relationship between the incidence of parasitic diseases and autoimmunity in both the developing and the industrialized world.

One of the most studied case scenario is the inverted correlation between the distribution of auto-immune disorders and the incidence of the helminth infection worldwide. This observation has even lead researchers to the helminthic therapy concept, which is based on the deliberate infestation of a helminth or the helminth eggs in order to treat auto-immune and other inflammatory disorders. Briefly, the immune response developed against the parasitic worm infection, mainly a Th2-skewed response, could counteract the immuno-pathological reactions, usually referred as Th1-polarised response, driving autoimmune diseases. For example, the CIA model we used in this study is induced in mice or rats after immunization of CII emulsified in CFA, which is known to polarize the cellular and humoral responses towards Th1 and the production of CII-specific IgG2a and IgG2b Abs. However, in this case, the T. brucei parasitic infection also drives a Th1-mediated response in mice. Therefore the substantial impact of T. brucei infection on the onset of CIA cannot be attributed to the occurrence of a counter-neutralizing Th immune response as it is the case in helminth infection. However, in C57BL/6 mice, the “early” presence of interferon-gamma protects against the development of CIA through the suppression of Interleukin(IL)-17. Previous results by our group have put forward the impact of different African trypanosome strains on various immature and mature B cells subsets [14, 17]. In addition, we demonstrated that a T. brucei infection was able to abolish the memory or ongoing responses against unrelated antigens, such as the acellular pertussis vaccines [14, 22]. The major detrimental actors in the CIA model are the arthritogenic anti-CII specific Abs. Interestingly, we observed that the absence of RA symptoms positively correlates with a drastic decrease of CII specific Ab titers of the IgG2a and IgG2b isotypes, the main isotypes implicated in the disease. In 2000, a study by Mattsson et al. showed that rats infected with T. brucei on the same day they were vaccinated with CII antigen in adjuvant, significantly exhibited a delayed onset associated with decreased titers of anti-CII IgG but without affecting T cell-mediated DTH response to CII. However, postponing the infection by only a week abolishes this onset difference. These results contrast with our observation revealing a conserved shift in the appearance of the clinical symptoms of CIA even when the mice are infected two weeks post-vaccination. As T. brucei-infected DBA/1 mice succumbed from the infection within thirty days post-infection, we were not able to assess the evolution of the clinical scores beyond forty-five days post-vaccination. However, using a trypanocidal drug Berenil, we could follow the evolution of the clinical symptoms. Interestingly, we found that Berenil treatment restored the clinical signs of RA in mice that were previously vaccinated and infected. This re-emergence correlated with an increase of CII specific Ab titers of the IgG2a and IgG2b isotypes.

Most importantly, a more physiological infection approach using T. brucei-parasitized tsetse flies gave exactly the same phenotype characterized by a drastic delay in the onset of CIA, which is associated to a substantial impairment of anti-CII Ab levels of the different isotypes. However, Berenil treatment noticeably restores these titers. The decrease incidence of RA signs starting after day 45, which is associated to the reemergence of T. brucei parasites in the blood, suggest that Trypanosomes could alleviate the clinical outcome most likely via its impact on B cells. These observations again contrast with previous results done in rats showing only a clear improvement of CIA onset when T. brucei is administered the day of immunization with CII in complete Freund’s adjuvant. Other uninfectious procedures, e.g. the administration soluble CII within the eye’s anterior chamber of a mouse prior the immunization with CII emulsified in adjuvant, were shown to dampen, not the B cell response, but the T cell-mediated DTH response to CII via the induction of regulatory macrophages and CD8+ T cells [24, 25].

The CIA mouse model used in this study shares many clinical symptoms with RA in humans. Surprisingly and most interestingly, old epidemiological data have shown a lower incidence of RA in some Human African trypanosome-endemic countries of the African continent, e.g. Democratic Republic of Congo and Nigeria, compared to the one observed in some European countries at the same time. With the recent development of molecular techniques, it will be really meaningful to confirm these results starting a new epidemiological study focusing on this particular theme. If the conclusions of these previous data are confirmed, understanding the molecular mechanisms used by the Trypanosomes to dampen B cell responses might lead to the development of new therapeutics against B cell-mediated AD as well as other diseases.

EBV reactivation can occur 3 to 6 months after transplantation, typically in patients with chronic GVHD. However, progression to disease is relatively rare. Fever and neutropenia may occur as a result of EBV symptoms, which are similar to those of infectious mononucleosis. Most EBV reactivations are subclinical and require no therapy. In addition, aplastic anemia, oral hairy leukoplakia, and post-transplant lymphoproliferative disease (PTLD) can occur. PTLD occurs less frequently after HSCT than after transplantation of other solid organs. EBV-related PTLD occurs in cases of unrelated donor transplantation, T-cell-depleted transplantation, GVHD, and use of an anti-lymphocyte antibody to prevent GVHD. The diagnosis of EBV-associated PTLD can be established by tissue biopsy for histopathology and detection of EBV. Among other herpesviruses, human herpes virus 6 (HHV6) may be responsible for meningitis and hemorrhagic cystitis.

Background

The HIV epidemic in Romania is increasingly driven in the last years by intravenous drug users (IDUs) and men having sex with men (MSM). This study compared sex and injection risk behaviors among male and female IDUs admitted in MMT in our center.

Methods

From July 2015 through June 2016, all new patients admitted in MMT (136) were asked to complete a questionnaire regarding HIV risk behaviors and were then tested for HIV, HCV and HBV.

Results

24 % of the sample were female and were more likely to be in a stable relationship 49 %, than men 34 %. There were no significant differences between the ages of females vs. males, with the average age being about 34.5 years old. Males reported more daily median injecting than females in the 30 days prior to entering treatment (5 vs. 3) and also report having more STD (38 % vs. 31 %). Females had higher HIV-positive serology results than males (36 % vs. 31 %). On HIV risk, females reported using a common container (55 % vs. 46 %) more frequently. Although male participants reported more sex with multiple partners (23 % vs. 17 %), females reported significantly more sex without a condom (63 % vs. 47 %) and more sex with an IDU partner (65 % vs. 42 %).

Conclusions

There is a high risk behavior and HIV prevalence among IDUs. Thus there is a need for rapid introduction of interventions to address this problem.

Although dogs and cats largely share equivalent immune systems, there are clear differences between the species as to how the elements of the immune system interact – creating species diversity in susceptibility to, and clinicopathological expression of, immune-mediated, neoplastic and infectious diseases. No simple immunological model can summarize these differences in immune function, but immunity might be regulated by distinct genetic backgrounds and potentially by differences in the intestinal microbiome in dogs and cats. If cats are really less susceptible than dogs to arthropod-borne infectious diseases, it remains possible that such resistance relates to differential immune function. However, there are still much simpler explanations that might account for the species difference in occurrence of vector-borne diseases and much work is still required to characterize more accurately the true prevalence and clinical significance of these infections in the cat.

In the 1950s and 1960s, there was optimism that, with vaccination and antibiotics freely available, conquest of most infections would follow. During the last four decades, this opinion has been reversed. Infectious disease continues to exert a heavy burden on health and prosperity. The various infectious disease issues are most often considered in isolation, but when viewed together, they represent a powerful argument for renewed emphasis on hygiene, which alongside vaccination strategies remain key to containing infectious disease.10

During the 1980s, there was a rapid increase in reported cases of food poisoning in the United Kingdom, particularly related to Salmonella and Campylobacter.11 Although reported cases have somewhat declined, food, waterborne, and non-food-related infectious intestinal diseases (IIDs) remain at unacceptable levels. The latest study of IID (food and non-foodborne IID) reported that the true incidence in the community is 43% higher than in the mid-1990s: this study estimated 17 million cases a year in the United Kingdom.12 The estimated cost of food-related IID is £1.5 billion a year, including resource and welfare losses.12 Norovirus, mainly spread from person-to-person, is the most significant cause of intestinal infections in the developed world, including 3 million cases per year in the United Kingdom.12

Evidence shows that respiratory hygiene involving hands and surfaces can limit spread of respiratory infections, particularly colds, and also influenza.13–15 Since respiratory and intestinal viral infections are not treatable by antibiotics, prevention through hygiene is key.

In developed countries, about 7% of inpatients acquire an infection in hospital.16 Recent figures show a decline in health-care-associated infection (HCAI), in the United Kingdom, particularly of Clostridium difficile and MRSA (methicillin-resistant Staphylococcus aureus),17,18 while other causes of HCAI have emerged, including new epidemic strains of Escherichia coli, Pseudomonas spp. and viruses.

Governments, looking at prevention as a means to reduce health spending, have introduced shorter hospital stays and increased homecare. This requires new policies to prevent HCAIs in community settings19 where there is no evidence of a decline. Until recently, most episodes of C. difficile infection were believed to result from acquisition in health-care settings. There is now increasing evidence of multiple other potential sources, including asymptomatic patients, and sources in the wider environment, such as water, farm animals or pets, and food.20 The contribution of cases acquired from these sources to the overall burden of disease is unclear, particularly with concerns about increased community-associated C. difficile infection.21

Societal changes mean that people with greater susceptibility to infectious disease make up an increasing proportion of the population, up to 20% or more.10 The largest proportion comprises the elderly who have reduced immunity, often exacerbated by other illnesses. It also includes the very young and family members with invasive devices such as catheters and people whose immuno-competence is impaired as a result of chronic and degenerative illness (including HIV/AIDS) or drug therapies such as cancer chemotherapy.

Emerging pathogens and new strains are a significant concern. It is remarkable that norovirus, Campylobacter and Legionella were largely unknown as human pathogens before the 1970s, with others such as E. coli O157 and O104 emerging in subsequent decades. It is now thought likely that we shall identify many more, the latest being Zika virus.22 Agencies worldwide recognise that for threats such as new influenza strains, SARS (severe acute respiratory syndrome) and Ebola, hygiene is a first line of defence during the early critical period before mass measures such as vaccination become available.23 The low infectious dose observed for several of the emerging pathogens, such as E. coli O157:H7 and norovirus, is an additional concern that emphasises the role that hygiene can play in prevention.24,25

Antibiotic resistance is a global priority.26 Hygiene addresses this problem by reducing the need for antibiotic prescribing and reducing ‘silent’ spread of antibiotic resistant strains in the community and hospitals.27 As persistent nasal or bowel carriage of these strains spreads in the healthy population, this increases the risk of infection with resistant strains in both hospitals and the community.27

Infections can act as co-factors in diseases, such as cancer and chronic degenerative diseases. Syndromes such as Guillain–Barré28 and triggering of allergy by viral infections29 add to the burden of hygiene-related infection.

Respiratory diseases after HSCT are mainly caused by CARVs. Other viruses, such as herpesviruses and adenovirus, may also result in respiratory infections. Majority of the patients present with upper respiratory infection, and 18-44% of these patients may progress to lower respiratory infection with mortality of 23-50%. The incidence of respiratory diseases after allo-HSCT ranges from 3.5% to 29%, and the incidence of viral pneumonia is 2.1-14%. Typical clinical manifestations include fever, cough, myalgias. Dyspnea is an important symptom of viral pneumonia. Some of CARVs infections show a pronounced seasonality. For example, RSV and influenza virus reach a peak incidence during the winter and spring. CARVs may also result in epidemic outbreak in the wards. Herpesvirus pneumonia is usually caused by reactivation of latent viruses which occurs in severe immunosuppression such as early period of transplantation and GVHD.

Viral hepatitis is the third cause of hepatic impairment in the recipients of allo-HSCT, and usually occurs in 3–6 months after transplantation. The most frequent pathogens of viral hepatitis are hepatitis B virus (HBV) and hepatitis C virus (HCV). Besides, other viruses such as CMV and HSV may also result in hepatitis. Hepatitis B and C can be caused by either virus reactivation or blood transmission. Since the carriage rates of HBV and HCV vary in different regions, the incidence of viral hepatitis varies. Increasing virus loads in blood is valuable for diagnosis. Of note, the diagnosis of viral hepatitis should be based on exclusion of other transplant complications (e.g., sinusoidal obstruction syndrome [SOS] and GVHD). Attributed to effective prophylaxis and antiviral treatment, the mortality of hepatitis B and C is low.

In the logistic regression analyses we found that age was strongly associated with disease severity (Table 5). In HMPV-infected children, age groups 12–23 months (OR = 3.01, P = 0.067) and ≥24 months (OR = 3.97, P = 0.021) were associated with the highest risk for severe disease, while in the youngest age group (<6 months) RSV-infected children had the highest risk for severe disease (OR = 2.11, P = 0.002). Prematurity was associated with higher risk in both HMPV- (OR = 3.36, P = 0.005) and RSV-infected children (OR = 1.58, P = 0.035). Chronic disease was also an important factor, being significantly associated with higher risk in RSV-infected children (OR = 2.26, P < 0.001) and close to significant in HMPV-infected children (OR = 2.22, P = 0.059). High viral load was associated with higher risk for severe disease in RSV-infected children only (OR = 7.91, P = 0.047) and not in those with HMPV. No significant interactions were present among variables included in the two final models, respectively. Finally, viral co-detection was not associated with increased risk for severe disease, and this factor was not included in the final models for HMPV and RSV. Other factors, not included in the predefined models, such as genotype (HMPV), gender, siblings and day care attendance, were also analyzed with logistic regression, but none of these factors yielded any significant contributions (data not shown).

The present data from our large population-based study collected during a nearly 9-year-long period show that LRTI with HMPV clinically manifests itself independently of the co-detection of other viruses, and does not differ in relation to HMPV genotypes. Furthermore, clinical manifestations and final diagnoses in children with HMPV and RSV LRTI are quite similar. However, the clinical course varies in relation to age, and the age effect differed among single virus HMPV- and RSV-infected children. Lastly, our data confirm that hospitalized children born preterm and children with chronic diseases have an increased risk of developing severe LRTI among HMPV- and RSV-infected.

Using a broad panel of sensitive nucleic-acid based viral tests, we detected more than one virus in 38% of the children with LRTI and HMPV. All patient characteristics, including rates of prematurity and chronic diseases, clinical manifestations and clinical courses were surprisingly equal in those with single HMPV infection and HMPV with viral co-detection. On this basis, and on observations done by others, it seems evident to conclude that viral co-detections in HMPV-infected children usually have no cumulative clinical effects to that of HMPV alone. Our population-based data also clearly shows that HMPV/RSV-coinfection is a rare event, and is usually not associated with increased severity, as has been suggested from smaller studies based on selected groups of children.

We detected a broad spectrum of HMPV genotypes (A2, A2a, A2b, B1 and B2), but no samples were positive for genotype A1. In other studies, genotype A1 has also been the most seldom genotype detected [13–15,17,36]. Our data clearly show that the present HMPV genotype variations do not relate to any particular premorbid condition, and causes infection with quiet similar clinical manifestations and outcomes in children. Consequently, our findings confirm results from previous studies with smaller sample sizes [13–15,36,37]. However, Schuster et al. genotyped 192 HMPV-positive in children <2 years old in Jordan enrolled during three years, and found that HMPV genotype A infection was associated with an increased need for oxygen compared to genotype B infection. In another study, including 68 HMPV-positive hospitalized children <3 years of age enrolled during four winter seasons in Canada by Papenburg et al., infection with HMPV genotype B was associated with either an increased oxygen need, PICU attendance or a hospitalization >5 days. The diverging findings in these two studies compared to our study may be explained by different age of the included children, and because the outcome “severe disease” in the two other studies probably included less ill children than in our study. Furthermore, naturally occurring genotype variations over shorter time intervals may also increase the risk of random findings.

The most prominent factor differing between HMPV and RSV in the present study was the difference in age distributions, which has been observed before. Two-thirds with HMPV infection were 1 to 5 years old and less than one-fifth was <6 months old, and nearly half of RSV-infected children were <6 months old. In addition, we confirmed findings from previous studies that more HMPV-infected children were preterm born and had a chronic disease. On the other hand, HMPV and RSV in many ways caused a quite similar spectrum of LRTI types. Looking at the entire groups of children with HMPV and RSV infections, bronchiolitis was the most common diagnosis in both viruses, although a 50% higher rate was observed in children with RSV. By contrast, HMPV-infected children apparently had pneumonia and otitis media more often. However, these findings were confounded by age. In children <6 months old with a single virus infection, 90% of both viral infections were classified as bronchiolitis, and in children older than 6 months, no significant differences in bronchiolitis and pneumonia rates were found. In previous studies, it has been shown that temperature and CRP may increase to higher levels in children with HMPV infection than in those with RSV, but we could not confirm this after adjusting for age.

We found that disease severity was very similar when we compared the entire groups of children with HMPV and RSV, and others have also previously reported this. However, age was strongly related to disease severity, and the age effect differed among single virus HMPV- and RSV-infected children. First of all, only one-fifth of the hospitalized children with single HMPV infection were younger than 6 months, compared to half of those with RSV. Secondly, HMPV infection was associated with a milder disease than RSV infection among children aged <6 months, as indicated by a less frequent need for oxygen, a shorter hospital stay and a lower severity score. Furthermore, the data provided evidence that in children aged 12–23 months old, HMPV infection may be more severe than RSV infection, with a longer need for oxygen treatment, more children in need of respiratory support, more children admitted to PICU, a longer hospital stay and a higher severity score. A possible explanation for these observations might have been that neonates attain higher concentrations of maternally derived protective antibodies against HMPV, as compared to RSV, during pregnancy and the first six months of life. However, data from a recent clinical study measuring HMPV and RSV antibody concentrations did not confirm this hypothesis. Another explanation might have been that HMPV-infected children more often than children with RSV had a primary and potentially more severe infection among those children aged 12–23 months, but it was not possible for us to assess whether children had a primary or secondary infection. In general, clinical manifestations in children with airway infections are related to the net effect of physical and genetic factors, as well as viral- and immune-mediated reactions in the maturing child, which are strongly correlated to the child’s age. We found that high RSV viral loads, but not high HMPV viral loads, were associated with severe disease. Thus, based on these clinical observations among our population of hospitalized children, it may be tempting to claim that RSV is a more potent virus than HMPV among infants, and that RSV infection more than HMPV is a virally driven disease. Recently, other researchers have published data supporting a similar assumption. In accordance with our findings, Roussy et al. found that HMPV viral loads were not associated with increased disease severity among hospitalized children (inpatients), but hospitalized patients had higher HMPV viral loads than outpatients. It has also been shown by others that LRTI may be associated with higher HMPV viral loads than URTI. For this reason, it seems that HMPV viral loads may relate to disease severity to a certain extent, but not among those with the most severe disease.

Most previous studies on risk factors for severe HMPV infections in children focused on age groups younger than 2–3 years old, high-risk patients or for children admitted to PICU, and disease severity has been defined by the use of various outcome variables. We included a population-based sample consisting of all children aged <16 years who were admitted with acute RTI, although the vast majority were aged <5 years. We used a compound severity score combining several outcome measures. Although this score has not been validated, it fit the routines at our department and rather rigorously defined severe disease, and provided reliable risk factor estimates. We confirmed that independent risk factors for both severe HMPV and RSV infections were the presence of chronic diseases and a history of prematurity. Children aged 12 to 23 months had a three-fold increased risk of developing severe HMPV infection, and those aged ≥24 months had a nearly four-fold increased risk. Among RSV-infected children, infants less than six months had a nearly double risk compared to older children. Having one or more chronic diseases doubled the risk in both virus types, but due to a significant co-variation, our data set could not be used to identify which chronic diseases more precisely increased the risk. Prematurity with a gestational age less than 36 weeks increased the risk of severe HMPV infection three-fold, as shown by others, and severe RSV infection for approximately 50%. However, prophylactic use of palivizumab in high-risk children may have confounded this risk estimation in relation to RSV. Hence, in hospitalized children, our data confirm the findings from other studies that particular age groups, prematurity and the presence of chronic diseases independently increase the risk of developing severe LRTI among children with HMPV infection [2,17,18,29,31–33] and RSV infection [18,24,27–30].

It is a strength of the present study that we prospectively enrolled children of all ages from the same county in Mid-Norway, and to the only existing hospital in this region during a nearly 9-year long period. NPA were taken from the majority of the admitted children, and 81.7% were included in the main study cohort. Moreover, we analyzed all NPA using a broad panel of sensitive virus tests during the entire period, which allowed us to examine viral co-detections thoroughly. Nonetheless, it may be a limitation that bacterial co-detections were not considered, but most children had low or moderately increased CRP values. Furthermore, during the entire study period almost all Norwegian children received conjugated pneumococcal vaccines, which has reduced the incidence of pneumococcal infections. Although this does not completely exclude pneumococcal coinfection, at least HMPV- and RSV-infected children may have been similarly influenced. Diagnostic and work-up biases could have affected our results negatively, since the clinicians were not blinded for the NPA results, and because patients were not treated after a study protocol.

In conclusion, HMPV infections among hospitalized children with LRTI were manifested independently of viral co-detection and HMPV genotypes. HMPV and RSV infections differed clinically to a certain extent, and these differences were mostly related to age. Among single virus-infected children, HMPV-infected aged <6 months had a milder disease and those aged 12–23 months had more severe disease, than children with RSV. A history of prematurity and chronic disease increased the risk of severe LRTI among HMPV- and RSV-infected children.

Once the microbiome has been acquired and evolved during childhood,48 the critical question becomes what factors maintain optimum composition and biodiversity, because loss of biodiversity is strongly associated with disease states, inflammation and decline.76–78

Increasingly, the answer appears to be that the optimal composition of the microbiota is maintained by diet,79 which needs to be diverse, and contain fibre (polysaccharides digested by the microbiota rather than the human host),80 and polyphenols found in plant products.81–83 A diet deficient in fibre can lead to progressive extinctions of important groups of organisms,54 which are cumulative and increasingly difficult to reverse in subsequent generations.42 Polyphenols and also fish oils also appear to modulate the composition of the microbiota.84,85

Citizens of high-income countries have less diverse microbiota than do hunter-gatherers.77–79 Other studies show that the elderly living in the community with healthy diets78 have higher gut microbiota diversity than those in long-stay residential care who have a less diverse diet. Studies in Sweden and Denmark show that reduced gut microbiota diversity in infants is associated with increased risk of allergic disease in childhood.86–88

Introduction of antibiotics in the 1950s and subsequent prescribing trends, show a compelling temporal fit with rising allergies since the 1970s. A 2014 review of evidence from over 50 epidemiological studies shows a reasonably consistent relationship between excessive antibiotic use, particularly in early childhood, and increased risk of allergic disease.89 Evidence showing that exposure to antibiotics during pregnancy increases the risk of allergic disorders in infants90,91 has been further confirmed in recent studies.92,93 Antibiotics, particularly macrolides, have lasting effects on the microbiota of young children and increase risks of asthma.92 This mirrors effects documented in animal models, where early disruption of gut microbiota causes long-term damage to metabolic regulation.94

Disruptions of maternal microbiota diversity by antibiotics or inadequate diet are found to be transmitted to future generations.54