Publications by authors named "Hayley Gans"

33 Publications

Varicella zoster immune globulin (human) (VARIZIG) in immunocompromised patients: a subgroup analysis for safety and outcomes from a large, expanded-access program.

BMC Infect Dis 2021 Jan 11;21(1):46. Epub 2021 Jan 11.

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 402, Houston, TX, 77030, USA.

Background: Immunocompromised children and adults are at increased risk for severe disease and death following varicella zoster virus infection. Varicella zoster immune globulin (human) (VARIZIG) is recommended for post-exposure prophylaxis to prevent or attenuate varicella infection in high-risk individuals.

Methods: An open-label, expanded-access program provided VARIZIG to high-risk individuals exposed to varicella or herpes zoster. Immunocompromised participants were stratified by type of immunocompromising condition ("oncologic immunodeficiency", "primary immunodeficiency", "solid organ transplant" [SOT], "hematopoietic cell transplant" [HCT], and "other"). Patient characteristics, type of exposure and varicella outcome, and safety data were assessed.

Results: This analysis included 40 adults (primary [n = 6] or oncologic [n = 10] immunodeficiencies, history of SOT [n = 5] or HCT [n = 6], and other [n = 13]), and 263 children (primary [n = 13] or oncologic [n = 152] immunodeficiencies, history of SOT [n = 36] or HCT [n = 17], and other [n = 45]). Among adults and children, 48% vs 72% were exposed to varicella, 38% vs 16% were exposed to herpes zoster, and 15% vs 12% had an unspecified exposure. Overall incidence of varicella infection in adults after VARIZIG use was 6%; incidence of varicella infection in children after VARIZIG use was 7%. Similar rates were noted in each subgroup. Most cases of varicella were mild, with two children developing > 100 lesions and no cases of varicella-related pneumonia or encephalitis. Varicella-related hospitalizations occurred primarily in children with oncologic immunodeficiencies. One serious adverse event (serum sickness) was considered related to VARIZIG and occurred in a child with oncologic immunodeficiency. There were no varicella- or VARIZIG-related deaths.

Conclusions: These data indicate that VARIZIG may reduce severity of varicella in immunocompromised children and adults.

Trial Registration: This study was retrospectively registered with the public clinical trial identification NCT00338442 at https://www.clinicaltrials.gov on 20 June 2006.
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http://dx.doi.org/10.1186/s12879-020-05656-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798258PMC
January 2021

Genetic associations with a fever after measles-containing vaccines.

Hum Vaccin Immunother 2020 Dec 22:1-7. Epub 2020 Dec 22.

School of Medicine, Stanford University , Stanford, CA, USA.

Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12-15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5-12 days after MMR ("MMR-associated") and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 ( = .036), B-57:01 ( = .018), C-06:02 ( = .006), C-14:02 ( = .022), and Class II loci DRB1-15 ( = .045). However, Bonferroni's adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever ( = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.
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http://dx.doi.org/10.1080/21645515.2020.1849520DOI Listing
December 2020

Standardization of post-operative antimicrobials reduced exposure while maintaining good outcomes in pediatric liver transplant recipients.

Transpl Infect Dis 2020 Nov 30:e13538. Epub 2020 Nov 30.

Lucile Packard Children's Hospital Stanford, Stanford, CA, USA.

Infections following orthotopic liver transplant (OLT) result in significant morbidity and mortality, warranting careful consideration of risks associated with antibiotic overuse and benefits of infection prevention. In the absence of specific guidelines for antimicrobial prophylaxis in pediatric OLT, we developed a standardized approach to post-operative (post-op) antimicrobial therapy including 48 hours of antibiotics, no vancomycin for post-op fever within the first 48 hours, and caspofungin only for certain situations. The goal was to reduce antimicrobial utilization and adverse outcomes associated with longer duration of and broader treatment while maintaining good outcomes. The impact of this standardization on antimicrobial utilization and clinical outcomes at the largest pediatric liver transplant center in the United States is described. All individuals receiving an OLT from 1/1/17-9/30/17 (N = 38) and 3/14/18-12/13/18 (N = 27) were included in the pre-intervention (PreI) and post-intervention (PostI) groups, respectively. The intervention resulted in a significant reduction in individuals receiving post-op broad-spectrum gram-negative antibiotics for >48 hours (76% PreI vs 44% PostI OLT recipients, P = .01) and post-op vancomycin use (50% PreI, vs 7.4% PostI, P < .001). There were no statistically significant differences between groups for post-op fever, positive pre-/post-operative cultures, receipt of massive transfusion, or hospital length of stay. In conclusion, following the implementation of a standardized approach to post-op prophylaxis, antimicrobial exposure was significantly reduced without affecting OLT recipient outcomes.
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http://dx.doi.org/10.1111/tid.13538DOI Listing
November 2020

Kinetics of SARS-CoV-2 positivity of infected and recovered patients from a single center.

Sci Rep 2020 10 29;10(1):18629. Epub 2020 Oct 29.

Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive detection in infected but recovered individuals has been reported. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system. We sought to define the kinetics and relevance of PCR-positive recurrence during recovery from acute COVID-19 to better understand risks for prolonged infectivity and reinfection. A series of 414 patients with confirmed SARS-Cov-2 infection, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020. Statistical analyses were performed of the clinical, laboratory, radiologic image, medical treatment, and clinical course of admission/quarantine/readmission data, and a recurrence predictive algorithm was developed. 16.7% recovered patients with PCR positive recurring one to three times, despite being in strict quarantine. Younger patients with mild pulmonary respiratory syndrome had higher risk of PCR positivity recurrence. The recurrence prediction model had an area under the ROC curve of 0.786. This case series provides characteristics of patients with recurrent SARS-CoV-2 positivity. Use of a prediction algorithm may identify patients at high risk of recurrent SARS-CoV-2 positivity and help to establish protocols for health policy.
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http://dx.doi.org/10.1038/s41598-020-75629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596704PMC
October 2020

A 10-Month-Old Female With Complicated Mastoiditis Due to Fusobacterium necrophorum: A Case Report and Literature Review.

J Pediatric Infect Dis Soc 2020 Jul;9(3):399-401

Division of Pediatric Infectious Diseases, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1093/jpids/piaa059DOI Listing
July 2020

Measles Maternal Antibodies With Low Avidity Do Not Interfere With the Establishment of Robust Quantity and Quality Antibody Responses After the Primary Dose of Measles, Mumps, and Rubella Vaccine Administered at 12-Months of Age.

J Pediatric Infect Dis Soc 2020 Dec;9(6):752-755

Department of Pediatrics, Stanford University Medical School, Stanford, California, USA.

In this study, we illustrate, for the first time, that preexisting low-avidity neutralizing measles maternal antibodies do not interfere with the development of high concentrations of high-avidity measles antibodies in children immunized at age 12 months. This suggests that the quality of measles maternal antibodies, rather than the quantity, impacts immunogenicity of primary measles immunization.
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http://dx.doi.org/10.1093/jpids/piz074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864143PMC
December 2020

Parental risk factors for fever in their children 7-10 days after the first dose of measles-containing vaccines.

Hum Vaccin Immunother 2020 04 8;16(4):875-880. Epub 2019 Nov 8.

Division of Research, Vaccine Study Center, Kaiser Permanente Northern California, Oakland, CA, USA.

We evaluated whether parental clinical conditions were associated with fever after a first dose of measles-containing vaccine (MCV) in the child in a cohort study including 244,125 children born in Kaiser Permanente Northern California between 2009 and 2016 who received MCV between ages 1 and 2 years. Each child was linked with his/her mother and father when possible. Parental clinical conditions present before and after their child's birth were identified. We defined fever in the children as clinic and emergency department visits with a fever code 7-10 days after a first dose of MCV ("MCV-associated fever"). We evaluated parental clinical conditions associated with MCV-associated fever using multivariate logistic regression analyses. After adjusting for multiple factors, including healthcare utilization, maternal fever [odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.06-1.32], fever after MCV (OR = 5.90, 95% CI 1.35-25.78), respiratory infections (OR = 1.20, 95% CI 1.10-1.31), migraine (OR = 1.14, 95% CI 1.05-1.24), syncope (OR 1.14, 95% CI 1.01-1.27), and essential thrombocythemia (OR = 1.93, 95% CI 1.15-3.25) were significantly associated with MCV-associated fever. Paternal respiratory infections (OR = 1.15, 95% CI 1.05-1.27), fever associated with respiratory infections (OR = 1.47, 95% CI 1.23-1.76), and vitiligo (OR = 1.63, 95% CI 1.06-2.53) were significantly associated with MCV-associated fever. Parental clinical conditions, specifically fever alone and fever associated with respiratory infection, are associated with fever in their child 7-10 days after MCV.
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http://dx.doi.org/10.1080/21645515.2019.1675458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227709PMC
April 2020

Preventing Measles in Immunosuppressed Cancer and Hematopoietic Cell Transplantation Patients: A Position Statement by the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2019 11 5;25(11):e321-e330. Epub 2019 Aug 5.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, Seattle Children's Hospital/University of Washington School of Medicine, Seattle, Washington. Electronic address:

Until recently, measles exposures were relatively rare and so, consequently, were an afterthought for cancer patients and/or blood and marrow transplant recipients and their providers. Declines in measles herd immunity have reached critical levels in many communities throughout the United States due to increasing vaccine hesitancy, so that community-based outbreaks have occurred. The reemergence of measles as a clinical disease has raised serious concerns among immunocompromised patients and those who work within the cancer and hematopoietic cell transplantation (HCT) community. Since live attenuated vaccines, such as measles, mumps, and rubella (MMR), are contraindicated in immunocompromised patients, and with no approved antiviral therapies for measles, community exposures in these patients can lead to life-threatening infection. The lack of data regarding measles prevention in this population poses a number of clinical dilemmas. Herein specialists in Infectious Diseases and HCT/cellular therapy endorsed by the American Society of Transplant and Cellular Therapy address frequently asked questions about measles in these high-risk cancer patients and HCT recipients and provide expert opinions based on the limited available data.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.034DOI Listing
November 2019

Risk Factors of Ambulatory Central Line-Associated Bloodstream Infection in Pediatric Short Bowel Syndrome.

JPEN J Parenter Enteral Nutr 2020 03 9;44(3):500-506. Epub 2019 Jun 9.

Pediatric Infectious Diseases, Stanford University, Stanford, California, USA.

Background: Children with short bowel syndrome (SBS) receiving home parenteral nutrition (HPN) are predisposed to ambulatory central line-associated bloodstream infection (A-CLABSI). Data describing risk factors of this infection in children are limited.

Methods: Retrospective cohort, single-center, case-crossover study of children ≤18 years old with SBS receiving HPN from January 2012 to December 2016. Univariate and multivariate mixed effect Poisson regression identified the relative risk (RR) of A-CLABSI with proposed risk factors.

Results: Thirty-five children were identified; median follow-up was 30 months. A-CLABSI rate was 4.2 per 1000 central line (CL) days. Univariate analysis identified younger age (RR: 0.92 per 12-month increase [95% confidence interval {CI}: 0.85-0.99; P = 0.036]), shorter small intestine length (RR: 0.96 per 10-cm increase [95% CI: 0.92-0.99; P = 0.008]), lower citrulline level (RR: 0.86 per 5-nmol/mL increase [95% CI: 0.75-0.99; P = 0.036]), and recent CL break (RR: 1.55 [95% CI: 1.06-2.28; P = 0.024]) as risk factors for A-CLABSI. Multivariate analysis showed increased A-CLABSI with clinical diagnosis of small intestine bacterial overgrowth (SIBO) (RR: 1.87 [95% CI: 1.1-3.17; P = 0.021]) and CL breaks (RR: 1.49 [95% CI: 1-2.22; P = 0.024]).

Conclusions: Factors influencing gut integrity increase A-CLABSI rate, supporting translocation as an important mechanism and target for prevention. Clinical diagnosis of SIBO increases A-CLABSI rate, but whether dysbiosis or diarrhea is responsible is an area for future research. CL maintenance is crucial, and prevention of breaks would likely decrease A-CLABSI rate.
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http://dx.doi.org/10.1002/jpen.1667DOI Listing
March 2020

Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

Clin Transplant 2019 09 1;33(9):e13587. Epub 2019 Jul 1.

Medicine, Pediatric Infectious Diseases Program for Immunocompromised Hosts, Stanford University, Stanford, California.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Pneumocystis jiroveci fungal infection transplant recipients. Pneumonia (PJP) may develop via airborne transmission or reactivation of prior infection. Nosocomial clusters of infection have been described among transplant recipients. PJP should not occur during prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX). Without prophylaxis, PJP risk is greatest in the first 6 months after organ transplantation but may develop later. Risk factors include low lymphocyte counts, cytomegalovirus infection (CMV), hypogammaglobulinemia, treated graft rejection or corticosteroids, and advancing patient age (>65). Presentation typically includes fever, dyspnea with hypoxemia, and cough. Chest radiographic patterns generally reveal diffuse interstitial processes best seen by CT scans. Patients generally have PO  < 60 mm Hg, elevated serum lactic dehydrogenase (LDH), and elevated serum (1 → 3) β-d-glucan assay. Specific diagnosis uses respiratory specimens with direct immunofluorescent staining; invasive procedures may be required. Quantitative PCR is a useful adjunct to diagnosis. TMP-SMX is the drug of choice for therapy; drug allergy should be documented before resorting to alternative therapies. Adjunctive corticosteroids may be useful early. Routine PJP prophylaxis is recommended for at least 6-12 months post-transplant, preferably with TMP-SMX.
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http://dx.doi.org/10.1111/ctr.13587DOI Listing
September 2019

Central line replacement following infection does not improve reinfection rates in pediatric pulmonary hypertension patients receiving intravenous prostanoid therapy.

Pulm Circ 2018 Jan-Mar;8(1):2045893218754886. Epub 2018 Jan 8.

3 10624 Department of Pediatrics, Division of Pediatric Infectious Diseases, Stanford University Medical Center , Stanford, CA, USA.

Treatment of pediatric pulmonary hypertension (PH) with IV prostanoids has greatly improved outcomes but requires a central line, posing inherent infection risk. This study examines the types of infections, infection rates, and importantly the effect of line management strategies on reinfection in children receiving IV prostanoids for PH. This study is a retrospective review of all pediatric PH patients receiving intravenous epoprostenol (EPO) or treprostinil (TRE) at one academic tertiary care center between 2000 and 2014. No patients declined participation in the study or were otherwise excluded. Infectious complications were characterized by organism(s), infection rates, time to next infection, and line management decisions (salvage vs. replace). Of the 40 patients followed, 13 sustained 38 infections involving 49 pathogens, with a predominance of gram-positive (GP) organisms (n = 35). The pooled infection rate was 1.06 per 1000 prostanoid days with no difference between EPO and TRE. No significant difference in reinfection rate was observed when comparing line salvage to replacement, regardless of organism type. Both overall and organism-type comparisons suggest longer time between line infections following line salvage compared with line replacement (732 vs. 410 days overall; 793 vs. 363 days for GP; 611 vs. 581 days for gram-negative [GN]; P > 0.05 for all comparisons). Central line replacement following blood stream infections in pediatric PH patients does not improve subsequent infection rates or time to next infection, and may lead to unnecessary risks associated with line replacement, including potential loss of vascular access. A revised approach to central line infections in pediatric PH is proposed.
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http://dx.doi.org/10.1177/2045893218754886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826011PMC
January 2018

Response to editor regarding "Improvement of psychiatric symptoms in youth following resolution of sinusitis".

Int J Pediatr Otorhinolaryngol 2018 09 6;112:208-209. Epub 2017 Sep 6.

Pediatric Divisions of Child & Adolescent Psychiatry, Stanford University School of Medicine, 700 Welch Road, Suite 125, Palo Alto, CA 94304, United States.

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http://dx.doi.org/10.1016/j.ijporl.2017.07.047DOI Listing
September 2018

Palatal Petechiae in the Absence of Group A Streptococcus in Pediatric Patients with Acute-Onset Neuropsychiatric Deterioration: A Cohort Study.

J Child Adolesc Psychopharmacol 2017 Sep 7;27(7):660-666. Epub 2017 Apr 7.

1 Divisions of Pediatric, Department of Allergy, Immunology, and Rheumatology, Palo Alto, California.

Background: Palatal petechiae are 95% specific for streptococcal pharyngitis. Despite this, and despite prior research demonstrating that Group A Streptococcus (GAS) is a common antecedent to pediatric acute-onset neuropsychiatric syndrome (PANS) episodes, we anecdotally observed a low rate of documented GAS in patients with PANS and palatal petechiae. This retrospective chart review was conducted to formally report the rate of palatal petechiae and concurrent GAS in a cohort of patients with PANS and investigate other etiologic factors.

Methods: The clinical notes of 112 patients seen at the Stanford PANS Clinic who met PANS research criteria were reviewed for mention of palatal petechiae. The medical records of patients who demonstrated palatal petechiae on physical examination were reviewed for signs of infection, a clinical history of trauma, and laboratory results that could indicate other causes of petechiae.

Results: Twenty-three patients had documented palatal petechiae on physical examination (ages 5-16, 13/23 [57%] male). Fifteen patients had a rapid GAS test and GAS culture in the Stanford PANS clinic, all with negative results. Evidence of recent GAS infection was found in 8/23 (32%) patients (elevated GAS titers [n = 6] or documentation of a positive rapid GAS test at another facility [n = 2]), one of whom also had potential herpes simplex virus (HSV) infection. One patient had potential HSV infection and recent palatal trauma. No patients had thrombocytopenia. 14/23 (61%) of patients with palatal petechiae had no discernable cause of petechiae. 10/19 (53%) of patients had antihistone antibodies.

Conclusions: Despite the established relationship between palatal petechiae and GAS, no patient with palatal petechiae in our clinic tested positive for GAS and only 32% had evidence of recent GAS. Most did not have an identifiable cause for the palatal lesions. This finding suggests the potential for alternative causes of palatal petechiae or undetectable GAS in our patient population. The high prevalence of palatal petechiae without GAS infection suggests that the pathogenesis of PANS is multifactorial and may involve disruption or inflammation of the microvasculature. Additional research is needed to further elucidate these findings.
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http://dx.doi.org/10.1089/cap.2016.0153DOI Listing
September 2017

Improvement of psychiatric symptoms in youth following resolution of sinusitis.

Int J Pediatr Otorhinolaryngol 2017 Jan 31;92:38-44. Epub 2016 Oct 31.

Pediatric Divisions of Allergy, Immunology, & Rheumatology, Stanford University School of Medicine, 700 Welch Road, Suite 301, Palo Alto, CA, 94304, USA. Electronic address:

Introduction: Accumulating evidence supports a role for inflammation in psychiatric illness, and the onset or exacerbation of psychiatric symptoms may follow non-CNS infections. Here, we provide the first detailed description of obsessive-compulsive and related psychiatric symptoms arising concurrently with sinusitis.

Methods: We reviewed the charts of 150 consecutive patients evaluated in our Pediatric Acute-onset Neuropsychiatric Syndromes clinic for documented sinusitis as defined by the American Academy of Pediatrics guidelines. Sinusitis treatments, sinonasal imaging, and neuropsychiatric symptoms before, during, and after sinusitis onset were noted. Patients were included in the final review if they had a clear diagnosis of isolated sinusitis (without concurrent illness and/or immunodeficiency), and were evaluated during an episode of sinusitis.

Results: 10/150 (6.6%) patients had isolated sinusitis at the time of their neuropsychiatric deterioration. Eight patients received antibiotics to treat sinusitis, three of whom also received sinus surgery. Neuropsychiatric symptoms improved in all eight patients concurrent with resolution of sinusitis per parent report and clinician assessment. One patient did not follow through with recommended sinus surgery or antibiotics and her psychiatric symptoms persisted. One patient was lost to follow-up.

Conclusions: Improvement of psychiatric symptoms correlated with resolution of sinus disease in this retrospective study. Identification, treatment, and resolution of underlying infections, including sinusitis, may have the potential to change the trajectory of some neuropsychiatric illnesses. Randomized clinical trials are needed.
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http://dx.doi.org/10.1016/j.ijporl.2016.10.034DOI Listing
January 2017

Pleural Effusion and Fever in an Immunocompromised Patient.

J Pediatric Infect Dis Soc 2015 Mar 19;4(1):e6-9. Epub 2014 Mar 19.

Department of Pediatrics, Division of Infectious Diseases, Lucile Packard Children's Hospital at Stanford University, Palo Alto, California.

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http://dx.doi.org/10.1093/jpids/piu018DOI Listing
March 2015

Fever and Renal Failure in a Child With DiGeorge Syndrome and Tetralogy of Fallot.

J Pediatric Infect Dis Soc 2015 Dec 19;4(4):373-5. Epub 2015 May 19.

Department of Pediatrics, Division of Infectious Diseases, Lucile Packard Children's Hospital at Stanford University, Palo Alto, California.

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http://dx.doi.org/10.1093/jpids/piv029DOI Listing
December 2015

Measles humoral and cell-mediated immunity in children aged 5-10 years after primary measles immunization administered at 6 or 9 months of age.

J Infect Dis 2013 Feb 8;207(4):574-82. Epub 2013 Jan 8.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.

Background: Given the high infant measles mortality rate, there is interest in whether a measles immunization regimen beginning at <12 months of age provides lasting immunity.

Methods: Measles-specific immune responses were evaluated in 70 children aged 5-10 years after primary measles vaccine administered at 6, 9, or 12 months.

Results: At 5-10 years of age, the stimulation index for measles T-cell proliferation was 11.4 (SE, 1.3), 10.9 (SE, 1.5), and 14.4 (SE 2.1) when the first measles dose was given at 6, 9, or 12 months, respectively. Neutralizing antibody concentration (geometric mean titer [GMT]) in those immunized at 6 months of age was 125 mIU/mL (95% confidence interval [CI], 42-377) in the presence of passive antibodies (PAs) and 335 mIU/mL (95% CI, 211-531) in those without PAs; in those immunized at 9 months, GMTs were 186 mIU/mL (95% CI, 103-335) and 1080 mIU/mL (95% CI, 642-1827) in the presence and absence of PAs, respectively. The GMT was 707 mIU/mL (95% CI, 456-1095) when vaccine was administered at 12 months (P ≤ .04).

Conclusions: Measles-specific T-cell responses were sustained at 5-10 years of age regardless of age at time of primary measles immunization. Neutralizing antibody concentrations were lower in cohorts given the first vaccine dose at 6 months of age and in the presence of PAs; however, responses could be boosted by subsequent doses. Starting measles vaccination at <12 months of age may be beneficial during measles outbreaks or in endemic areas.
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http://dx.doi.org/10.1093/infdis/jis719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549597PMC
February 2013

The status of live viral vaccination in early life.

Authors:
Hayley A Gans

Vaccine 2013 May 28;31(21):2531-7. Epub 2012 Sep 28.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.

The need for neonatal vaccines is supported by the high disease burden during the first year of life particularly in the first month. Two-thirds of childhood deaths are attributable to infectious diseases of which viruses represent key pathogens. Many infectious diseases have the highest incidence, severity and mortality in the first months of life, and therefore early life vaccination would provide significant protection and life savings. For some childhood viral diseases successful vaccines exist, such as against measles, mumps, rubella, varicella, influenza poliovirus, and rotavirus, but their use in the first year particularly at birth is not yet practiced. Vaccines against other key pathogens continue to elude scientists such as against respiratory syncytial virus. The obstacles for early and neonatal vaccination are complex and include host factors, such as a developing immune system and the interference of passively acquired antibodies, as well vaccine-specific issues, such as optimal route of administration, titer and dosing requirements. Importantly, additional host and infrastructure barriers also present obstacles to neonatal vaccination in the developing world where morbidity and mortality rates are highest. This review will highlight the current live viral vaccines and their use in the first year of life, focusing on efficacy and entertaining the barriers that exist. It is important to understand the successes of current vaccines and use this knowledge to determine strategies that are successful in young infants and for the development of new vaccines for use in early life.
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http://dx.doi.org/10.1016/j.vaccine.2012.09.043DOI Listing
May 2013

IMP-producing carbapenem-resistant Klebsiella pneumoniae in the United States.

J Clin Microbiol 2011 Dec 12;49(12):4239-45. Epub 2011 Oct 12.

Centers for Disease Control and Prevention, 1600 Clifton Rd. N.E., MS C16, Atlanta, GA 30329, USA.

The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) producing acquired carbapenemases have created a global public health crisis. In the United States, CRE producing the Klebsiella pneumoniae carbapenemase (KPC) are increasingly common and are endemic in some regions. Metallo-β-lactamase (MBL)-producing CRE have recently been reported in the United States among patients who received medical care in countries where such organisms are common. Here, we describe three carbapenem-resistant K. pneumoniae isolates recovered from pediatric patients at a single U.S. health care facility, none of whom had a history of international travel. The isolates were resistant to carbapenems but susceptible to aztreonam, trimethoprim-sulfamethoxazole, and fluoroquinolones. The three isolates were closely related to each other by pulsed-field gel electrophoresis and contained a common plasmid. PCR and sequence analysis confirmed that these isolates produce IMP-4, an MBL carbapenemase not previously published as present among Enterobacteriaceae in the United States.
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http://dx.doi.org/10.1128/JCM.05297-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233008PMC
December 2011

Challenges in infant immunity: implications for responses to infection and vaccines.

Nat Immunol 2011 Mar;12(3):189-94

Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1038/ni0311-189DOI Listing
March 2011

Preterm infants' T cell responses to inactivated poliovirus vaccine.

J Infect Dis 2010 Jan;201(2):214-22

Kaiser Permanente Vaccine Study Center, Oakland, California 94612, USA.

Background: The antigen-specific T cell responses of preterm infants to immunization are not well understood. The aim of the present study was to compare the T cell responses of preterm infants after inactivated poliovirus vaccination with those of term infants.

Methods: We prospectively enrolled 2-month-old preterm (gestational age, 33 weeks) and term (gestational age, 37 weeks) infants to receive 3 doses of diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus vaccine. Whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated with poliovirus vaccine, and memory T cell activation was analyzed by flow cytometry and lymphoproliferation, respectively. Levels of poliovirus neutralizing antibodies were measured in serum.

Results: We enrolled 33 preterm and 50 term infants. Preterm infants had fewer circulating CD4(+)CD45RO(+) memory (P = .005) and CD4(+)CD69(+)IFN-gamma(+) cells activated by staphylococcus enterotoxin B at 2 (P = .015) and 7 (P = .05) months of age. After immunization, preterm and term infants had comparable frequencies of poliovirus-specific CD4(+)CD45RO(+)CD69(+)IFN-gamma(+) memory T cells (P = .79). PBMCs from preterm infants had diminished poliovirus-specific lymphoproliferation (P<.001). Although all infants developed seroprotective poliovirus antibody titers, serotype 1 titers were lower among preterm infants (P = .03).

Conclusions: Preterm infants develop poliovirus-specific T cell responses that are comparable to those of term infants. However, they demonstrate nonspecific and poliovirus-specific functional T cell limitations, suggesting that investigations into whether T cell differences remain as preterm infants mature are warranted.
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http://dx.doi.org/10.1086/649590DOI Listing
January 2010

Age-related increase in the frequency of CD4(+) T cells that produce interferon-gamma in response to staphylococcal enterotoxin B during childhood.

J Infect Dis 2009 Dec;200(12):1921-7

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.

Background: The susceptibility of infants to infections is well defined clinically, and immunologic abnormalities have been described. Immune maturation is complex, however, and the interval during which changes occur during childhood has not been identified.

Methods: To assess age-related differences in the CD4(+) T cell responses, we evaluated the frequency of CD4(+) T cells that produced interferon (IFN) gamma in response to staphylococcal enterotoxin B (SEB) stimulation in 382 healthy infants and children (2 months to 11 years of age) and 66 adults. Flow cytometry was used to assess SEB-induced CD69 and CD40 ligand (CD40-L) expression and IFN-gamma production by CD4(+) and CD45RO(+)CD4(+) T cells.

Results: CD69 and CD40-L expression by CD4(+) and CD45RO(+)CD4(+) T cells were similar to adult levels from infancy, but the frequency of activated T cells that produced IFN-gamma remained lower than adult responses until children were 10 years of age.

Conclusions: These observations indicate that the IFN-gamma response of CD4(+) T cells to SEB remains limited for a much longer interval than was reported elsewhere, extending to the second decade of life. Observed differences in CD45RO(+)CD4(+) T cell function indicate that CD4(+) T cells with the same phenotypes do not possess equivalent functional capabilities.
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http://dx.doi.org/10.1086/648375DOI Listing
December 2009

Eosinophilic meningoencephalitis: psychiatric presentation and treatment.

Int J Psychiatry Med 2008 ;38(3):287-95

Stanford University School of Medicine, Palo Alto, California 94305-5719, USA.

Eosinophilic meningoencephalitis (EM) is usually a self-limited neurological illness commonly accompanied by a variety of neurological symptoms. The presence of acute psychotic symptoms in EM, however, has not previously been reported, and there is no literature to guide its treatment and management. In this case report, the onset of psychotic symptoms in a hypoactive delirium and their significant improvement following the administration of atypical antipsychotics are described in a boy with EM. This case report demonstrates the efficacy and safety of antipsychotic agents during the acute phase of meningoencephalitis.
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http://dx.doi.org/10.2190/PM.38.3.eDOI Listing
January 2009

Immune responses to mumps vaccine in adults who were vaccinated in childhood.

J Infect Dis 2008 Jun;197(12):1669-75

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.

Background: In a mumps outbreak in the United States, many infected individuals were adults who had received 2 doses of mumps vaccine. The persistence of cellular immunity to mumps vaccine has not been defined.

Methods: This was an observational, nonrandomized cohort study evaluating cell-mediated and humoral immunity to mumps in 10 vaccinated and 10 naturally immune adults. Mumps-specific T cell activation and interferon (IFN)-gamma production were measured using lymphoproliferative and flow cytometry assays, and mumps immunoglobulin (Ig) G was measured using enzyme-linked immunosorbent assay.

Results: T cell immunity to mumps was high in both groups; 70% of vaccinated and 80% of naturally immune individuals had a positive (> or =3) stimulation index (SI) (P = 1.0). The mean percentages of mumps-specific CD4+ T cells that expressed CD69 and produced IFN-gamma were equivalent in the 2 groups: 0.06% and 0.12%, respectively (P = .11). The mean SIs in the groups were also equivalent, although IFN-gamma concentrations from cultures stimulated with mumps antigen were higher in naturally immune adults than in vaccinated adults (P < or = .01). All adults were positive for mumps IgG.

Conclusion: T and B cell immunity to mumps was detected in adults at least 10 years after immunization. Except for IFN-gamma release, responses in vaccinated adults paralleled those observed in naturally immune individuals.
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http://dx.doi.org/10.1086/588195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561204PMC
June 2008

Effects of interleukin-12 and interleukin-15 on measles-specific T-cell responses in vaccinated infants.

Viral Immunol 2008 Jun;21(2):163-72

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.

Understanding the infant host response to measles vaccination is important because of their increased mortality from measles and the need to provide effective protection during the first year of life. Measles-specific T and B-cell responses are lower in infants after measles vaccination than in adults. To define potential mechanisms, we investigated age-related differences in measles-specific T-cell proliferation, CD40-L expression, and IFN-gamma production after measles immunization, and the effects of rhIL-12 and rhIL-15 on these responses. Measles-specific T-cell proliferation and mean IFN-gamma release from infant PBMCs were significantly lower when compared with responses of vaccinated children and adults. Infant responses increased to ranges observed in children and adults when both rhIL-12 and rhIL-15 were added to PBMC cultures. Furthermore, a significant rise in T-cell proliferation and IFN-gamma release was observed when infant PBMCs were stimulated with measles antigen in the presence of rhIL-12 and rhIL-15 compared to measles antigen alone. CD40-L expression by infant and adult T cells stimulated with measles antigen was comparable, but fewer infant CD40-L(+) T cells expressed IFN-gamma. These observations suggest that lower measles-specific T-cell immune responses elicited by measles vaccine in infants may be due to diminished levels of key cytokines.
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http://dx.doi.org/10.1089/vim.2007.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2599809PMC
June 2008

Age-dependent differences in IgG isotype and avidity induced by measles vaccine received during the first year of life.

J Infect Dis 2007 Nov 2;196(9):1339-45. Epub 2007 Oct 2.

W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

Background: Measles remains an important cause of death worldwide, and vaccinating individuals at an earlier age could lead to better control of the disease. However, persistence of maternal antibody and young age affect the quantity of vaccine-induced neutralizing antibody and may also affect antibody quality.

Methods: Enzyme immunoassay was used to analyze measles virus-specific IgG levels, avidity maturation, and isotype changes, using serum samples from infants who received measles vaccine at 6 months of age and measles-mumps-rubella (MMR)-II at 12 months of age (n=26), measles vaccine at 9 months of age and measles-mumps-rubella (MMR)-II at 12 months of age (n=48), or only MMR-II at 12 months of age (n=27).

Results: The median IgG level was lower among infants with maternal antibody than among those without maternal antibody. Compared with median avidity indices for infants aged 12 months, median values were lower for 6-month-old infants with maternal antibody (P=.0001), 6-month-old infants without maternal antibody (P=.001), 9-month-old infants with maternal antibody (P=.03), and 9-month-old infants without maternal antibody (P=.006). The median IgG3 level was highest at 6 months of age. IgG1 was predominant at 12 months. Low avidity responses at 6 or 9 months of age did not hinder higher avidity responses or the switch to IgG1 after secondary vaccination. The 2-dose regimen did not augment the response, compared with the response in infants who received 1 dose at 12 months of age.

Conclusions: Avidity and isotype maturation of measles vaccine-induced antibody are affected by age, providing insight into the ontogeny of the immune response to measles vaccine.
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http://dx.doi.org/10.1086/522519DOI Listing
November 2007

Immunogenicity of aerosol measles vaccine given as the primary measles immunization to nine-month-old Mexican children.

Vaccine 2006 Jan 24;24(5):683-90. Epub 2005 Aug 24.

Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Dr. Balmis # 148, Colonia Doctores, 06726 Mexico City, México.

Unlabelled: Aerosol measles vaccination has been found to be more immunogenic than subcutaneous administration as a booster in school aged children, and immunogenic in 12-month-old children as a primary dose. The objective of the study was to evaluate immunogenicity to aerosol measles vaccine in 9-month-old children.

Methods: Nine-months-old infants received Edmonston-Zagreb measles vaccine by aerosol (10(3.58) CCID50/0.1 mL, estimated retained dose 10(2.81) CCID50 or subcutaneous route (10(4.28) CCID50/0.5 mL); cellular and humoral immunity and adverse events were assessed.

Results: Measles-specific T cell proliferative responses developed in 42% of children given aerosolized vaccine compared with 67% of those who received subcutaneous vaccine (p = 0.01); the mean stimulation index (SI) was 4.4+/-0.7 versus 6.9+/-1, respectively, (p = 0.05). Seroconversion rates were 33 and 92% after aerosol or subcutaneous immunization (p < 0.001). Among infants who developed serologic responses, measles geometric mean titers (GMT; 95% CI) by neutralizing antibody assay were 215 mIU/mL (115-400) in aerosol vaccine recipients and 411 mIU/mL (345-490) in those given subcutaneous vaccine (p = 0.06).

Conclusions: The proportion of 9-month-old infants who developed cellular and/or humoral immunity to measles was lower in the aerosol group but measles antibody and T cell responses were comparable among those who developed measles immunity. Differences in response rates are attributable to the lower aerosol dose. Improving aerosol delivery or increasing the dose may enhance immunogenicity of primary aerosol measles vaccination in this age group.
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http://dx.doi.org/10.1016/j.vaccine.2005.08.045DOI Listing
January 2006

T cell immunity to measles viral proteins in infants and adults after measles immunization.

Viral Immunol 2004 ;17(2):298-307

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.

Vaccination of infants against measles remains of global importance, and proposed new vaccine strategies include the use of measles proteins or synthetic peptides as immunogens. We studied cell-mediated immunity to whole measles antigen and measles proteins in immune adults and infants after measles vaccine. Further, we measured CD8+ T cell responses to peptide pools corresponding to the nucelocapsid (N) measles protein in adults given measles vaccine. Cell-mediated immune responses to three of four measles proteins were equivalent to those against whole measles antigen in immune adults. Responses to the fusion (F) protein were lower in infants compared to whole measles antigen (p < or = 0.03). Infant responses to both whole measles antigen and the F protein were lower compared with these responses in adults (p < or = 0.001). CD8+ T cell responses to N peptide pools varied, and differed between immune HLA-A2-positive individuals compared with naive and HLA-A2-negative subjects after measles vaccination. The measles-specific T cell adaptive response of infants is limited compared to adults, including responses to the F protein.
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http://dx.doi.org/10.1089/0882824041310522DOI Listing
September 2004

Humoral and cell-mediated immune responses to an early 2-dose measles vaccination regimen in the United States.

J Infect Dis 2004 Jul 26;190(1):83-90. Epub 2004 May 26.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5208, USA.

Background: Shifts in peak measles incidence to children <12 months old and the associated high mortality support the study of an early 2-dose measles vaccine regimen.

Methods: Fifty-five infants were vaccinated with measles vaccine at age 6 (n=32) or 9 (n=23) months, followed by measles-mumps-rubella (MMR)-II vaccine at age 12 months. A control group received MMR-II only at age 12 months. Measles-specific humoral and cell-mediated immunity were evaluated before, 12 weeks after measles immunization, and 24 weeks after MMR-II.

Results: Measles-specific T cell proliferation after both doses of vaccine was equivalent, regardless of age or the presence of passive antibodies. Seroconversion rates, geometric mean titers, and the percentage of infants with antibody titers >120 mIU after the first measles vaccine were lower in infants vaccinated at age 6 months, regardless of the presence of passive antibodies, but measles humoral responses increased after the administration of MMR-II vaccine in children initially vaccinated at age 6 or 9 months.

Conclusion: Measles vaccination elicits T cell responses in infants as young as 6 months old, which may prime the humoral response to the second dose. Initiating measles vaccination as an early 2-dose regimen results in an immunologic response that is likely to have clinical benefits in developed and developing countries.
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http://dx.doi.org/10.1086/421032DOI Listing
July 2004