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Rotavirus and norovirus are considered main causes of viral gastroenteritis. Currently, adenovirus and CMV are increasingly recognized as important pathogens of viral gastroenteritis in the recipients of allo-HSCT. Astrovirus-associated gastroenteritis which usually occurs in children is rarely observed in the recipients of allo-HSCT. Few data are available on the incidence of viral gastroenteritis after allo-HSCT. Van Kraaij et al. documented that 19% of HSCT recipients (including allo- and auto-HSCT) developed viral gastroenteritis. Fortunately, the mortality caused by rotavirus and norovirus-related gastroenteritis is rare. The most common clinical manifestation of viral gastroenteritis is diarrhea, followed by vomiting and nausea. Rotavirus and norovirus infections are seasonal with a peak incidence in winter. Most of the patients acquire the viruses from community. The median onset time of adenovirus and CMV gastroenteritis are 60–90 days after transplantation, and usually associated with acute GVHD.
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.
The incidence of viral infections was high in allo-HCT patients while in auto-HCT patients viral infections were episodic. The most frequent viral infection after allo-HCT were CMV, BKV and EBV. Most viral infections occurred within the first 4 months after allo-HCT and over 80% required pharmacotherapy or symptomatic therapy. The median time of treatment of specific viral infection ranged from 7 (for EBV) to 24 days (for CMV). The highest infection-related mortality was observed in case of CMV infection, whereas primary diagnosis did not influence survival from viral infection. The risk factors for viral infections were allo-HCT, acute leukemia, a/cGVHD, MUD/MMUD vs MSD. The risk factor for death from viral infection were CMV-IgG seropositivity in acute lymphoblastic leukemia recipients, MUD/MMUD vs MSD. The incidence of EBV infection requiring pre-emptive treatment with rituximab in allo-HSCT children was 19.3%. In 30.8% of cases of EBV infection, these episodes were preceded by other viral infection treated with antivirals, which did not prevent development of significant EBV-DNA-emia with the need of rituximab treatment in 81.5% of cases. This is clinically proven evidence that antiviral drugs do not prevent EBV reactivation in allo-HCT pediatric patients. Additionally, in 47.7% of these cases GVHD was a risk factor, possibly facilitating development of significant EBV-DNA-emia during antiviral therapy of other infections.
HAdV causes a lytic infection of the mucoepithelial cells of the conjunctiva and cornea as well as a latent infection of lymphoid and adenoid cells.10 Members of Groups B and D HAdV cause both GIT and ocular infections. See Table 1 for the subtypes of Group B and D HAdV.11,12 HAdV type 3, 7, and 21 of Group B can cause keratoconjunctivitis, urinary tract infection, respiratory infection, and GIT infection. Group D HAdV can also cause both ocular and GIT infection. Some group B HAdV subtypes infect the respiratory tract. Group B HAdV including type 3, 7, 14, and 21 have been associated with acute respiratory distress (ARD) outbreaks.2,12 HAdV types that cause ARD are transmitted through aerosolized droplets. It is important to note that both respiratory droplets and the fecal-oral transmission route from individuals with acute adenoviral infection, or even post-infection adenoviral shedding, play an important role in the transmission dynamics of HAdV infections.2,13
Persistent HAdV secretions in the tears may also occur even years following the resolution of acute ocular infection. T cells in tonsillar and adenoid lymphoid tissue serve as reservoirs for harboring HAdV, making it possible to develop latent adenoviral infections.3,13,14 Reactivation of persistent latent adenovirus in the host is likely facilitated through the blockade of types I and II interferon (IFN) response that is required to inhibit expression of the HAdV E1A gene.3
Immunosuppressive steroid therapy can suppress the production of cytokines including TNF-alpha, type I IFN, and type II IFN, as well as depleted T cells and NK cells.3,15,16 This inadvertently reduces the secretion of antiviral cytokines that play a major role in inhibiting viral replication. Inhibition of the IFN response allows for expression of the HAdV E1A gene, which results in reactivation and replication of HAdV DNA in epithelial cell associated with latently infected lymphoid tissue and consequential dissemination of HAdV.3 Thus, immunosuppression could facilitate dissemination of adenovirus into the community since subclinical adenoviral infection of tonsillar and adenoid lymphoid tissue serve as a source of transmitting adenoviruses, particularly in immunocompromised children with no prior exposure and immunity to a particular strain of adenovirus.17 Additionally, asymptomatic passage of adenovirus in the stool of patients with previous adenoviral GIT infection can also occur.3,11
Kosulin et al suggested that latent HAdV infection of the gut lymphoid cell could serve as a source of release of HAdV particles in the community.18 Garnett et al demonstrated the asymptomatic persistence of group C adenovirus in human mucosal T lymphocytes or lymphoid tissue following primary adenoviral infection.17 The stimulation of these adenovirus containing mucosal T-lymphocytes results in reactivation of latent HAdV with consequential leakage of reactivated viruses into intestinal epithelial cells, where adenoviruses undergo replication and subsequent shedding in stool.11,17,19-21 This is indicative of persistent subclinical HAdV infection of the gut-associated lymphoid tissue.20
Immunocompetent individuals are likely to shed less HAdV into their stool, in contrast to those who are immunocompromised, where significant amounts of HAdV are released. Immunocompromised individuals are also more likely to have reactivation of HAdV with productive infection of intestinal epithelial cells and consequential extensive viral dissemination in the community. As such, in the immunocompromised state, reactivation of persistent latent HAdV is an essential cause of HAdV dissemination.18 These resultant, latent adenoviral infections are considered a significant challenge in managing and containing the virus within the community due to persistent adenoviral shedding and its high propensity of spread via hand-to-eye contact by those contaminated with fecal matter.18
Another significant challenge in managing adenoviral infections, particularly in Group D HAdV, is the propensity for this group to cause oculogenital infection. Several published cases have demonstrated that Group D HAdV can be associated with concurrent urethritis and conjunctivitis.22–26 HAdV 19 and 37 specifically have been sequestered from genital tracts of young adults with EKC, indicating the possibility of sexual transmission.25,26 Group D HAdV type 37, for example, has been isolated from sexually active men with adenoviral urethritis.24 Additionally, Liddle et al discussed eight cases of individuals presenting with concurrent conjunctivitis and adenoviral urethritis.23 Avolio et al also presented a case of two male patients with HAdV D37 associated urethritis and conjunctivitis, in which one of the spouses contracted adenoviral conjunctivitis via oculogenital contact. These cases highlight the importance of testing for the presence of adenovirus in clinical specimens collected from both urethral and conjunctival swab in men presenting with conjunctivitis, dysuria, and scant urethral discharge.22
Though molecular iodine has long been established as an effective antiseptic agent, its formidable toxicity upon contact to mucosal surfaces deterred it for use in clinical the clinical setting.30 However, combining iodine with povidone allowed for this antiseptic to be safely and routinely used in the ophthalmic setting, and has even shown promise in the management of EKC affected individuals.
Povidone-iodine (PVI) is a broad-spectrum microbicide solution, which exists in multiple forms that are easily accessible, and a cost-effective disinfectant agent. Since its discovery, it has been routinely utilized in the medical field as an antiseptic agent for laboratory and surgical purposes. Furthermore, it has found much purpose in the ophthalmic setting as an effective disinfecting solution due to its proven toxicity against viruses, bacteria, parasites, fungi, yeasts, molds, and protozoans.31 Diluted forms of PVI are commercially sold as Betadine (Alcon Laboratories, Inc., Fort Worth, TX 76134) in 5% and 10% concentrations and can be further weakened as medical use requires. It is critical to note that, unlike other antiseptics, PVI does not lose antimicrobial activity with decreased available iodine concentration in solution when a diluent is added.30
The mode of action requires the oxidation of pathogen nucleotides, amino acids, and proteins, damaging vital bacterial cellular mechanisms.32 Additionally, in vitro investigation indicates that PVI impedes the host’s inflammatory response to a viral pathogen by affecting both host and pathogen parameters.33 This may give insight into how in-office PVI irrigation may alleviate inflammatory symptoms associated with EKC. Specific pathogen consequences include inhibition of production and release of exotoxins (such as α-hemolysin, phospholipase C, and lipase) and suppression of bacterial enzymes (such as elastase and ß-glucuronidase).32
Host factors involve modulation of antioxidant and free radical activity, inhibition of inflammatory effector cells and mediators (such as TNF-α and ß-galactosidase), inhibiting matrix metalloproteinase production, and enhancing healing signals via activation of T cells and macrophages.32 Globally, PVI characteristics that make it ideal for clinical use include broad antimicrobial spectrum, lack of resistance, ability to penetrate biofilms, low cytotoxicity, suitable tolerability, and overall favorable risk/benefit profile.32 Such versatility, ease of access, and ubiquitous use in antisepsis have been further promoted by biochemical characteristics of the compound. The combination of a synthetic carrier homopolymer (2-pyrrolidnone, 1-ethenyl-), which has no innate germicidal ability, and iodine forms PVI.34 In aqueous form, free iodine is released into solution from the PVI complex, which is what provides the microbicidal activity.32
Studies have shown that PVI exhibits antimicrobial activity proportional to the concentration of free iodine released in any given solution of specified dilution, regardless of PVI concentration.30 In addition to its well-documented antimicrobial activity, a study examining the virucidal efficacy of 0.01%, 0.1%, 1%, and 10% PVI demonstrated that 0.1% solution was actually the most effective against HAdV 3, as it maximized free iodine concentration.30 Specifically, PVI formulations have been proven effective against non-enveloped human viruses including HAdV, although, it has been postulated to be adenoviral type dependent.35,36
PVI has been shown to demonstrate virucidal reductions for ocular HAdV types 3, 4, 5, 7, and 8 at 1–5 mins and types 37, and 64 at 15–60 mins for various concentrations.36 This may indicate that time of exposure, not concentration of PVI, to disinfection is critical and that virucidal activity for PVI at different concentrations may require temporal consideration when evaluating specific virus types. Though PVI has been tested in vitro, in animal models, and clinically for its use in disinfection and wound healing for many decades, the use of a PVI irrigation in-office for EKC remains off-label.32 The theory behind in-office PVI irrigation is to reduce viral load on the ocular surface and to decrease viral shedding. A commonly implemented protocol in clinical practice involves anesthetizing the affected eye(s), then instilling a pre-irrigation NSAID drop, followed by four to five drops of 5% PVI solution. The patient then rolls his or her closed eye(s) for 60 s to maximize exposure (including swabbing of the eyelid margins), followed by lavage of the ocular surface with sterile saline irrigation solution (Figure 1). Finally, a post-irrigation NSAID drop is instilled. Anecdotally, patients may report exasperation of their conjunctivitis symptoms for 12–24 hrs after this procedure; however, the overall risk/benefit consideration regularly tips the decision in favor of preforming PVI irrigation.32
Interestingly, Cheung et al have indicated that multiple types of adenovirus can be involved in a single outbreak and as PVI has proven viricidal activity in multiple ocular types of HAdV, it would be sensible to consider PVI irrigation to decrease colonization of the ocular surface in this disease picture.37 The most powerful tool in limiting the severity of adenoviral conjunctivitis outbreaks includes reduction of viral shedding and limiting contamination of objects, workspaces, and surfaces in public places to avoid horizontal transmission, as mentioned previously in this manuscript.38 Gargling or flushing with PVI has been postulated as an effective measure in disrupting the transmission of respiratory viral spread.39 Hence, PVI irrigation can be a powerful tool to help in the reduction of transmission of adenoviral keratoconjunctivitis.
PVI has also shown value in treatment formulations. A large clinical trial for the use of 1.25% PVI ophthalmic solution in the treatment of pediatric conjunctivitis displayed efficacy in treatment of bacterial, chlamydial, and viral conjunctivitis.40 Interestingly, a clinical trial looking at 0.5% PVI (in combination with artificial tears at pH 4.2 for enhanced tolerability) for the treatment of adenoviral keratoconjunctivitis found faster recovery from disease at two weeks, with three drops administered thrice daily.34
In view of the serial interval of 24 days, we assume the following values for the progression rates: latent period (1/σ) = 7 days, occult infectious period (1/γ1) = 14, symptomatic infectious period (1/γ2) = 7days. The analysis results are listed in Table 3. It shows that the turning point occurs at day 76 since 10 March 2011 (with 95% confidence interval ranging from day 67 to day 89). The effect of countermeasures on contact rate is ω = 0.067 [0.002,0.431]. The basic reproductive number before effective countermeasures is R0 = 2.69 [1.90,3.92] and under countermeasures it reduces to Rc = 0.186 [0.006,0.969]. The initial number of occult infections on 10 March 2011 is about 7 with 95% confidence interval ranging from 1 to 32. The proportion of symptomatic cases among infections is ρ = 0.085 [0.053, 0.134]. This implies that at the end of the outbreak, there are about 344 asymptomatically infected pupils along with 32 symptomatic cases.
In the above statistical estimation of R0, we implicitly assume that all infections are symptomatic. To see whether the ignorance of asymptomatic infections affects the estimation of R0, we consider in transmission dynamics model a special situation where all infections are assumed to be symptomatic (Table 3). Although the estimate of R0 decreases under the presumed situation, its mean surely stays within the 95% confidence interval of the true epidemics. To see how the results depend on the assumption of life history stage durations, three other different combinations of three durations were examined (Table 4). The estimates of R0 are not very sensitivity to the variation in three durations given the same serial interval. It is worth mentioning that the dispersion of the negative binomial likelihood in Eq (11) is very close to the unit for all the above different situations. This justifies Poisson likelihood used in Renewal equation method.
Human immunodeficiency virus (HIV) belong to family Retroviridae, genus Lentivirus, species Human immunodeficiency virus. HIV infection has been a major global health problem for almost three decades. With the introduction of highly active antiretroviral therapy (HAART) in 1996, and the advent of effective prophylaxis and management of opportunistic infections, AIDS mortality has decreased markedly. In developed countries, this once fatal infection is now being treated as a chronic condition. As a result, rate of morbidity and mortality from other medical conditions leading to end-stage liver, kidney, and heart disease is steadily increasing in individuals with HIV. Renal diseases directly related to HIV infection include HIV-associated nephropathy (HIVAN), immune complex diseases, and thrombotic microangiopathy. Although the widespread use of HAART has decreased the incidence of HIV-related renal disease, the overall prevalence of renal disease continues to increase among patients with HIV. The most aggressive HIV-related renal disease is HIVAN, which occurs in approximately 10% of patients with HIV. These patients can progress to end-stage renal disease (ESRD) within weeks to months.
Recent studies confirm that outcome of renal transplantation in adequately selected HIV-infected patients receiving kidneys from HIV-negative donors is similar to that of HIV-negative RT recipients. Main challenges in the clinical management of HIV-infected RT recipients are the pharmacologic interactions between immunosuppressive agents and some classes of antiretroviral drugs and a higher rate of acute rejection in comparison with HIV-negative RT recipients. Currently, organ transplantation from HIV-infected donors is an absolute contraindication in Western countries but its potential utility is under consideration Recently, Muller et al. reported the outcome of four HIV-infected RT recipients who received their grafts from two HIV-infected donors in South Africa, being the first clinical experience published involving this type of transplants. After 12 months of followup, all recipients had a functioning renal allograft with a good renal function, and HIV infection was controlled under different antiretroviral regimens. South Africa is a country with a high HIV prevalence in the general population, and HIV infection is an absolute exclusion criterion for access to dialysis or RT. Muller et al. suggested that the use of HIV-infected donors would increase the donor pool, providing renal allografts to HIV-infected patients otherwise sentenced to death as a consequence of end-stage renal disease. Deceased HIV-infected patients represent a potential of approximately 500–600 donors per year for HIV-infected transplant candidates. In the current era of HIV management, a legal ban on the use of these organs seems unwarranted and likely harmful.
HIV-infected patients receiving renal transplants may be at higher risk of acute rejection (up to 25%) and the optimal management of immunosuppression in HIV-infected individuals remains unknown. Treatment of rejection with cytolytic agents such as thymoglobulin may result in prolonged depression of CD4 counts and significant infection-related morbidity. The risks of antilymphocyte therapy should be balanced with the risks for rejection in HIV-infected recipients.
Human herpesvirus 3-Varicella zoster (VZV) belongs to subfamily Alphaherpesvirinae, genus Varicellovirus, species Human herpesvirus 3. VZV causes two distinct clinical diseases following transplantation. Ninety percent of adult solid-organ transplant recipients are VZV seropositive pretransplantation, and thus VZV reactivation in this group will cause herpes zoster. The remaining 10% are VZV seronegative and are thus at risk of primary infection. The incidence of VZV in renal transplant recipients is lower than HSV and is approximately 4 to 12%. VZV causes a spectrum of disease in solid organ transplant recipients, ranging from localized dermatomal zoster (involving a few adjoining dermatomes) to multidermatomal or disseminated zoster with or without visceral involvement. In a cohort of 869 adult solid organ transplants (434 renal transplant recipients), 7.4% of the renal transplant recipients had herpes zoster with a median time to onset of 9 month. The main complications of a VZV infection in this immunosuppressed population were disseminated intravascular coagulation (DIC) and hepatitis in almost half and pneumonitis in 29% of patients. Infections of the allograft and of the CNS as well as pancreatitis were also described. Concomitant bacterial or CMV infections have been reported too.
Unilateral vesicular lesions in a dermatomal pattern are usually sufficiently characteristic of herpes zoster to enable a clinical diagnosis; however, culture of VZV in susceptible cell culture lines, demonstration of multinucleated giant cells on Tzanck smear, and/or direct immunofluorescence is recommended for confirmation. These techniques can also be used for diagnosis in cases of primary infection. Pretransplant screening for previous VZV infection should be performed and naïve patients should be vaccinated with live attenuated varicella vaccine before transplant whenever possible to avoid primary VZV infection after transplantation, an often severe disease with a high mortality rate. However, due to the fact that the VZV vaccine is a live vaccine, the vaccine should not be given it if transplant is expected within four to six weeks to prevent active viral shedding at the time of transplant. A VZV naïve transplant patient who is exposed to someone infected with varicella should receive varicella immune globulin within 96 hours of exposure (if available). If VZIG is not available, or the patient presents greater than 96 hours following exposure, acyclovir may be considered for postexposure prophylaxis. Posttransplant prophylaxis against reactivation of VZV and also HSV is recommended to prevent severe recurrences and consists of ganciclovir in patients needing CMV prophylaxis. Those patients who do not require CMV prophylaxis can receive valacyclovir or acyclovir for approximately one to three months posttransplant. After transplantation, most authorities defer vaccination with live vaccines; killed vaccine appears to be beneficial [67, 68]. VZ-immunoglobulin is recommended for immunocompromised individuals with exposures to varicella or zoster; protection is incomplete.
Sub-Saharan Africa has the highest burden of malaria, with more than 90% of malaria cases and deaths, primarily in children aged less than 5 years. The benefit of routine post-arrival screening for malaria in asymptomatic cases is unclear and not recommended given the limited sensitivity of diagnostic tests, such as blood films and rapid antigen tests.
U.S.-bound refugee children from sub-Saharan Africa that are endemic for Plasmodium falciparum malaria would have received pre-departure presumptive treatment with artesunate combination therapy unless contraindicated in certain specific groups (e.g., pregnant or lactating women, children with body weight less than 5 kg at time of departure). U.S.-bound refugee children from a malaria-endemic country or from sub-Saharan Africa who present with a febrile illness should be promptly evaluated to exclude malaria.
Other infectious diseases, especially of the skin, such as impetigo, candidiasis, tinea, scabies, and pediculosis are frequently diagnosed in refugee and internationally adopted children and adolescents, reflecting unhygienic living situations, overcrowding, and social marginalization. Outbreaks of vaccine-preventable diseases (e.g., measles), and gastrointestinal and cutaneous infections have been reported in the early settlement period. Health care workers must be aware of the clinical presentations of other tropical infectious diseases prevalent in the refugee country of origin, such as typhoid fever, Zika, cysticercosis, echinococcosis, leprosy, cutaneous diphtheria, chronic helminthiasis, and louse-borne relapsing fever.
The Bayesian estimates of parameters of general growth model were based on the priors: U(0.002,0.3), U(0,1) and U(0,10) for growth rate, deceleration exponent and the number of initial accumulative cases, respectively. The model fitting is shown in Fig 3. The deceleration exponent p is estimated to have a median 0.992 and 95% confidence interval: [0.954,1.0] and it therefore is very close to the unit. This indicates that the exponential growth model is a good approximate to the increase of accumulative incidence in HAV cases. The growth rate has a median 0.0358 and 95% confidence interval ranging from 0.0339 to 0.0379. Assume the serial interval is equal to the direct estimate from observed infector-infectee pairs, 23.9 days, R0 from Eq (7) is estimated to have a mean 2.35 and 95% confidence interval [2.24,2.48].
The primary causes of morbidity and non-relapse mortality following HCT are acute and chronic GVHD, organ dysfunction and infection.15 Changes in the transplantation procedure and the implementation of effective supportive care strategies have decreased the incidence of infectious complications early after conditioning therapy for allo-HCT, but have also prolonged the risks beyond day +100.6 These late infections might be caused by all types of microorganisms; however, the risks are predictable and surmountable with the use of tailored prevention strategies.6 There are only a few articles focused on viral complications in children after HCT.4,5,16,17 Herein we reported the results of multicenter nationwide study of the epidemiology, risk factors and outcome of viral infections in children and adolescents after HCT over a period of six consecutive years. All patients were treated with the same therapeutic protocols, using comparable principles of supportive therapy.
We shown high incidence of viral infections in allo-HCT patients whereas in auto-HCT patients the incidence was episodic, comparably with other studies.4,5 This disproportion is a result of allogeneic source of stem cells, T-cell depletion or CD34 selection, moderate-to-severe GVHD and use of immunosuppressive drugs (especially steroids) in allo-HCT patients.11
We observed that CMV had the highest incidence from all viral infections. CMV is one of the most difficult infections that occur after allo-HCT.18 The CMV serostatus of the donor and recipient before transplantation significantly influence the incidence of CMV recurrence, whereas the immunosuppressive status of the recipient is the most important factor for CMV infection.10 Monitoring by a sensitive technique such as PCR tests of whole blood allows intervention before development of CMV disease. Pre-emptive therapy can be used as a standalone strategy or combined with antiviral prophylaxis. Recently, letermovir, given as prophylaxis, was shown to reduce the risk of clinically significant CMV infection.18 We have shown that ganciclovir and foscarnet were the most frequently used drugs in our cohort for the therapy of CMV reactivation; accordingly to currently recommended first-line pre-emptive treatment.18 Nevertheless, management of patients with resistant or refractory CMV infection or CMV disease is a challenge. Combination therapy (ganciclovir and foscarnet), cidofovir, leflunomide or artesunate can be considered in patients resistant or refractory to other second-line and third-line antiviral drugs, and immunosuppression should always be reduced, if possible.18
We observed that cumulative incidence of BKV infection was 23.8% with survival rate of 90.7%. Cesaro et al. reported that BKV-related hemorrhagic cystitis occurred in 8–25% of pediatric and 7–54% of adult recipients undergoing allo-HCT.19 Specific anti-BKV prophylaxis is not available and fluoroquinolones are not recommended given the lack of significant effects on BKV replication and hemorrhagic cystitis severity, and the selection of antibiotic resistance.19 In our study cidofovir was the most frequently used drug in the treatment of BKV infection. Cidofovir at a dose of 3–5 mg/kg every 1–2 weeks with probenecid, or 0.5–1.5 mg/kg 1–3 times/week without probenecid, were used by other authors for the treatment of BKV hemorrhagic cystitis, although without strong recommendation on its use in these doses.19
The clinical manifestations of ADV infections in immunocompetent hosts include upper respiratory disease, gastroenteritis or (kerato-)conjunctivitis and are self-limited in most cases, although severe manifestations including encephalitis, myocarditis, and pneumonia have been sporadically observed. In immunocompromised patients, ADV can cause systemic disease and lethal organ damage.20 Prophylactic antiviral therapy with available antiviral drugs is currently not recommended and intravenous cidofovir is currently regarded as a standard of care in cases of ADV disease.20 Children are more frequently affected with ADV than adults (6–28% vs 0–6%, respectively);20 we observed 10.7% incidence of ADV infection with 90.3% survival rate.
A relatively low percentage of infections with CARV origin was observed in our analysis. CARV respiratory tract infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing HCT.12,21 In the late 1990s the frequency of documented respiratory virus infections was 3.5% among allo-HCT and 0.4% among auto-HCT.22 However, in that time period, viral antigen detection by immunofluorescence or enzyme immunoassays were used in diagnostics.22 During the last decade, rapid and highly sensitive molecular tests have been developed and made available, with the most recent multiplex PCR platform that can detect multiple viral pathogens.21 Choi et al. reported in allo-HCT children the incidence 28.1% of RhV infection, 25.8% RSV, 18% HPIV, 1.1% hMPV; yet more than half of the infections were acquired during hospitalization.17 In the case of CARV infections, ribavirin and intravenous immunoglobulin are recommended in hMPV, HPIV and RSV infections, while there is insufficient evidence for the specific recommendation against infections caused by coronavirus and RhV.12
We observed a relatively low (1.2%) rate of influenza A infection, with no cases of influenza B infection, which may be due to environmental prophylaxis (annual vaccination of patients, household contacts, and hospital and prophylactic use of neuraminidase inhibitors during influenza season in some cases). The current guidelines of the 4th European Conference of Infections in Leukemia (ECIL-4) recommend diagnosis based on PCR of material collected from the respiratory tract, especially broncho-alveolar lavage.23 Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza.23
RV and NoV are important pathogens of viral gastroenteritis in children. We observed that cumulative incidence of RV was 5% while NoV was 0.5%, treated only with symptomatic therapy and no deaths were observed. In other studies the incidence of RV infection varied from 2.3% in adult allo-HCT and auto-HCT recipients up to 19.6% in pediatric allo-HCT recipients.24,25 In pediatric HCT, the incidence of NoV-associated gastroenteritis was reported in 12.9% with no NoV-related mortality.26 PCR as well virus antigen detection in stool are commonly used in diagnosis of RV and NoV infection. No specific prophylaxis against RV- and NoV-related gastroenterocolitis is available; however, oral immunoglobulins and nitazoxanide were used in some studies.24,27
In immunocompetent individuals primary EBV infection or reactivation induces usually asymptomatic infection or infectious mononucleosis.28 In immunocompromised patients most EBV reactivations are subclinical and require no therapy.8 However, it may be manifested as encephalitis/myelitis, pneumonia, hepatitis and EBV-associated tumors as PTLD.8,29 After transplantation 14–65% of recipients developed EBV reactivation,28 while the incidence of EBV-PTLD varies from 0.45% to 29%, according to the source of hematopoietic cells, the associated cell manipulation, and the details of immunosuppressive regimens used.30 We observed high incidence of EBV infection (22.7%) in allo-HCT patients, while there were no cases in auto-HCT setting. In 80.3% (143/175) of EBV reactivations rituximab was used and 93.3% of patients survived this infection. We also observed that in almost 1/3 of EBV reactivations, these episodes were preceded by other viral infection treated with antivirals, which did not prevent the development of significant EBV-DNA-emia with the need of rituximab treatment. This is clinically proven evidence that antiviral drugs do not prevent EBV reactivation in allo-HCT pediatric patients. Antiviral agents, such as ganciclovir, are not active against EBV, presumably because of low levels of viral thymidine kinase expression during lytic phase, and a lack of expression during latency.8 Intravenous immunoglobulins also have no impact in PTLD. Neither ganciclovir/foscarnet nor cidofovir therapy/prophylaxis have any impact on the development of EBV-PTLD, so antiviral agents are not recommended.8 Prospective monitoring of EBV-DNA-emia is recommended in patients after allo-HCT, and these patients should be closely monitored for symptoms and/or signs attributable to EBV infection and PTLD.8 The following pre-emptive therapies are recommended after high-risk allo-HCT: rituximab (375 mg/m2/weekly), reduction of immunosuppressive therapy (if possible), donor EBV-specific cytotoxic T-cells (EBV-CTL) infusion (if available).8 Compared with rituximab, adoptive cellular immunotherapy has higher response rate (50–88%) and fewer relapse.28
We found that allo-HCT, acute leukemia, a/cGVHD, MUD/MMUD-HCT were the risk factors for viral infections. CMV donor/recipient serostatus, era of transplantation, MUD-HCT, and cGVHD were found in other studies as risk factors for viral infection.4 We have also found that CMV-IgG seropositivity in ALL recipients, and MUD/MMUD-HCT were the risk factors for deaths from viral infection in children after HCT. This is a unique observation, as there is no study available analyzing this issue.
Caprine herpesvirus 1 (CpHV-1) is an Alphaherpesvirus
[1] responsible for lethal systemic infections in 1- to 2-week-old kids, and for mild to subclinical infections in adult goats,. Clinical manifestations in adult goats involve the respiratory or the reproductive tract depending on the site of virus entry although CpHV-1 infects preferentially the genital mucosa. Following primary genital infection, the virus replicates in the mucosal epithelium and spreads to sacral ganglia to establish latency. Genital CpHV-1 infections are characterized by painful erythematous-oedematous lesions evolving into vesicles and ulcers healing in two weeks; balanoposthitis, vaginitis, infertility or abortion are often observed during primary or recurrent infections. Although the CpHV-1 infection is distributed worldwide and major economical losses occur in Mediterranean countries, no vaccines are commercially available. An ideal vaccine against CpHV-1 should prevent primary infection and replication in the vaginal mucosa and should interfere with the establishment of latency; in fact, reactivation of latent virus and mucosal shedding are responsible for CpHV-1 transmission to other animals in the same flock and to newborns. Interestingly, CpHV-1 shares several biological features with human HSV-2, such as, the tropism for the vaginal epithelium, the type of genital lesions and the establishment of latency in sacral ganglia,,.
Experimental studies in goats have shown that parenteral immunization with inactivated CpHV-1 plus Montanide ISA™ 740 or vaginal immunization with inactivated CpHV-1 plus LTK63, provide partial protection against a vaginal challenge with virulent CpHV-1,. In addition, intranasal vaccination with a live attenuated gE negative Bovine herpesvirus 1 (BoHV-1) vaccine was shown to confer partial cross-reactive protection to goats challenged vaginally with CpHV-1. Collectively, the above studies have suggested that either virus neutralization (VN) activity in serum or CpHV-1-specific vaginal IgA contribute to protection although the precise role played by antibody responses to protection against vaginal CpHV-1 infection needs to be specifically addressed. In addition, the role played by cell-mediated immune responses in controlling CpHV-1 infection and reactivation remains unknown.
The present study was undertaken to determine if the use of a potent adjuvant could augment the immunogenicity and the protective efficacy of an inactivated CpHV-1 vaccine. To this end, goats were subcutaneously immunized with a beta-propiolactone-inactivated CpHV-1 vaccine and MF59™ as adjuvant. The oil-in-water emulsion MF59™ was employed since it is licensed for human use with an influenza vaccine since 1997, it has a large safety database, and it is known to induce both antibody and cell-mediated immune responses in various preclinical models and humans, although it has never been tested for efficacy in ruminants.
The results presented herein provide the first evidence that the addition of the MF59™ adjuvant greatly enhances the immunogenicity and protection afforded by an inactivated CpHV-1 vaccine.
The experiments were approved by the Italian Ministry of Health (Prot. n. 2174/07) and were carried out at the University of Bari according to the National Guide for Care and Use of Experimental Animals.
Data pertaining to the characteristics for each epidemiological cluster is presented in Table 1. Among the 8,648 TB clusters investigated from 2013 to 2016, schools (2,925 clusters, 33.8%), accounted for the highest proportion of outbreaks according to facility type, followed by medical institutions (2,100 clusters, 18.8%), and social welfare facilities (1,624 clusters, 13.2%). In terms of the gender and age of the first index case, the total cluster had a higher proportion of men (4,870 clusters, 56.3%) than women; and the age group of 19–34 years accounted for the highest proportion (2,483 clusters, 28.7%). Regarding the sputum test of the index case, the highest rate of smear positivity was found to be 59.2% (5,188 clusters), while culture positivity was 31.7% (2,740 clusters). On chest radiography, the proportion of cases with cavity-negative TB was the highest at 61.5% (5,320 clusters), followed by cavity-positive cases, at 26.7% (2,306 clusters). The highest duration of symptoms for the index case was 1–3 weeks (3,371 clusters, 39.0%), followed by those with no symptoms (2,551 clusters, 29.5%), and those with symptoms for 4–5 weeks (1,275 clusters, 14.7%). For epidemiological investigation by year, the rate for the year 2015–2016 was 69.0% (2,678 clusters), which was 2.23-fold higher than that of the year 2013–2014.
Table 2 shows the rates of need for treatment, treatment initiation, and treatment completion by type of facility and year group. The total LTBI diagnosis rate for contacts who completed the latent TB test was 15.2% (95% CI, 14.8%–15.6%). Highest LTBI diagnosis rates by type of facility, were noted in correctional institutions (32.5%; 95% CI, 27.8%–37.2%), and by year, in the 2015–2016 group; the diagnosis rate increased with the advancement of years. The rate of need for treatment of contacts who were diagnosed with latent TB was 10.2% (95% CI, 9.9%–10.6%). Correctional institutions showed the highest rate of need for treatment of contacts at 18.9%, followed by the workplace, at 16.8%. By year, the need for treatment of contacts was 12.0% in 2015–2016; this value was approximately 2-fold higher than that in 2013–2014.
The treatment initiation rate of contacts diagnosed with latent TB needing treatment was 69.4% (95% CI, 68.3%–70.5%). By year, the treatment initiation rate of contacts significantly and progressively decreased in recent years, with a decline from 76.3% in 2013 to 64.2% in 2016 (P < 0.001).
The treatment completion rate of contacts who started treatment was 76.6% (95% CI, 75.5%–77.7%). Among facility type, schools showed the highest treatment completion rate at 81.1%, compared with the workplace, at 69.6%. The treatment completion rate of contacts progressively decreased in the recent years.
All participants gave written informed consent and the research was approved by internationally accredited ethics committees including Universidad Peruana Cayetano Heredia (Lima, Peru) and Imperial College London (London, United Kingdom). The study involved adults from 15 years of age. Informed consent was obtained from the next of kin, carers or guardians on the behalf of the young adults involved in the study.
To analyze the patterns of transmission of the EVD infection after a community member in a latent stage has been arrived, stochastic simulation results were obtained by 2,000 trials. In the analysis of simulation results, the total number of patients is the sum of and from the mathematical model.
Figure 2 depicts the changes of numbers of patients as the result from 2,000 trials in SI; more specifically, the number of patients of the 5 randomly selected results, mean of total number of patients from the entire simulation, and the upper bound of 95% confidence interval (CI) of patient number (a percentile of 97.5% of all 2,000 trials), are represented in gray curved lines, red solid lines, and red dashed lines, respectively. The results demonstrated that there can be at the most 3.5 patients within the 95% CI after 25 days the first imported case of a patient, and that the number of patients remains less than 1 on average.
Figure 3 shows the distribution of each simulation result as a box plot, regarding the predicted number of patients and epidemic duration that points to the recovery of the last patients. Table 3 lists the results for each EVD response scenario; total number of patients for C group and HCW group; median and maximum, and minimum values of the CI; maximum number of new cases per day; epidemic duration; and the probability of estimated total cases having greater than or equal to 10, 20, and 30 patients, which is calculated by the ratios of number of trials with those patients numbers, as well as the basic reproductive number before the intervention.
In SI, the median for the total predicted number of patients was calculated as 2 and the maximum number as 11. The probability of having more than or equal to 10 patients was 4.1%, and median epidemic duration was approximately 44 days. It is of interest to note that the results are similar to that of EVD cases in the USA.
In SII with 3-day of diagnosis delay, a total of 5 cases (2 in C and 3 in HCW) are predicted to occur. The maximum number of new patients in a day is predicted to be 2 at day 23 from the first domestic imported case, and the epidemic duration is estimated to be approximately 2 months (58 days). If there is a 6-day of diagnosis delay, a total of 7 patients are expected, and the duration of epidemics would extend to 69 days.
In SIII with 1 case missing, the median number of infected patients becomes 8 (3 in C and 5 in HCW). At the most 3 new patients would be observed per day in the day 24 after the first EVD patient arrives, and the epidemic duration is expected approximately 77 days. Impact of 1 case missing is equal nearly an 8-day diagnosis delay in SII, within around 88 days of epidemic, the median number of infected cases would involve 15 patients (5 in C and 10 in HCW), and it is predicted that at day 24, at the most 5 patients would appear per day. When there are 2 case missing, there is a 75.7% chance that more than 10 new cases would occur.
A delay in the diagnosis of the first EVD patient arrival and secondary cases have resulted in an increase in the number of EVD patients and epidemic duration. If the assumption is made that no diagnosis is confirmed nor the first EVD patient is isolated for 3 days after he or she has been hospitalized (SII: 3 days), it was found that 1 new secondary case in the C and 2 cases from HCWs would additionally occur compared to the numbers from the prompt diagnosis and isolation against the first imported case (SI); The epidemic duration is supposed to increase by 14 days, and the probability of having more than 10 cases is 10.5%, which is 6.4% points higher than that of the prompt diagnosis and isolation scenario against the first domestic case. When there is 6 days of diagnosis delay, 5 more secondary infection cases (2 C and 3 HCW patients) are estimated to occur, and epidemic duration is likely to be 25 days longer, compared to those in the scenario involving early diagnosis and isolation of the first case. The probability of having more than 10 new patients is found to be 21.2%.
In SIII with 1 case missing, it is calculated that additional 2 and 4 new secondary cases in the C and HCWs would be involved compared to SI, respectively. The outbreak duration is increased by 33 days. The probability of involving more than 10 new patients is 32.8%, which is 8 times greater compared with SI, while the probability involving more than 20 patients is shown to be 1.6%. It is predicted that when there are 2 case missing, additional 13 cases with secondary infection would occur, resulting in a total of 15 patients. The results of 2 case missing have shown a much greater scale of epidemic; the probability of having more than 10 patients is more than doubled, and that of having more than 20 patients is 12.68 times higher compared with missing a case until 1 secondary infection patient is found. In particular, when compared to SI, the total number of patients increased from 2 to 15, and the probability of having more than 10.0% of the total predicted patients increased from 4.1% to 75.7%. The simulation results demonstrate that an EVD epidemic can arise when secondary infection occurs because of missed diagnosis of the primary infection case.
In the simulation, most of the increase in total patients in SII and SIII compared with that in SI is from the HCW group, as characteristics of EVD transmission that the risk of infection is shown to be higher for HCWs.
In this study, EVD mathematical model in Korea was built and simulations were performed that predict the scale of new patients and the duration of epidemics, considering the intervention policy similar to that in USA, under the SII and SIII. If EVD outbreak situation similar to the USA case is considered, it is expected that there would be 1 secondary infected HCW. However, if there is a 6-day of diagnosis delay, it was observed that a total of 7 new patients are expected. When there are 2 missing cases, the total number of patients becomes 15 in terms of median number, and within the CI, a maximum number of 35 cases can occur.
There has been no EVD outbreak in Korea, and thus, the parameters of the model were estimated from the Western Africa EVD epidemic. The transmission rate in Korea cannot be the same as that of Sierra Leone where social contact patterns are dissimilar. However, as was observed in 2015 Middle East respiratory syndrome epidemic, which demonstrated that Korea can have higher rate of spread than that of the country of the origin, it cannot be ascertained that the transmission rate would be low in Korea.
Simulation results showed that, it is highly critical that the first infected patient undergo confirmatory diagnosis as soon as possible, followed by promptly activating the intervention policy such as isolation. Therefore, to facilitate prompt identification of patients and to diagnosis, it can be emphasized that it is necessary to construct a contingency system such as monitoring and tracing for infectious diseases, as well as identification of international travel history.
It is estimated by the World Health Organization (WHO) that approximately 36.9 (34.3~41.9) million persons worldwide are infected with human immunodeficiency virus (HIV), which is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS), including 1.7 million in the United States. Influenza A virus can cause acute respiratory infection in humans and animals throughout the world, and has continued to be a significant public health threat, leading to substantial global morbidity and mortality and an average of approximately 23,600 deaths annually in the United States alone.
The impact of influenza virus on HIV infection has not been well investigated. Little is known about influenza virus infection in HIV-positive individual. HIV infection has been shown to be related to worse prognosis of influenza. HIV-infected patients in Canada who also had pandemic 2009 influenza A (H1N1) virus (pH1N1) infection had more severe illness than those who did not have the co-infection, and fatality was higher than for patients who were not co-infected in California (USA). Recent reports indicate that adults with AIDS experience substantially elevated influenza-associated mortality.
Influenza virus infection has been associated with viremia in human and animal models. Viral RNA has been detected in blood in severe human pH1N1 infection. Encapsidated pH1N1 RNA is stable in blood derived matrices and influenza viruses can be transmitted by blood transfusion in ferrets. Normally, influenza A virus infection is confined to the airways where the virus replicates in respiratory epithelial cells. Cumulated reports indicate that influenza viruses can infect and replicate in blood cells, such as dendritic cells, primary monocytes/macrophages, and T cells.
Infection with HIV-1 can result in apoptotic cell death through activation of both death receptor-mediated and Bax/mitochondrial-mediated apoptotic pathways, which cause a progressive depletion of a select group of immune cells namely the CD4+ T helper cells leading to immunodeficiency. While HIV directly and selectively infects CD4+ T cells, the low levels of infected cells in patients is discordant with the rate of CD4+ T cell decline and argues against the role of direct infection in CD4 loss. A viral protein, neuraminidase (NA), derived from the human influenza virus was reported to enhance the level of HIV-1-mediated syncytium formation and HIV-1 replication. However, it is not known whether influenza A virus in blood affects HIV-1 replication, or reactivates HIV-1 replication in HIV-1-infected cells. Here, we showed that pandemic influenza A (H1N1) virus infection increased apoptotic cell death and HIV-1 replication in HIV-1 infected Jurkat cells.
As shown in Table 3, multilevel logistic regression analysis was performed using the diagnosis of latent TB in contacts, need for treatment, treatment initiation, and treatment completion as dependent variables, and the characteristics of the index case and cluster as independent variables; years were considered as a random effect. All indicators showed significant differences depending on year (MOR, 1.133–1.189). Compared to school, the other facilities that the index case belonged to, such as the workplace, showed a significantly higher rate of latent TB diagnosis in contacts (P < 0.001). Correctional institutions had a high risk for latent TB diagnosis (OR, 6.37; 95% CI, 5.92–6.86). By year cluster, LTBI became significantly lower with the progression of years (OR, 0.75; 95% CI, 0.61–0.91). Among contacts, men index cases had a 1.16-fold higher LTBI diagnosis rate than women index cases. Compared to the 70 years or older age group, all other age groups showed a significantly higher LTBI diagnosis rate in contacts; however, there was no apparent pattern (P < 0.001).
When the need for treatment of latent TB was used as a response variable, most variables showed significance similar to that of latent TB diagnosis. When compared by type of facility that index cases belonged to, other facilities showed significantly high ORs for rates of need for treatment of latent TB compared to schools (P < 0.001). In particular, the risk for the need for treatment was the highest in correctional facilities (OR, 4.49; 95% CI, 4.13–4.89; P < 0.001). When OR was examined by year, the rate of need for treatment of contacts with latent TB was significantly lower in the most recent year (OR, 0.82; 95% CI, 0.67–0.99; P < 0.05). Men index cases had a 1.11-fold higher rate of need for treatment of contacts with latent TB compared to women cases; this was significantly higher in all ages of index cases (P < 0.001).
When treatment initiation of latent TB was used as a response variable, most variables were statistically significant. Other facilities except the workplace had significantly higher ORs of treatment initiation rate in contacts (P < 0.01), while the OR of the workplace was significantly lower, at 0.72 (95% CI, 0.654–0.793). By year cluster, the treatment initiation rate in latent TB became significantly lower in the most recent year (OR, 0.65; 95% CI, 0.49–0.87; P < 0.01). Compared to women cases, men index cases had a 1.19-fold higher rate of treatment initiation among contacts with latent TB. By age group, the 13–18 years and 40–49 years groups showed significantly higher rates than the group aged 70 years and above (P < 0.001); the rates in the other age clusters were not significant.
Multilevel logistic regression analysis using treatment completion in latent TB as the response variable, found that all variables except the gender of the index case and sputum test results were significant. When examined by facility type of index cases, all facilities except other facilities demonstrated significantly lower treatment completion rates among contacts (P < 0.01). Unlike other indicators, when OR was examined by year, it showed no significant results.
From 2013 on, EBOV of the type Zaire has caused the largest outbreak to date in West Africa with reported 29,000 disease cases and 11,000 deaths. An untreated acute Ebola infection causes severe illness with a fatality rate of on average 50% (World Health Organization, 2017a). EBOV is a negative-stranded RNA virus that replicates in immune cells, with the ability to persist in immune-privileged sites such as the central nervous system and may thus lead to viral relapse (Jacobs et al., 2016). No specific treatment is currently available, but recently a clinical trial with a newly developed vaccine (rVSV-ZEBOV) has shown to be highly protective against the Ebola disease (Henao-Restrepo et al., 2017).
To capture the Ebola infection dynamics, Nguyen et al. (2015) used the target cell-limited model and compared EBOV to pandemic IAV. EBOV infection time is significantly slower than IAV infection time (9.5 h vs. 30–80 min) (Holder et al., 2011; Pinilla et al., 2012; Nguyen et al., 2015). Furthermore, the viral replication rate has been estimated as ~63 ffu/mL day−1 cell−1, EBOV is hence highly efficient with a virion half-live of ~23 h (c = 1.05 day−1) (Nguyen et al., 2015). Unfortunately, these results are uncertain due to parameter identifiability problems. Nonetheless, the target cell-limited model confirmed the viral growth seen in experimental data, starting at day 3 post infection with a complete target cell depletion at day 6. Madelain et al. (2015) extended the target cell-limited model by an eclipse phase (non-/virus-producing infected cells) and found a half-life for virus-producing infected cells of 6.4 h and a basic reproductive ratio of R0 ~ 9. The authors furthermore studied the antiviral effect in mice treated with Favipiravir, an antiviral drug that blocks the RNA-dependent RNA polymerase in a broad spectrum of RNA viruses (Furuta et al., 2013). By inhibiting the virus production rate p, they found a sharp decrease in viral load that was associated with an increasing drug efficacy of 95, 98.5, and 99.6% at days 2, 3, and 6 after the onset of treatment. Since Favipiravir achieves its maximal efficacy after 3 days, an early treatment initiation is suggested (Madelain et al., 2015). With patient data of survivors and fatalities from the Uganda Ebola disease outbreak in 2000/2001, Martyushev et al. (2016) studied the relationship between virus replication and disease severity. For this purpose, they extended the target cell-limited model by two target cell populations: potential target cells (T2), that are recruited via proinflammatory cytokines (e.g., recruited macrophages, hepatocytes, splenocytes, and endotheliocytes), which become susceptible target cells (T1), that are the primary target for viral replication (e.g., macrophages and dendritic cells). Ebola disease severity is described by a 2 log(10) higher plasma viral load, that is correlated with an extensive recruitment of potential target cells and a 2.2-fold higher basic reproductive ratio; R0 ~ 6 for fatal cases and R0 ~ 2.8 for nonfatal cases. Hence, the higher viral load in fatal cases and a massive infection/hypersecretion of cytokines by active virus-producing replication cells is associated with the potential severity of the Ebola disease (Wauquier et al., 2010; Martyushev et al., 2016). Additionally, antiviral intervention of (i) an antibody-based therapy that affects the de novo infection (k), (ii) a siRNA-based treatment that blocks viral production (p), and (iii) a nucleoside analog-based therapy (e.g., Favipiravir) have been evaluated in mono- and combination therapy. The combination of nucleoside analog-based therapy and siRNA-based turned out to be most efficient if initiated 4 days post symptom onset, while the antibody-based therapy seemed insufficient (Martyushev et al., 2016). The authors then demonstrated that a critical inhibition rate of 80.5% in fatal cases and 58.5% in nonfatal cases is needed to prevent fatal outcomes of the Ebola virus disease.
There are many ways to treat a viral infection. On the one hand, infection can be treated by interfering with the virus itself, such as direct inhibition or killing of the virus, interference of virus adsorption, prevention of virus penetrating cells, and inhibition of virus biosynthesis and release. On the other hand, treatment can boost the antiviral capacity of the host, so that the host has the ability to kill the virus via its own immune system. The effect of antiviral drugs is mainly achieved by interfering with one of the stages in the virus replication cycle. The current antiviral drugs can be divided into the following categories based on their mechanisms of action: Penetration and dehulling inhibitors, DNA polymerase inhibitors, reverse transcriptase inhibitors, protein inhibitors, neuraminidase inhibitors, and broad-spectrum antiviral drugs.
The main therapeutic drugs frequently used in clinical practice are nucleoside analogues represented by ACV, which affects the virus mainly by affecting the DNA replication process. Although ACV is very effective to treat HSV-1 infection, it is likely for the virus to develop into drug-resistant strains with long term use, due to mutations of DNA polymerase or mutational thymidine nucleoside kinase. The mutagenicity of some nucleoside analogues are high, such as ganciclovir, and hence less safe to use. Moreover, HSV vaccine research is mainly aimed at genital herpes. Yet the vaccine is not effective against genital herpes, let alone other HSV infections. Therefore, it is of great significance to develop new anti-HSV-1 drugs with lower toxicity by acting via a different mechanism compared to the nucleoside analogue. The issue of drug resistance should also be tackled; the drugs to be developed should not introduce a selective pressure that induces the virus to evolve into drug resistant strains.
Viruses are small obligate intracellular parasites that are unable to reproduce independent of their host. Outbreaks of infectious viral diseases are a major global health concern, a circumstance that is evident by recent large epidemics of influenza, zika fever, Ebola virus disease, and the Middle East Respiratory Syndrome (MERS). According to the United Nations, the recent zika outbreak caused socio-economic costs of approximately US$7-18 billion in Latin America and the Caribbean from 2015 to 2017 (United Nations, 2017). A recent study estimated the socio-economic costs for symptomatic dengue cases (58.40 million) with US$8.9 billion in 141 countries in 2013 (Shepard et al., 2016). This number is expected to rise further in the coming years. Factors such as climate change and increasing air travel are furthermore increasing the risk of global pandemic infections; examples are recent global influenza outbreaks as much as the emergence of tropical infections such as Dengue Virus infections in previously unaffected regions in the United States and Europe (Mackey et al., 2014). To control this global threat, novel therapeutic and antiviral treatment approaches are urgently needed. To amplify the development of such novel drugs and to optimize treatment strategies, a comprehensive understanding of the viral infection dynamics, their parasitic interaction with their host, as well as host defense strategies against the invader are of major importance. In recent years, targeting viral agents that are essential for the viral replication has proven highly effective (Asselah et al., 2016). However, the emergence of resistance against these direct acting antiviral compounds leads more and more to treatment failure and multi-drug resistant viral strains (Poveda et al., 2014). In order to circumvent drug-resistance, novel antiviral strategies focus on the host by supporting the immune response or targeting host factors required for the viral life cycle. The advantage of these methods are higher barriers for the development of resistance and novel opportunity of broad-spectrum antivirals (Zeisel et al., 2013).
Mathematical modeling has proven to be a powerful tool to study viral pathogenesis and has yielded insights into the intracellular viral infection dynamics, the effect of the immune system, the evaluation of treatment strategies, and the development of drug resistance (Bonhoeffer et al., 1997; Perelson, 2002; Rong and Perelson, 2009; Perelson and Ribeiro, 2013; Boianelli et al., 2015; Perelson and Guedj, 2015; Ciupe and Heffernan, 2017). Modeling can deepen our understanding on different scales: From the molecular scale of intracellular virus-host interactions, extracellular cell-to-cell infection at the population scale, to virus spread within organs or whole organisms (Kumberger et al., 2016). In order to quantitatively study the viral growth at a molecular level and to investigate host requirements and limitations, first intracellular models have been developed for bacteriophages (Buchholtz and Schneider, 1987; Eigen et al., 1991; Endy et al., 1997), Baculovirus (Dee and Shuler, 1997), and Semliki Forest Virus (Dee et al., 1995). By studying cell-to-cell infection, early models for Human Immunodeficiency Virus (HIV) (Ho et al., 1995; Wei et al., 1995; Perelson et al., 1996, 1997; Stafford et al., 2000) provided insights into the pathogenesis, treatment strategies, and virus control by the immune system.
On the population scale, the target cell-limited model (Nowak and Bangham, 1996; Nowak et al., 1996; Bonhoeffer et al., 1997; Perelson, 2002; Wodarz and Nowak, 2002) has been extensively used to investigate the virus-host interaction of HIV, Hepatitis C Virus (HCV), and Influenza A Virus (IAV), which will be explained in this review in more detail. Furthermore, we describe the latest achievements made by modeling the dynamics of Ebola Virus (EBOV), Dengue Virus (DENV), and Zika Virus (ZIKV) that caused the most recent viral outbreaks. In addition, we give an introduction into the target cell-limited model with its extensions and applications to investigate the effects of direct antiviral therapy and immune response and highlight the most important achievements made by viral modeling of the intracellular, extracellular and the integration of both, the multi-scale level.
The unpaired Student’s t test was used for data analyses as indicated, and a value of p < 0.01 was considered very significant (**).
This study revealed the occurrence of FeLV viral RNA and provirus DNA among naturally infected Malaysian cats. Based on the U3LTR-gag sequence, Malaysian FeLV isolates are highly conserved and more closely related to K01803 isolate from UK compared to Taiwanese and other reference isolates. Presence of multiple enhancers some of which have been linked with FeLV induced tumours may contribute to the development of poor prognostic outcome in naturally infected Malaysian cats although this needs further investigation. Overall, this is the first molecular study for evidence of FeLV in Malaysia. We also identified several motifs that have potential implications in FeLV-induced leukemogenesis. Future studies need to explore association between FeLV positive status and occurrence of feline tumour in Malaysian cats. The present findings is useful in designing molecular diagnostics for clinical applications and for improved understanding of FeLV infection outcome and epidemiology.