Risk factors for extended-spectrum β-lactamase positivity in uropathogenic Escherichia coli isolated from community-acquired urinary tract infections

The aim of this prospective cohort study was to determine the risk factors for community-acquired urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-positive Escherichia coli and the distribution of the ESBL enzyme types. Structured forms were filled in for patients diagnosed with community-acquired UTI in four different geographical locations in Turkey. The forms and the isolates were sent to the central laboratory at Baskent University Hospital, Ankara. Antimicrobial susceptibility was determined according to the CLSI criteria. PCR and DNA sequencing were used to characterize the bla_TEM, bla_CTX-M and bla_SHV genes. Multivariate analysis was performed using logistic regression. A total of 510 patients with UTI caused by Gram-negative bacteria were included in this study. ESBLs were detected in 17 of 269 (6.3%) uropathogenic E. coli isolates from uncomplicated UTIs and 34 of 195 (17.4%) E. coli isolates from complicated UTIs (p <0.001). According to multivariate analysis, more than three urinary tract infection episodes in the preceding year (OR 3.8, 95% CI 1.8–8.1, p <0.001), use of a β-lactam antibiotic in the preceding 3 months (OR 4.6, 95% CI 2.0–0.7, p <0.001) and prostatic disease (OR 9.6, 95% CI 2.1–44.8, p 0.004) were found to be associated with ESBL positivity. The percentages of isolates with simultaneous resistance to trimethoprim-sulphamethoxazole, ciprofloxacin and gentamicin were found to be 4.6% in the ESBL-negative group and 39.2% in the ESBL-positive group (p <0.001). Forty-six of 51 ESBL-positive isolates (90.2%) were found to harbour CTX-M-15. Therapeutic alternatives for UTI, particularly in outpatients, are limited. Further clinical studies are needed to guide the clinicians in the management of community-acquired UTIs.     

Household acquisition and transmission of extended-spectrum β-lactamase (ESBL) -producing Enterobacteriaceae after hospital discharge of ESBL-positive index patients

ObjectivesThis study aimed to determine rates and risk factors of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) acquisition and transmission within households after hospital discharge of an ESBL-PE-positive index patient.MethodsTwo-year prospective cohort study in five European cities. Patients colonized with ESBL-producing Escherichia coli (ESBL-Ec) or Klebsiella pneumoniae (ESBL-Kp), and their household contacts were followed up for 4 months after hospital discharge of the index case. At each follow up, participants provided a faecal sample and personal information. ESBL-PE whole-genome sequences were compared using pairwise single nucleotide polymorphism-based analysis.ResultsWe enrolled 71 index patients carrying ESBL-Ec (n = 45), ESBL-Kp (n = 20) or both (n = 6), and 102 household contacts. The incidence of any ESBL-PE acquisition among household members initially free of ESBL-PE was 1.9/100 participant-weeks at risk. Nineteen clonally related household transmissions occurred (case to contact: 13; contact to case: 6), with an overall rate of 1.18 transmissions/100 participant-weeks at risk. Most of the acquisition and transmission events occurred within the first 2 months after discharge. The rate of ESBL-Kp household transmission (1.16/100 participant-weeks) was higher than of ESBL-Ec (0.93/100 participant-weeks), whereas more acquisitions were noted for ESBL-Ec (1.06/100 participant-weeks) compared with ESBL-Kp (0.65/100 participant-weeks). Providing assistance for urinary and faecal excretion to the index case by household members increased the risk of ESBL-PE transmission (adjusted prevalence ratio 4.3; 95% CI 1.3–14.1).ConclusionsESBL-PE cases discharged from the hospital are an important source of ESBL-PE transmission within households. Most acquisition and transmission events occurred during the first 2 months after hospital discharge and were causally related to care activities at home, highlighting the importance of hygiene measures in community settings.Clinical study registrationGerman Clinical Trials Register, DRKS-ID: DRKS00013250.     

Prevalence of the plasmid-mediated quinolone resistance genes, aac(6')-Ib-cr, qepA, and oqxAB in clinical isolates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae in Korea

In this study, we sought to determine the prevalence of the plasmid-mediated quinolone resistance (PMQR) genes aac(6')-Ib-cr, qepA, and oqxAB in extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae clinical isolates in South Korea. In total, 104 isolates (63 E. coli and 41 K. pneumoniae) were collected. We found that 23 of the 63 (36.5%) E. coli and nine of the 41 (22.0%) K. pneumoniae isolates were positive for aac(6')-Ib-cr. No isolate was positive for qepA, while transferable oqxAB was detected only in 10 (24.4%) K. pneumoniae isolates. Among the 32 aac(6')-Ib-cr-positive isolates, 30 (93.8%) were positive for both aac(6')-Ib-cr and bla(CTX-M) (CTX-M-15, -14, and -57). Our results suggest that PMQR determinants are highly prevalent in ESBL-producing E. coli and K. pneumoniae isolates in Korea.     

Cefotaxime for the detection of extended-spectrum β-lactamase or plasmid-mediated AmpC β-lactamase and clinical characteristics of cefotaxime-non-susceptible Escherichia coli and Klebsiella pneumoniae bacteraemia

We investigated the performance of cefotaxime for the detection of extended-spectrum β-lactamase (ESBL) or plasmid-mediated AmpC β-lactamase (pAmpC) and the clinical characteristics of cefotaxime-non-susceptible Escherichia coli or Klebsiella pneumoniae (CTXNS-EK) bacteraemia. All of the consecutive bloodstream isolates between 2005 and 2010 in a Japanese university hospital were characterised using polymerase chain reaction (PCR). Risk factors and outcomes of CTXNS-EK were analysed by multivariate logistic regression analysis. We identified 58 CTXNS-EK (15.6%) from 249 E. coli and 122 K. pneumoniae. Cefotaxime with a minimum inhibitory concentration (MIC) of >1 μg/mL had a sensitivity of 98.3% and a specificity of 99.7% for the detection of ESBL or pAmpC. CTXNS-EK had increased from 4.5% in 2005 to 23% in 2009. Risk factors for CTXNS-EK were previous isolation of multidrug-resistant bacteria, use of oxyimino-cephalosporins or fluoroquinolones, and high Sequential Organ Failure Assessment (SOFA) score. Patients with CTXNS-EK bacteraemia less frequently received appropriate empirical therapy than patients with cefotaxime-susceptible EK bacteraemia (81% vs. 97%, p<0.001) and died within 30 days (21% vs. 5%, p=0.001). Using the current breakpoints of the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST), cefotaxime alone can identify ESBL or pAmpC producers. CTXNS-EK is an important and increasingly prevalent bacteraemia pathogen.     

Large IncHI2-plasmids encode extended-spectrum β-lactamases (ESBLs) in Enterobacter spp. bloodstream isolates,and support ESBL-transfer to Escherichia coli

We investigated the prevalence of extended-spectrum β-lactamases (ESBLs) in Enterobacter spp. bloodstream isolates from 19 hospital laboratories in Norway during 2011. A total of 62/230 (27%) isolates were resistant to third-generation cephalosporins and four (1.7%) were ESBL-positive; blaCTX-M-15 (n = 3) and blaSHV-12 (n = 1). This is comparable to the prevalence of ESBLs in clinical isolates of Escherichia coli and Klebsiella pneumoniae in Norway during the same period. All ESBL-positive isolates were multidrug resistant (MDR) and harboured plasmid-mediated quinolone resistance. Three isolates supported transfer of large IncHI2-plasmids harbouring ESBL- and MDR-encoding genes to E. coli recipients by in vitro conjugation.     

Propensity-matched analysis of the impact of extended-spectrum β-lactamase production on adults with community-onset Escherichia coli,Klebsiella species,and Proteus mirabilis bacteremia

Background

The presence of extended-spectrum β-lactamase (ESBL) in Escherichia coli, Klebsiella species, and Proteus mirabilis (EKP) is of great microbiological and clinical importance. The study dealing with the direct impact of ESBL producers on the outcome of patients with community-onset bacteremia is lacking.

Molecular epidemiology over an 11-year period (2000 to 2010) of extended-spectrum β-lactamase-producing Escherichia coli causing bacteremia in a centralized Canadian region

A study was designed to assess the importance of sequence types among extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates causing bacteremia over an 11-year period (2000 to 2010) in a centralized Canadian region. A total of 197 patients with incident infections were identified; the majority presented with community-onset urosepsis, with a significant increase in the prevalence of ESBL-producing E. coli during the later part of the study. The majority of E. coli isolates produced either CTX-M-15 or CTX-M-14. We identified 7 different major sequence types among 91% of isolates (i.e., the ST10 clonal complex, ST38, ST131, ST315, ST393, ST405, and ST648) and provided insight into their clinical and molecular characteristics. ST38 was the most antimicrobial-susceptible sequence type and predominated during 2000 to 2004 but disappeared after 2008. ST131 was the most antimicrobial-resistant sequence type, and the influx of a single pulsotype of this sequence type was responsible for the significant increase of ESBL-producing E. coli strains since 2007. During 2010, 49/63 (78%) of the ESBL-producing E. coli isolates belonged to ST131, and this sequence type had established itself as a major drug-resistant pathogen in Calgary, Alberta, Canada, posing an important new public health threat within our region. We urgently need well-designed epidemiological and molecular studies to understand the dynamics of transmission, risk factors, and reservoirs for E. coli ST131. This will provide insight into the emergence and spread of this multiresistant sequence type.     

Susceptibility of European Escherichia coli clinical isolates from intra-abdominal infections,extended-spectrum β-lactamase occurrence,resistance distribution,and molecular characterization of ertapenem-resistant isolates (SMART 2008–2009)

A total of 3160 clinical isolates of Escherichia coli from intra-abdominal infections were collected during 2008–2009 from 13 European countries. The frequency of extended-spectrum β-lactamase (ESBL)-producing isolates in Europe was 11%. The most active antibiotics tested were typically imipenem, ertapenem, and amikacin, although the activity of all non-carbapenem antibiotics was lower when tested against ESBL-positive isolates than when tested against ESBL-negative isolates. Ertapenem exhibited 99.3% susceptibility with all isolates, and 96.8% susceptibility with ESBL-positive isolates. With application of the ertapenem CLSI clinical breakpoint for resistance (MIC ≥1 mg/L), only six isolates (0.2%) were ertapenem-resistant, and only three of these were available for molecular characterization. Of those three, only one was ESBL-positive (CTX-M-14), and two were carbapenemase-positive (OXA-48). All three were negative for, VIM, NDM and KPC carbapenemases. Although the level of ertapenem resistance in E. coli is very low, further monitoring of ertapenem susceptibility and molecular characterization of ertapenem-resistant isolates is needed.     

Comparative activity of plazomicin against extended-spectrum cephalosporin-resistant Escherichia coli clinical isolates (2012–2017) in relation to phylogenetic background,sequence type 131 subclones,blaCTX-M genotype,and resistance to comparator agents

Extended-spectrum cephalosporin-resistant Escherichia coli (ESCREC) are a growing threat. Leading ESCREC lineages include sequence type ST131, especially its (bla_CTX-M-15-associated) H30Rx subclone and (bla_CTX-M-27-associated) C1-M27 subset within the H30R1 subclone. The comparative activity against such strains of alternative antimicrobial agents, including the recently developed aminoglycoside plazomicin, is undefined, so was investigated here. We assessed plazomicin and 11 comparators for activity against 216 well-characterized ESCREC isolates (Minnesota, 2012–2017) and then compared broth microdilution MICs with phylogenetic and clonal background, beta-lactamase genotype (bla_CTX-M; group 1 and 9 variants), and co-resistance. Percent susceptible was > 99% for plazomicin, meropenem, imipenem, and tigecycline; 96–98% for amikacin and ertapenem; and ≤ 75% for the remaining comparators. For most comparators, MICs varied significantly in relation to multiple bacterial characteristics, in agent-specific patterns. By contrast, for plazomicin, the only bacterial characteristic significantly associated with MICs was ST131 subclone: plazomicin MICs were lowest among O16 ST131 isolates and highest among ST131-H30R1 C1-M27 subclone isolates. Additionally, plazomicin MICs varied significantly in relation to resistance vs. susceptibility to comparator agents only for amikacin and levofloxacin. For most study agents, antimicrobial activity against ESCREC varied extensively in relation to multiple bacterial characteristics, including clonal background, whereas for plazomicin, it varied only by ST131 subclone (C1-M27 isolates least susceptible, O16 isolates most susceptible). These findings support plazomicin as a reliable alternative for treating ESCREC infections and urge continued attention to the C1-M27 ST131 subclone.

     

Agonistic autoantibodies to the α(1) -adrenergic receptor and the β(2) -adrenergic receptor in Alzheimer's and vascular dementia

Although primary causes of Alzheimer's and vascular dementia are unknown, the importance of preceding vascular lesions is widely accepted. Furthermore, there is strong evidence for the involvement of autoimmune mechanisms. Here, we report the presence of agonistic autoantibodies directed at adrenergic receptors in the circulation of patients with mild to moderate Alzheimer's and vascular dementia. In 59% of these patients, agonistic autoantibodies against the α(1) -adrenergic receptor and the β(2) -adrenergic receptor were identified. The majority of positive patients (66%) contained both types of autoantibodies in combination. In a control group of patients with neurological impairments others than Alzheimer's and vascular dementia, only 17% were found to harbour these autoantibodies. The autoantibodies to the α(1) -adrenergic receptor interacted preferably with the extracellular loop1 of the receptor. They were further studied in IgG preparations from the column regenerate of a patient who underwent immunoadsorption. The α(1) -adrenergic receptor autoantibodies specifically bound to the extracellular loop1 peptide of the receptor with an apparent EC(50) value of 30 nm. They mobilized intracellular calcium in a clonal cell line expressing the human form of the α(1) -adrenergic receptor. Our data support the notion that autoimmune mechanisms play a significant role in the pathogenesis of Alzheimer's and vascular dementia. We suggest that agonistic autoantibodies to the α(1) -adrenergic and the β(2) -adrenergic receptor may contribute to vascular lesions and increased plaque formation.     

Characterization of the Contribution to Virulence of Three Large Plasmids of Avian Pathogenic Escherichia coli χ7122 (O78:K80:H9)

Despite the fact that the presence of multiple large plasmids is a defining feature of extraintestinal pathogenic Escherichia coli (ExPEC), such as avian pathogenic E. coli (APEC), and despite the fact that these bacteria pose a considerable threat to both human and animal health, characterization of these plasmids is still limited. In this study, after successfully curing APEC of its plasmids, we were able to investigate, for the first time, the contribution to virulence of three plasmids, pAPEC-1 (103 kb), pAPEC-2 (90 kb), and pAPEC-3 (60 kb), from APEC strain χ7122 individually as well as in all combinations in the wild-type background. Characterization of the different strains revealed unique features of APEC virulence. In vivo assays showed that curing the three plasmids resulted in severe attenuation of virulence. The presence of different plasmids and combinations of plasmids resulted in strains with different pathotypes and levels of virulence, reflecting the diversity of APEC strains associated with colibacillosis in chickens. Unexpectedly, our results associated the decrease in growth of some strains in some media with the virulence of APEC, and the mechanism was associated with some combinations of plasmids that included pAPEC-1. This study provided new insights into the roles of large plasmids in the virulence, growth, and evolution of APEC by showing for the first time that both the nature of plasmids and combinations of plasmids have an effect on these phenomena. It also provided a plausible explanation for some of the conflicting results related to the virulence of ExPEC strains. This study should help us understand the virulence of other ExPEC strains and design more efficient infection control strategies.Escherichia coli strains are members of the normal intestinal microflora of most mammals and birds. They colonize their primary habitat, the lower intestinal tract of the host, within the first few hours of the host''s life (37, 54). E. coli strains are very versatile organisms, and the environment is considered their secondary habitat; approximately one-half of all living E. coli cells are actually living outside their hosts. Even though most E. coli strains are commensals and their presence provides a benefit to the host, a subset of these bacteria has acquired the ability to cause intestinal and extraintestinal diseases. These bacteria can be distinguished from commensals by their virulence factors (29, 37).Extraintestinal pathogenic E. coli (ExPEC), including avian pathogenic E. coli (APEC), pose a considerable threat to both human and animal health due to potential economic losses stemming from illness (30, 55, 62). ExPECs are responsible for a broad spectrum of infections in humans, including urinary tract infection (UTI), newborn meningitis (NBM), and septicemia. In addition, they are involved in animal diseases, such as avian colibacillosis, one of the most significant and widespread infectious diseases occurring in poultry and the cause of increased mortality, condemnations, and decreased production (3, 16). The most common disease syndromes associated with E. coli in birds are lower-respiratory-tract infections (air sacculitis), cellulites, meningitis, and septicemia (3).The different groups of E. coli have evolved mainly by acquisition of genes via horizontal gene transfer, a common phenomenon in bacteria that occurs even between very distantly related species (12, 45). This mechanism contributes to the evolution of E. coli variants, resulting in the development of novel strains and pathotypes. Conjugative plasmids are known to mediate transfer of genes between bacteria in diverse environments (42, 67). Acquisition of plasmids by bacteria is one of the fastest ways for survival in and adaptation to one or multiple hosts, as plasmids can encode multiple traits, including antibiotic and heavy metal resistance, virulence, and persistence in different environments (21).ExPEC strains (ExPECs) are differentiated from other pathotypes by the presence of specific virulence genes that allow them to spread systemically in hosts (62). ExPECs, particularly APEC isolates, carry multiple large plasmids (13, 32-35) belonging to different incompatibility groups (35), and the most prevalent plasmids in APEC strains (APECs) are the IncFIB, IncFIC, IncFIIA, IncI1, incP, incB/O, and IncN plasmids, some of which encode virulence factors. Additionally, plasmids encoding multiple drug resistance have been isolated from both APEC and uropathogenic E. coli (UPEC) strains. To date, few studies have undertaken sequencing and characterization of plasmids from avian isolates, particularly the ColV and ColBM plasmids from the IncFIB incompatibility group, which are considered common among ExPEC strains (22, 32, 33, 48, 66). Each of these plasmids has a conserved region harboring the FIB replicon, the ColV and/or ColBM operon, several known virulence genes, and iron acquisition and transport operons. According to recent studies the zoonotic risk seems to be related to the presence of large plasmids in APECs (48, 61).A fuller understanding of ExPEC virulence mechanisms is needed to develop treatments and preventative measures for use against ExPEC infections (55). Reductionism has been used for many years as a critical and powerful tool for identification of key genes responsible for microbial pathogenesis. However, the limitations of this approach for understanding the pathogenicity of bacteria include the multifactorial nature of virulence and the complex cross-regulation of gene expression. The ExPECs that cause diseases in humans and animals are very diverse, and although serotype and virulence factors are related to this diversity, the exact molecular mechanism behind the extensive diversity has not been elucidated yet.APEC strain χ7122 (O78:K80:H9) has been used for many years as a model strain to study the molecular mechanisms of APEC pathogenicity. The results of such studies have contributed greatly to increasing our understanding of the virulence of both human and animal ExPECs. This bacterium has three large plasmids, pAPEC-1 (103 kb), pAPEC-2 (90 kb), and pAPEC-3 (60 kb) (48). Most known virulence factors associated with APEC, including iron acquisition systems, tsh, and colicin V, are located on pAPEC-1, whereas the contents of pAPEC-2 and pAPEC-3 are completely unknown.Despite the fact that the presence of multiple large plasmids is a defining feature of the APEC pathotype (13, 32-35), characterization of these plasmids is still very limited. The exact role of many of them, as well the epistatic interactions between them, are unknown. The study of these plasmids has been complicated by their diversity and by the difficulty of curing them from the wild type. The few previous studies dedicated to understanding the role of the large plasmids of APEC in virulence were done in either E. coli K-12 (15, 31, 63) or avian commensal E. coli backgrounds (61, 70), which did not necessarily show the true functions of these plasmids in the wild-type background host strain.A plasmidless strain obtained from a wild-type APEC strain would provide a better background to evaluate the potential virulence of individual plasmids. In this study, after successfully curing APEC of its plasmids, we were able to investigate the contribution to virulence of each of the three large plasmids of APEC χ7122 by generating a plasmidless strain, strains with each plasmid individually, and strains with two plasmids in different combinations. We then determined the genetic locations of different virulence genes and compared the plasmid-containing derivative strains to the wild-type strain in terms of virulence, growth rate, serum resistance, iron uptake, and lipopolysaccharide (LPS) and iron-regulated outer membrane protein (IROMP) profiles. The results of this study provide new insights into the role of large plasmids in virulence, growth, and evolution of APEC by showing for the first time that both the nature of plasmids and combinations of plasmids have an effect on these factors. They also provide a plausible explanation for some conflicting results related to the virulence of ExPECs.     

Increased circulating levels of SDF-1 (CXCL12) in type 2 diabetic patients are correlated to disease state but are unrelated to polymorphism of the SDF-1β gene in the Iranian population

Several environmental and genetic factors are believed to influence the onset of diabetes and its complications. It has also been established that cytokines play a key role in the pathogenesis of type 2 diabetes. Previous studies have revealed that the polymorphism at the stromal-derived factor 1β (SDF-1β) 3′A regulates the expression of SDF-1 (CXCL12). This study was aimed to explore this polymorphism in parallel with SDF-1 serum levels in type 2 diabetic patients. In this assessment, peripheral blood samples were collected from 200 type 2 diabetic patients and 200 healthy controls. DNA was extracted, and a PCR-RFLP screening was applied to examine the SDF-1β 3′A polymorphism. We also applied the ELISA technique to measure serum levels of SDF-1. Our results showed that there were no significant correlations between SDF-1β 3′Α polymorphism in type 2 diabetic patients when compared to controls. However, our results showed that the serum levels of SDF-1 were significantly increased in the patients when compared to controls. Based on the results of this study, we concluded that SDF-1β 3′Α polymorphism does not play a role in the pathogenesis of type 2 diabetes but that elevated serum levels of SDF-1 may be important for the etiology of type 2 diabetes but are unrelated to the SDF-1β 3′Α polymorphism.     

The Changes in the T helper 1 (Th1) and T helper 2 (Th2) Cytokine Balance During HIV-1 Infection are Indicative of an Allergic Response to Viral Proteins that may be Reversed by Th2 Cytokine Inhibitors and Immune Response Modifiers – a Review and Hypothesis

The HIV-1 infection in humans induces an early cellular immune response to react to the viral proteins with a cytotoxic T cell (CTL) response that fails to inhibit virus replication and the spread of the virus. It became evident that the progression of the disease causes chronic changes to the immune system of which a gradual increase in IgE antibodies is one of its features. When the HIV-1 epidemic began, the relation between the gradual increase in IgE content and AIDS was not understood, but later it became a marker for disease prognosis. The advances in the knowledge on T helper 1 (Th1) and T helper 2 (Th2) cells revealed that Th1 cells produce cytokines that stimulate the proliferation of CTLs. Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. Studies on both Th1 and Th2 cytokine synthesis revealed an aberration in HIV-1 infected people. Clerici and Shearer presented a hypothesis (1993) whereby Th1 cell activity declines and Th2 activity increases (the Th1 --> Th2 switch hypothesis) in HIV-1 infected people. In fact, experiments concerning this hypothesis ultimately supported the premise that the switch involves a critical change in the cytokine balance, which leads to the contraction of AIDS. However, the research community must still discern why such a Th1 --> Th2 switch takes place in infected people and how it can be reversed. The present review points to the fact that a similar Th1 --> Th2 switch constitutes the response of allergic people to environmental allergens. HIV-1 patients and allergic people that are exposed to allergens respond with an increased synthesis of Th2 cytokines and IgE, together with a decrease in Th1 cytokines. The studies on allergen-induced Th2 cells revealed that the Th2 cytokine IL-4 induces B cells to synthesize IgE, and cytokine IL-5 is the inducer of eosinophilia, just as in HIV-1 infection. The difference between the HIV-1 infection and allergies is the ability of IL-4 to induce the synthesis in T cells of the HIV-1 coreceptor CXCR4 that selects from the replicating virus a syncytium-inducing (SI) virus, a variant virus that replicates rapidly. The present hypothesis implicates the viral proteins in the induction of Th2 cytokine synthesis. This suggests that in viral proteins, allergen-like domains may be responsible for the activation of Th2 cytokine synthesis. Based on the analogy of the responses of humans to allergens and HIV-1, the following hypotheses is suggested: (a) Removal of allergen-like domains from viral genes by genetic engineering may provide viral proteins for vaccine development. (b) Attempts to treat allergic patients with IL-4 receptor inhibitors suggests that the "Th2 --> Th1 Reversion" constitutes a possible approach to inhibiting the Th2 cytokines and inducing a revival of the anti-viral Th1 response.