Consequences of Undervaccination - Measles Outbreak, New York City, 2018-2019.

BACKGROUND: Measles was declared eliminated in the United States in 2000, but the risk of outbreaks owing to international importations remains. An outbreak of measles in New York City began when one unvaccinated child returned home from Israel with measles; onset of rash occurred on September 30, 2018, 9 days after the child returned home. METHODS: We investigated suspected cases of measles by conducting interviews, reviewing medical and immunization records, identifying exposed persons, and performing diagnostic testing. Measles-mumps-rubella (MMR) vaccine (given as either MMR or measles-mumps-rubella-varicella vaccine and collectively referred to as MMR vaccine) uptake was monitored with the use of the Citywide Immunization Registry. The total direct cost to the New York City Department of Health and Mental Hygiene was calculated. RESULTS: A total of 649 cases of measles were confirmed, with onsets of rash occurring between September 30, 2018, and July 15, 2019. A majority of the patients (93.4%) were part of the Orthodox Jewish community, and 473 of the patients (72.9%) resided in the Williamsburg area of Brooklyn, New York. The median age was 3 years; 81.2% of the patients were 18 years of age or younger, and 85.8% of the patients with a known vaccination history were unvaccinated. Serious complications included pneumonia (in 37 patients [5.7%]) and hospitalization (in 49 patients [7.6%]); among the patients who were hospitalized, 20 (40.8%) were admitted to an intensive care unit. As a result of efforts to promote vaccination, the percentage of children in Williamsburg who received at least one dose of MMR vaccine increased from 79.5% to 91.1% among children 12 to 59 months of age. As of September 9, 2019, a total of 559 staff members at the Department of Health and Mental Hygiene (7% of the agency) had been involved in the measles response. The cost of the Department of Health and Mental Hygiene response was $8.4 million. CONCLUSIONS: Importation of measles and vaccination delays among young children led to an outbreak of measles in New York City. The outbreak response was resource intensive and caused serious illness, particularly among unvaccinated children.

Non-mumps Viral Parotitis During the 2014-2015 Influenza Season in the United States.

Background: During the 2014-2015 US influenza season, 320 cases of non-mumps parotitis (NMP) among residents of 21 states were reported to the Centers for Disease Control and Prevention (CDC). We conducted an epidemiologic and laboratory investigation to determine viral etiologies and clinical features of NMP during this unusually large occurrence. Methods: NMP was defined as acute parotitis or other salivary gland swelling of >2 days duration in a person with a mumps- negative laboratory result. Using a standardized questionnaire, we collected demographic and clinical information. Buccal samples were tested at the CDC for selected viruses, including mumps, influenza, human parainfluenza viruses (HPIVs) 1-4, adenoviruses, cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex viruses (HSVs) 1 and 2, and human herpes viruses (HHVs) 6A and 6B. Results: Among the 320 patients, 65% were male, median age was 14.5 years (range, 0-90), and 67% reported unilateral parotitis. Commonly reported symptoms included sore throat (55%) and fever (48%). Viruses were detected in 210 (71%) of 294 NMP patients with adequate samples for testing, ≥2 viruses were detected in 37 samples, and 248 total virus detections were made among all samples. These included 156 influenza A(H3N2), 42 HHV6B, 32 EBV, 8 HPIV2, 2 HPIV3, 3 adenovirus, 4 HSV-1, and 1 HSV-2. Influenza A(H3N2), HHV6B, and EBV were the most frequently codetected viruses. Conclusions: Our findings suggest that, in addition to mumps, clinicians should consider respiratory viral (influenza) and herpes viral etiologies for parotitis, particularly among patients without epidemiologic links to mumps cases or outbreaks.

Reportable Bacterial Infections among New York City-Born Infants, 2001-2009.

OBJECTIVE: To determine rates of reportable bacterial infections among infants in New York City and identify populations at risk and preventable causes of morbidity. STUDY DESIGN: This retrospective cohort study matched live births in New York City from 2001-2009 to reported cases of bacterial infections among infants less than 1 year of age. Characteristics recorded on birth certificates were compared between infants with bacterial enteric infection, bacterial nonenteric infection, and no reportable bacterial infection. Multinomial logistic regression and multivariable logistic regression were used to identify risk factors for infection. RESULTS: Bacterial infection was reported in 4.6 cases per 1000 live births. Of 4524 infants with a reportable infection, the majority (2880, 63%) had an enteric infection. Asian/Pacific Islanders in Brooklyn were the borough-level race/ethnic group with the highest enteric infection rate (8.5 per 1000 live births). Citywide, infants with enteric infections were disproportionately male, from higher poverty neighborhoods, born to foreign-born mothers, and enrolled in Special Supplemental Food Program for Women, Infants, and Children or Medicaid. In contrast, infants with nonenteric infections were more likely to have low birthweight and mothers characterized by US birth and black race or white Hispanic race/ethnicity. CONCLUSIONS: Distinct patterns of risk factors for enteric and nonenteric bacterial infections among infants were identified. The results suggest that infants born to Asian/Pacific Islander mothers residing in Brooklyn should be a focus of enteric disease prevention. More research is necessary to better understand what behaviors increase the risk of enteric disease in this population.

N-WASP has the ability to compensate for the loss of WASP in macrophage podosome formation and chemotaxis.

Wiskott-Aldrich syndrome protein (WASP) and its homologue neural-WASP (N-WASP) are nucleation promoting factors that integrate receptor signaling with actin cytoskeleton rearrangement. While hematopoietic cells express both WASP and N-WASP, WASP deficiency results in altered cell morphology, loss of podosomes and defective chemotaxis. It was determined that cells from a mouse derived monocyte/macrophage cell line and primary cells of myeloid lineage expressed approximately 15-fold higher levels of WASP relative to N-WASP. To test whether N-WASP can compensate for the loss of WASP and restore actin cytoskeleton integrity, N-WASP was overexpressed in macrophages, in which endogenous WASP expression was reduced by short hairpin RNA (shWASP cells). Many of the defects associated with the loss of WASP, such as podosome-dependent matrix degradation and chemotaxis were corrected when N-WASP was expressed at equimolar level to that of the wild-type WASP. Furthermore, the ability of N-WASP to partially compensate for the loss of WASP may be physiologically relevant since activated murine WASP-deficient peritoneal macrophages, which show enhanced N-WASP expression, also show an increase in matrix degradation. Our study suggests that expression levels of WASP and N-WASP may influence their roles in actin cytoskeleton rearrangement and shed light to the complex intertwining roles WASP and N-WASP play in macrophages.

Phagocytosis inhibits F-actin-enriched membrane protrusions stimulated by fractalkine (CX3CL1) and colony-stimulating factor 1.

Cryptococcus neoformans is the only encapsulated human-pathogenic fungus and a facultative intracellular pathogen that can reside in macrophages without host cell lysis. In the present study, we investigated how phagocytosis of C. neoformans affected the macrophage response to chemoattractants such as fractalkine (FKN) (CX3CL1) and colony-stimulating factor 1 (CSF-1). Phagocytosis of immunoglobulin G (IgG)-opsonized C. neoformans and IgG- or C3bi-opsonized sheep erythrocytes was performed using a RAW 264.7 subline (LR5 cells) and bone marrow-derived macrophages (BMM). The chemotactic response to FKN or CSF-1 was quantitated by measurement of the formation of F-actin-enriched membrane protrusions (ruffles), which showed that FKN or CSF-1 stimulated strong transient ruffling in both LR5 cells and BMM. This stimulated cell ruffling was inhibited by phagocytosis in an intracellular-pathogen-number-dependent manner. The inhibition of ruffling was not simply a result of reduced membrane availability since membrane sequestration by sucrose treatment did not inhibit the ruffling response. The phagocytosis process was required to inhibit ruffling as BMM from Fc gamma (-/-) mice that bound C. neoformans but did not ingest it retained the ability to ruffle in response to chemoattractants. These results imply that the inhibition of FKN- or CSF-1-stimulated cell ruffling was a direct consequence of the phagocytosis process. Since cell ruffling is a prelude to chemotaxis, this observation links two functions of macrophages that are critical to host defense, chemotaxis and phagocytosis. Phagocytosis-induced chemotactic suppression may enhance host defense by keeping these antimicrobial effector cells at infected sites and reduce the likelihood of microbial spread by wandering macrophages containing infectious cargo.

Rubella Surveillance and Diagnostic Testing among a Low-Prevalence Population, New York City, 2012-2013.

The New York City Department of Health and Mental Hygiene (DOHMH) receives clinical and laboratory reports for rubella. Because rubella immunoglobulin M (IgM) assays may produce false-positive results and rubella infections may be asymptomatic, interpretation of positive IgM results can be challenging. Rubella reports received by DOHMH in 2012 to 2013 were reviewed. The rubella IgM testing purpose was determined through case investigation. Results of IgM testing by indirect enzyme-linked immunosorbent assay (ELISA) and capture enzyme immunoassay (EIA) were compared to determine positive predictive value (PPV) and specificity. DOHMH received 199 rubella reports; 2 were true cases. Of all reports, 77.9% were tested for rubella IgM erroneously, 19.6% were tested for diagnostic purposes, 2.0% had unknown test purpose, and 0.5% were not tested. PPV of indirect ELISA was 6% overall, 14% for diagnostic tests, and 0% for tests ordered erroneously. PPV of capture EIA was 29% overall, 50% for diagnostic tests, and 0% for tests ordered erroneously. Overall, specificity was 52% for indirect ELISA and 85% for capture EIA. Limiting rubella IgM testing to patients for whom rubella diagnosis is suspected and using a more specific IgM assay have the potential to reduce false-positive rubella IgM results.

Delayed recognition of fatal invasive meningococcal disease in adults.

INTRODUCTION: Invasive meningococcal disease can be difficult to detect early in its course when patients may appear well and the severity of their illness is obscured by non-specific complaints. CASE PRESENTATION: We report five cases of meningococcal sepsis in adult patients who presented to an emergency department early in the course of their disease, but whose severity of illness was not recognized. CONCLUSION: Suspicion of meningococcal sepsis should be heightened in the setting of hypotension, tachycardia, elevated shock index, leukopaenia with left shift, thrombocytopaenia and hypokalaemia, prompting early sepsis care.

The chemotactic defect in wiskott-Aldrich syndrome macrophages is due to the reduced persistence of directional protrusions.

Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor that is required for macrophages to directionally migrate towards various chemoattractants. The chemotaxis defect of WASp-deficient cells and its activation by Cdc42 in vivo suggest that WASp plays a role in directional sensing, however, its precise role in macrophage chemotaxis is still unclear. Using shRNA-mediated downregulation of WASp in the murine monocyte/macrophage cell line RAW/LR5 (shWASp), we found that WASp was responsible for the initial wave of actin polymerization in response to global stimulation with CSF-1, which in Dictyostelium discoideum amoebae and carcinoma cells has been correlated with the ability to migrate towards chemoattractants. Real-time monitoring of shWASp cells, as well as WASp⁻/⁻ bone marrow-derived macrophages (BMMs), in response to a CSF-1 gradient revealed that the protrusions from WASp-deficient cells were directional, showing intact directional sensing. However, the protrusions from WASp-deficient cells demonstrated reduced persistence compared to their respective control shRNA and wild-type cells. Further examination showed that tyrosine phosphorylation of WASp was required for both the first wave of actin polymerization following global CSF-1 stimulation and proper directional responses towards CSF-1. Importantly, the PI3K, Rac1 and WAVE2 proteins were incorporated normally in CSF-1 - elicited protrusions in the absence of WASp, suggesting that membrane protrusion driven by the WAVE2 complex signaling is intact. Collectively, these results suggest that WASp and its phosphorylation play critical roles in coordinating the actin cytoskeleton rearrangements necessary for the persistence of protrusions required for directional migration of macrophages towards CSF-1.

Syk is required for monocyte/macrophage chemotaxis to CX3CL1 (Fractalkine).

CX3CL1 (fractalkine), the only member of the delta subclass of chemokines, is a known chemotactic factor for monocytes/macrophages as well as NK cells and T lymphocytes. In several pathologies, excessive production of CX3CL1 at specific sites leads primarily to monocyte/macrophage recruitment, which causes tissue and vascular damage. Despite their clinical relevance, the mechanisms underlying monocyte/macrophage chemotaxis to CX3CL1 remain poorly documented. The present report addresses this issue and identifies cell signaling crucial for this process. Using the murine monocyte/macrophage RAW cell line, we show that CX3CL1 treatment elicits a rapid and transient increase in F-actin and the formation of F-actin-enriched cell protrusions. CX3CL1 also triggers tyrosine phosphorylation of proteins localized in those protrusions. The protein tyrosine kinase Syk is activated upon CX3CL1 treatment, and reduction of Syk expression using RNA-mediated interference results in a specific and massive impairment of RAW cell migration to CX3CL1. Similar results are obtained using the Syk inhibitor, piceatannol. Cells with reduced Syk expression also exhibit a major defect in CX3CL1-induced cytoskeletal remodeling. These data suggest that in monocytes/macrophages, Syk is essential for proper reorganization of the actin cytoskeleton in response to CX3CL1 and is therefore required for cell chemotaxis to CX3CL1.