Viral infections and inborn errors of immunity.

PURPOSE OF REVIEW: The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper immunoglobulin E (IgE) syndromes, epidermodysplasia verruciformis, and X-linked agammaglobulinemia as examples of inborn errors of immunity associated with specific presentations of viral infection and disease. RECENT FINDINGS: Advances in both genetic and viral diagnostics have broadened our understanding of viral pathogenesis in the setting of immune dysfunction and the variable phenotype of inborn errors of immunity. Dedicator of cytokinesis 8 (DOCK8) deficiency is now recognized as an inborn error of immunity within the hyper IgE syndrome phenotype and is associated with unusually aggressive cutaneous disease caused by herpes simplex and other viruses. Studies of patients with epidermodysplasia verruciformis have proven that rarely detected human papillomavirus subtypes may cause malignancy in the absence of adequate host defenses. Finally, patients with X-linked agammaglobulinemia may remain at risk for severe and chronic viral infections, even as immune globulin supplementation reduces the risk of bacterial infection. SUMMARY: Susceptibility to viral infections in patients with inborn errors of immunity is conferred by specific, molecular defects. Recurrent, severe, or otherwise unusual presentations of viral disease should prompt investigation for an underlying genetic defect.

A Worm's Tale or Why to Avoid the Raccoon Latrine: A Case of Baylisascaris procyonis Meningoencephalitis.

The raccoon roundworm Baylisascaris procyonis (B. procyonis) may infect humans to cause severe or fatal meningoencephalitis, as well as ocular and visceral larva migrans. Young children are at greater risk for cerebral larva migrans with severe meningoencephalitis, and early empiric therapy may improve outcomes. Familiarity with characteristic brain imaging findings may prompt earlier diagnosis, particularly in the setting of CSF eosinophilia. We report a case of a 19-month-old boy who presented with truncal ataxia and was found to have peripheral and CSF eosinophilia. MRI demonstrated symmetric, confluent T2 hyperintense signal in the cerebral and cerebellar deep white mater, which helped differentiate B. procyonis meningoencephalitis from other infectious and non-infectious causes of eosinophilic meningoencephalitis. Early recognition and treatment of B. procyonis meningoencephalitis are important for improved outcomes, and careful review of neuroimaging can play a critical role in suggesting the diagnosis.

SARS-CoV-2 antibody responses in solid organ transplant recipients.

Antibody responses among immunocompromised solid organ transplant recipients (SOT) infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) may be diminished compared to the general population and have not been fully characterized. We conducted a cohort study at our transplant center to investigate the rate of seroconversion for SARS-CoV-2 IgG antibodies among SOT recipients who were diagnosed with Coronavirus disease 2019 (COVID-19) and underwent serum SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) testing. The 61 patients who were included in the final analysis underwent initial SARS-CoV-2 IgG testing at a median of 62 days (Interquartile range 55.0-75.0) from symptom onset. Note that, 51 of 61 patients (83.6%) had positive SARS-CoV-2 IgG results, whereas 10 (16.4%) had negative IgG results. Six (60%) out of 10 seronegative patients underwent serial IgG testing and remained seronegative up to 17 weeks post-diagnosis. Use of belatacept in maintenance immunosuppression was significantly associated with negative IgG antibodies to SARS-CoV-2 both in univariate and multivariate analyses (Odds ratio 0.04, p = .01). In conclusion, the majority of organ transplant recipients with COVID-19 in our study developed SARS-CoV-2 antibodies. Further longitudinal studies of the durability and immunologic role of these IgG responses and the factors associated with lack of seroconversion are needed.

SARS-CoV-2 Among Infants <90 Days of Age Admitted for Serious Bacterial Infection Evaluation.

OBJECTIVES: To determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants hospitalized for a serious bacterial infection (SBI) evaluation and clinically characterize young infants with SARS-CoV-2 infection. METHODS: A retrospective chart review was conducted on infants <90 days of age hospitalized for an SBI evaluation. The study was conducted at 4 inpatient facilities in New York City from March 15, 2020, to December 15, 2020. RESULTS: We identified 148 SBI evaluation infants who met inclusion criteria. A total of 22 infants (15%) tested positive for SARS-CoV-2 by nasopharyngeal reverse transcription polymerase chain reaction; 31% of infants admitted during periods of high community SARS-CoV-2 circulation tested positive for SARS-CoV-2, compared with 3% when community SARS-CoV-2 circulation was low (P < .001). The mean age of infants with SARS-CoV-2 was higher than that of SARS-CoV-2-negative infants (33 [SD: 17] days vs 23 [SD: 23] days, respectively; P = .03), although no age difference was observed when analysis was limited only to febrile infants. An isolated fever was the most common presentation of SARS-CoV-2 (n = 13; 59%). Admitted infants with SARS-CoV-2 were less likely to have positive urine culture results (n = 1 [5%] versus n = 25 [20%], respectively; P = .002), positive cerebrospinal culture results (n = 0 [0%] versus n = 5 [4%], respectively; P = .02), or be admitted to intensive care (n = 2 [9%] versus n = 47 [37%]; P < .001), compared with infants without SARS-CoV-2. CONCLUSIONS: SARS-CoV-2 was common among young infants hospitalized for an SBI evaluation during periods of high but not low community SARS-CoV-2 circulation in New York City, although most infants did not require intensive care admission.

Multisystem inflammatory syndrome in children (MIS-C) and retropharyngeal edema: A case series.

Multisystem inflammatory syndrome in children (MIS-C) is thought to follow SARS-CoV-2 infection and presents with fever and multisystem dysfunction. We report three children with suspected MIS-C found to have retropharyngeal edema without evidence of a bacterial etiology. We raise the possibility that an association between MIS-C and retropharyngeal edema exists.

A Multicenter Consortium to Define the Epidemiology and Outcomes of Pediatric Solid Organ Transplant Recipients With Inpatient Respiratory Virus Infection.

BACKGROUND: Respiratory virus infection (RVI) in pediatric solid organ transplant (SOT) recipients poses a significant risk; however, the epidemiology and effects of an RVI after pediatric SOT in the era of current molecular diagnostic assays are unclear. METHODS: A retrospective observational cohort of pediatric SOT recipients (January 2010 to June 2013) was assembled from 9 US pediatric transplant centers. Charts were reviewed for RVI events associated with hospitalization within 1 year after the transplant. An RVI diagnosis required respiratory symptoms and detection of a virus (ie, human rhinovirus/enterovirus, human metapneumovirus, influenza virus, parainfluenza virus, coronavirus, and/or respiratory syncytial virus). The incidence of RVI was calculated, and the association of baseline SOT factors with subsequent pulmonary complications and death was assessed. RESULTS: Of 1096 pediatric SOT recipients (448 liver, 289 kidney, 251 heart, 66 lung, 42 intestine/multivisceral), 159 (14.5%) developed RVI associated with hospitalization within 12 months after their transplant. RVI occurred at the highest rates in intestine/abdominal multivisceral (38%), thoracic (heart/lung) (18.6%), and liver (15.6%) transplant recipients and a lower rate in kidney (5.5%) transplant recipients. RVI was associated with younger median age at transplant (1.72 vs 7.89 years; P < .001) and among liver or kidney transplant recipients with the receipt of a deceased-donor graft compared to a living donor (P = .01). The all-cause and attributable case-fatality rates within 3 months of RVI onset were 4% and 0%, respectively. Multivariable logistic regression models revealed that age was independently associated with increased risk for a pulmonary complication (odds ratio, 1.24 [95% confidence interval, 1.02-1.51]) and that receipt of an intestine/multivisceral transplant was associated with increased risk of all-cause death (odds ratio, 24.54 [95% confidence interval, 1.69-327.96]). CONCLUSIONS: In this study, hospital-associated RVI was common in the first year after pediatric SOT and associated with younger age at transplant. All-cause death after RVI was rare, and no definitive attributable death occurred.

A Multicenter Consortium to Define the Epidemiology and Outcomes of Inpatient Respiratory Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described. METHODS: A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed. RESULTS: Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P < .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death. CONCLUSION: Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.

Loss of Innate Host Defense Following Unprotected Vaginal Sex.

BACKGROUND: Multiple host defense mechanisms protect the female genital tract from pathogens, but the impact of sexual intercourse on defense is unknown. METHODS: As part of a hypothesis-generating study, 17 women provided cervicovaginal lavage (CVL) specimens at baseline (all had abstained from sexual intercourse, masturbation, and vaginal product use for 72 hours prior to screening), 2-6 hours and 10-14 hours after vaginal intercourse with a male condom, and 2-6 hours and 10-14 hours after vaginal intercourse without a male condom (5 visits total, including the baseline visit). Vaginal pH, concentrations of immune molecules, and antimicrobial activity at postcoital visits were compared to baseline values. RESULTS: Vaginal pH and the transforming growth factor ß1 level increased, but human beta-defensin 2 (HBD-2), HBD-3, and interleukin 8 levels decreased after unprotected sex. Median Escherichia coli inhibitory activity in CVL specimens decreased significantly from baseline at the visit 2-6 hours after unprotected sex (63% [range, -34% to 99%] vs 5% [range, -51% to 100%]; P = .02) and remained low at the visit 10-14 hours after unprotected sex (6% [range, -19% to 92%]; P = .02). Pooled human seminal plasma enhanced E. coli growth in vitro in a dose-dependent manner and, when added to CVL samples with high anti-E. coli activity, reversed the inhibition. CONCLUSIONS: Unprotected vaginal sex results in a reduction in endogenous anti-E. coli activity, which may reflect, in part, enhancement of bacterial growth by seminal plasma. This finding may contribute to the risk of E. coli vaginal colonization following sexual intercourse.

Chronic HIV Infection Is Associated with Upregulation of Proinflammatory Cytokine and Chemokine and Alpha Defensin Gene Expression in Colorectal Mucosa.

HIV may induce gastrointestinal (GI) mucosal immune dysregulation similar to inflammation observed in ulcerative colitis (UC). Colorectal biopsies from healthy controls (N=12) and from participants with HIV (N=20) or UC (N=9) were subjected to real time (RT)-PCR for selected cytokines, chemokines, antimicrobial peptides, Toll-like receptors, and inflammatory signaling and epithelial barrier proteins. HIV long terminal repeat relative copy number (RCN) in HIV participant biopsies was quantified by RT-PCR. Mean interleukin (IL)-6 mRNA levels did not differ significantly between HIV and UC participants (p=0.48) but were significantly higher relative to control mRNA levels only for HIV participants (p=0.03). Mean IL-8 and human defensin (HD) 5 mRNA levels were similar between HIV and UC participants (p=1.0 and p=0.35, respectively) and were significantly greater in both groups relative to controls (p<0.05 for all). Human beta-defensin (HBD)-2 mRNA levels were higher in UC relative to HIV and control participants (p<0.01 for both). Conversely, HBD-1 mRNA levels were downregulated in UC vs. HIV participants (p=0.01). Mediator gene expression did not differ significantly between HIV participants with detectable (N=10) or nondetectable (N=10) plasma viral loads. Tissue HIV relative copy number (RCN) correlated with plasma viral load (r=0.88, p<0.01) but not with mediator mRNA levels. The results of this study indicate that both chronic HIV infection and UC are associated with similar patterns of IL-6, IL- 8, and HD5 expression in colorectal biopsy tissue. These findings suggest overlapping mechanisms for GI mucosal inflammation in these two illnesses and merit further investigation in larger studies.

Altered biomarkers of mucosal immunity and reduced vaginal Lactobacillus concentrations in sexually active female adolescents.

BACKGROUND: Genital secretions collected from adult women exhibit in vitro activity against herpes simplex virus (HSV) and Escherichia coli (E. coli), but prior studies have not investigated this endogenous antimicrobial activity or its mediators in adolescent females. METHODOLOGY/PRINCIPAL FINDINGS: Anti-HSV and anti-E.coli activity were quantified from cervicovaginal lavage (CVL) specimens collected from 20 sexually active adolescent females (15-18 years). Soluble immune mediators that may influence this activity were measured in CVL, and concentrations of Lactobacillus jensenii and crispatus were quantified by PCR from vaginal swabs. Results for adolescents were compared to those obtained from 54 healthy, premenopausal adult women. Relative to specimens collected from adults, CVL collected from adolescent subjects had significantly reduced activity against E. coli and diminished concentrations of protein, IgG, and IgA but significantly increased anti-HSV activity and concentrations of interleukin (IL)-1α, IL-6 and IL-1 receptor antagonist. Vaginal swabs collected from adolescent subjects had comparable concentrations of L. crispatus but significantly reduced concentrations of L. jensenii, relative to adult swabs. CONCLUSIONS/SIGNIFICANCE: Biomarkers of genital mucosal innate immunity may differ substantially between sexually active adolescents and adult women. These findings warrant further study and may have significant implications for prevention of sexually transmitted infections in adolescent females.

Humoral and cell-mediated immune responses to monovalent 2009 influenza A/H1N1 and seasonal trivalent influenza vaccines in high-risk children.

OBJECTIVE: Humoral and cell-mediated immune responses to monovalent 2009 pandemic influenza A (H1N1/2009) and seasonal trivalent influenza (TIV) vaccines were evaluated in healthy children and children with asthma, sickle cell disease (SCD), systemic lupus erythematosus (SLE), and solid organ transplantation (SOT). STUDY DESIGN: Blood was collected from 112 subjects at the time of H1N1/2009 vaccination and 46 ± 15 days later for hemagglutination inhibition titers and γ-interferon ELISPOT responses to H1N1/2009 vaccine and TIV; unvaccinated children also received TIV at enrollment. RESULTS: A significant increase in the percentage of subjects with seroprotective hemagglutination inhibition titers to both vaccines was observed in all high-risk groups. Children with asthma and SCD were most likely to achieve seroprotective titers to H1N1/2009, whereas <50% of subjects with SOT and SLE had a seroprotective response. Subjects with SOT and SLE also had lower rates of seroprotection after TIV, and subjects with SLE had the lowest ELISPOT responses to both vaccines. Overall, 73% of healthy children exhibited protective responses to TIV; only 35% achieved seroprotection for H1N1/2009. CONCLUSIONS: This evaluation of immune responses to H1N1/2009 in high-risk children suggests suboptimal responses for SOT and SLE subjects, but not for subjects with SCD or asthma. Higher antigen dose, additional dose regimens, or both for immunocompromised children warrant further investigation.

Viral infections in pediatric solid organ transplantation recipients and the impact of molecular diagnostic testing.

PURPOSE OF REVIEW: The review highlights advances in the diagnosis and treatment of viral infections in organ transplant recipients, with emphasis on the most significant pathogens for liver transplant recipients. RECENT FINDINGS: The development of molecular diagnostics has markedly improved the ability to rapidly identify infections in transplantation patients and has improved clinical care. Multiplex polymerase chain reaction (PCR) has enhanced the ability to identify respiratory viruses, permitting earlier treatment. Monitoring for cytomegalovirus and Epstein-Barr virus by PCR offers the opportunity for preemptive interventions. However, imperfect negative predictive values may result in failure to treat early disease, and poor positive predictive values may lead to increased risk of rejection in patients in whom immunosuppression is prematurely reduced and/or unnecessary administration of antiviral therapy. For several viral pathogens, there is an absence of specific and well tolerated therapies, and several treatment modalities have not been rigorously evaluated in controlled clinical trials. SUMMARY: Viral infections remain a leading cause of morbidity and mortality in the solid organ transplantation population, particularly in pediatric patients. Whereas diagnostic testing has greatly improved, there is an urgent need for the development of novel therapies, including adoptive immunotherapy, to provide well tolerated and effective therapy.

A prospective, comparative study of the immune response to inactivated influenza vaccine in pediatric liver transplant recipients and their healthy siblings.

BACKGROUND: Annual influenza vaccination is routinely recommended for pediatric solid organ transplant recipients. However, there are limited data defining the immune response to the inactivated vaccine in this population. METHODS: This prospective study compared the humoral and cell-mediated immune responses to the trivalent subvirion influenza vaccine in pediatric liver transplant recipients with those in their healthy siblings. All subjects received inactivated influenza vaccine. Hemagglutination inhibition and interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assays for New Caledonia and Shanghai strains were performed at baseline, after each vaccine dose, and 3 months after the series. Seroconversion was defined as a 4-fold increase in antibody titers; seroprotection was defined as an antibody titer > or =1:40. An increase in the number of T cells secreting IFN-gamma was considered to be a positive enzyme-linked immunosorbent spot response. RESULTS: After 1 dose of vaccine, transplant recipients achieved rates of antibody seroprotection and seroconversion that were similar to those achieved by their healthy siblings. However, for both influenza strains, IFN-gamma responses by enzyme-linked immunosorbent spot were significantly attenuated in transplant recipients after 2 doses of vaccine. No cases of influenza or vaccine-related serious adverse events were documented in the study. CONCLUSIONS: The diminished cell-mediated immune response to influenza vaccination that was observed in pediatric liver transplant recipients suggests that the current vaccine strategy may not provide optimal protection. Because of concerns regarding potential emergence of more virulent influenza strains, further studies are warranted to determine if IFN-gamma responses are predictive of efficacy and to identify the optimal vaccination strategy to protect populations with a high risk of infection.

Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections.

Molecular umbrella compounds may function as novel topical microbicides to prevent human immunodeficiency virus (HIV) and herpes simplex virus (HSV) infections. In a preliminary structure-activity investigation, one umbrella compound, designated Spm8CHAS, was identified which inhibited both HIV and HSV infections with no cellular toxicity. The objectives of the current studies were to define its spectrum of antiviral activity, characterize its mechanism of action, and explore the possibility of combining Spm8CHAS with HIV-specific reverse transcriptase inhibitors. Spm8CHAS inhibited infections by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical tissue explants exposed to HIV-1(BaL) in the presence of Spm8CHAS were completely protected (50% inhibitory concentration [IC(50)], 13.6 microg/ml), and transfer of virus to target T cells via migratory cells was abolished (IC(50), 3.8 microg/ml). Spm8CHAS inhibited HSV-2 infection of epithelial cells 10,000-fold if present throughout the infection. Notably, adding Spm8CHAS to cultures following HSV entry significantly reduced viral infection, indicating that the drug also acts postentry. Subsequent studies indicated that Spm8CHAS blocks cell-to-cell spread of HSV. Confocal microscopy using a fluorescently labeled analog of Spm8CHAS demonstrated that this conjugate crosses the plasma cell membrane and is transported to the nucleus. Combinations of Spm8CHAS with UC-781 or 9-[R-2-(phosphonylmethoxy)propyl] adenine monohydrate in vitro exhibited additive anti-HIV activity with preserved anti-HSV activity. The abilities of Spm8CHAS to inhibit primary isolates of HIV, block HSV infection postentry, and cross cell membranes support the development of a combination microbicide containing Spm8CHAS with an HIV-specific reverse transcriptase inhibitor to prevent both HIV and HSV infections by multiple mechanisms.

Prioritizing prevention of HIV and sexually transmitted infections: first-generation vaginal microbicides.

PURPOSE OF REVIEW: As the HIV/AIDS pandemic continues unabated, novel control measures for the spread of HIV and other sexually transmitted infections are urgently needed. Topical microbicides are designed to prevent transmission of sexually transmitted infections when applied vaginally. The microbicides discussed in this review may provide a new opportunity for decreasing the spread of HIV and other sexually transmitted infections. RECENT FINDINGS: Epidemiological studies suggest a synergistic relationship between HIV and sexually transmitted infections, particularly between HIV and genital herpes infection. Compounds have been developed to block transmission of HIV-1 and herpes simplex virus, as well as Neisseria gonorrhoea and Chlamydia trachomatis. Several of these compounds have advanced to clinical trials as candidate microbicides. Candidate compounds fall into the following categories: detergents or surfactants that inactivate viral particles, anionic polymers that block attachment of virus to target cells, vaginal acid-buffering agents that maintain a protective vaginal pH, and antiretroviral drugs specific for HIV. Evaluation of the safety of topical microbicides remains problematic. Clinical experiences indicate that current models to assess safety in vitro and in vivo may be insufficient to assess the safety of vaginal microbicides. A critical direction of future studies is to identify which assay(s) provide surrogate laboratory markers of safety that correlate with clinical outcomes. SUMMARY: The spread of HIV, and its increasing burden of disease in women, necessitates the development of novel prophylactic strategies. Topical microbicides offer women an empowering preventative option but require vigorous testing for safety and effectiveness.