Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021.

BACKGROUND: Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. METHODS: Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. RESULTS: Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. CONCLUSIONS: Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.

Surveillance for Lyme Disease After Implementation of a Revised Case Definition - United States, 2022.

Lyme disease, a tickborne zoonosis caused by certain species of Borrelia spirochetes, is the most common vectorborne disease in the United States. Approximately 90% of all cases are reported from 15 high-incidence jurisdictions in the Northeast, mid-Atlantic, and upper-Midwest regions. After the implementation of a revised surveillance case definition in 2022, high-incidence jurisdictions report cases based on laboratory evidence alone, without need for additional clinical information. In 2022, 62,551 Lyme disease cases were reported to CDC, 1.7 times the annual average of 37,118 cases reported during 2017-2019. Annual incidence increased most in older age groups, with incidence among adults aged ≥65 years approximately double that during 2017-2019. The sharp increase in reported Lyme disease cases in 2022 likely reflects changes in surveillance methods rather than change in disease risk. Although these changes improve standardization of surveillance across jurisdictions, they preclude detailed comparison with historical data.

Association Between Prolonged Shedding of Zika Virus in Human Semen and Male Reproductive Tract Inflammation.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes congenital defects. Sexual transmission of ZIKV was confirmed in a recent epidemic; however, mechanisms behind ZIKV infection and persistence in the male reproductive tract (MRT) are unknown. Previously, we found that approximately 33% of men with symptomatic ZIKV infections shed ZIKV RNA in semen, and some men shed ZIKV RNA for >3 months. Here, we evaluated the semen of 49 ZIKV-infected men to identify immune factors correlating with long-term ZIKV shedding in semen and ZIKV-infected cell types in semen. We found that prolonged ZIKV RNA shedding in semen was associated with MRT inflammation, indicated by higher leukocyte counts and inflammatory cytokine concentrations in semen of long-term versus short-term shedders. In addition, we found ZIKV RNA in seminal leukocytes and epithelial cells. This study of human semen from ZIKV-infected men provides critical insights into the effects of ZIKV on MRT health.

Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response.

This report provides CDC recommendations to U.S. health care providers regarding treatment, pre-exposure prophylaxis, and postexposure prophylaxis of plague. Yersinia pestis, the bacterium that causes plague, leads to naturally occurring disease in the United States and other regions worldwide and is recognized as a potential bioterrorism weapon. A bioweapon attack with Y. pestis could potentially infect thousands, requiring rapid and informed decision making by clinicians and public health agencies. The U.S. government stockpiles a variety of medical countermeasures to mitigate the effects of a bioterrorism attack (e.g., antimicrobials, antitoxins, and vaccines) for which the 21st Century Cures Act mandates the development of evidence-based guidelines on appropriate use. Guidelines for treatment and postexposure prophylaxis of plague were published in 2000 by a nongovernmental work group; since then, new human clinical data, animal study data, and U.S. Food and Drug Administration approvals of additional countermeasures have become available. To develop a comprehensive set of updated guidelines, CDC conducted a series of systematic literature reviews on human treatment of plague and other relevant topics to collect a broad evidence base for the recommendations in this report. Evidence from CDC reviews and additional sources were presented to subject matter experts during a series of forums. CDC considered individual expert input while developing these guidelines, which provide recommended best practices for treatment and prophylaxis of human plague for both naturally occurring disease and following a bioterrorism attack. The guidelines do not include information on diagnostic testing, triage decisions, or logistics involved in dispensing medical countermeasures. Clinicians and public health officials can use these guidelines to prepare their organizations, hospitals, and communities to respond to a plague mass-casualty event and as a guide for treating patients affected by plague.

Estimating the Frequency of Lyme Disease Diagnoses, United States, 2010-2018.

By using commercial insurance claims data, we estimated that Lyme disease was diagnosed and treated in ≈476,000 patients in the United States annually during 2010-2018. Our results underscore the need for accurate diagnosis and improved prevention.

Zika Virus Shedding in Semen of Symptomatic Infected Men.

BACKGROUND: Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has been linked to adverse birth outcomes. Previous reports have shown that person-to-person transmission can occur by means of sexual contact. METHODS: We conducted a prospective study involving men with symptomatic ZIKV infection to determine the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. Specimens were obtained twice per month for 6 months after illness onset and were tested by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for ZIKV RNA and by Vero cell culture and plaque assay for infectious ZIKV. RESULTS: A total of 1327 semen samples from 184 men and 1038 urine samples from 183 men were obtained 14 to 304 days after illness onset. ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. ZIKV RNA shedding in semen decreased substantially during the 3 months after illness onset but continued for 281 days in 1 man (1%). Factors that were independently associated with prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness. Infectious ZIKV was isolated from 3 of 78 semen samples with detectable ZIKV RNA, all obtained within 30 days after illness onset and all with at least 7.0 log10 ZIKV RNA copies per milliliter of semen. CONCLUSIONS: ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. In contrast, shedding of infectious ZIKV appeared to be much less common and was limited to the first few weeks after illness onset. (Funded by the Centers for Disease Control and Prevention.).

Antimicrobial Treatment Patterns and Illness Outcome Among United States Patients With Plague, 1942-2018.

BACKGROUND: Plague is a rare and severe zoonotic illness with limited empiric evidence to support treatment recommendations. We summarize treatment information for all patients with plague in the United States (US) as collected under the auspices of public health surveillance. METHODS: We reviewed use of specific antimicrobials and illness outcome among cases of plague reported from 1942-2018. Antimicrobials were a priori classified into high-efficacy (aminoglycosides, tetracyclines, fluoroquinolones, sulfonamides, and chloramphenicol) and limited-efficacy classes (all others). Logistic regression models were created to describe associations between use of specific antimicrobial classes and illness outcome while controlling for potential confounding factors. RESULTS: Among 533 total reported plague cases during 1942-2018, 426 (80%) received high-efficacy antimicrobial therapy. Mortality differed significantly among those receiving high-efficacy therapy (9%) and only limited-efficacy therapy (51%). Aminoglycosides and tetracyclines were used more commonly than other classes, and their use was associated with increased odds of survival of plague. Gentamicin use was associated with higher mortality than streptomycin, and aminoglycoside use was linked to higher mortality than for tetracyclines. Fluoroquinolones have been used in treatment of >30% of patients in recent years and limited data suggest clinical effectiveness. CONCLUSIONS: Most US patients with plague have received effective antimicrobials. Aminoglycosides and tetracyclines substantially improve survival of plague, and fluoroquinolones may be equally as effective, yet lack sufficient data. Early recognition and early treatment with any of these antimicrobial classes remain the most important steps to improving survival of plague.

Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939-2019.

BACKGROUND: Plague, caused by the bacterium Yersinia pestis, has killed millions in historic pandemics and continues to cause sporadic outbreaks. Numerous antimicrobials are considered effective for treating plague; however, well-defined information on the relative efficacy of various treatments is lacking. We conducted a systematic review of published data on antimicrobial treatment of plague reported in aggregate. METHODS: We searched databases including Embase, Medline, CINAHL, Cochrane Library, and others for publications with terms related to plague and antimicrobials. Articles were included if they contained 1) a group of patients treated for plague, with outcomes reported by antimicrobial regimen, and 2) laboratory evidence of Y. pestis infection or an epidemiologic link to patients with laboratory evidence of Y. pestis. Case fatality rate by antimicrobial regimen was calculated. RESULTS: In total, 5837 articles were identified; among these, 26 articles published between 1939 and 2008 met inclusion criteria. A total of 2631 cases of human plague reported within these articles were included. Among cases classified by primary clinical form of plague, 93.6% were bubonic, 5.9% pneumonic, and 0.5% septicemic with associated case fatalities of 14.2%, 31.1%, and 20.0%, respectively. Case fatality rate among patients who received monotherapy with tetracyclines, chloramphenicol, aminoglycosides, or sulfonamides was 1.3%, 1.4%, 7.5%, and 20.2%, respectively. Fluoroquinolones were only given as part of combination therapy. Penicillin was associated with a case fatality rate of 75%. CONCLUSIONS: Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague. Additional research is needed to determine the efficacy of fluoroquinolones as monotherapy.

Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937-2019.

BACKGROUND: Yersinia pestis remains endemic in Africa, Asia, and the Americas and is a known bioterrorism agent. Treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in illness but can have serious side effects. Alternatives such as fluoroquinolones, tetracyclines, and sulfonamides are potentially safer but lack robust human data on efficacy. METHODS: We searched PubMed Central, Medline, Embase, and other databases for articles in any language with terms related to plague and antimicrobials. Articles that contained case-level information on antimicrobial treatment and patient outcome were included. We abstracted information related to patient demographics, clinical features, treatment, and fatality. RESULTS: Among 5837 articles screened, we found 762 published cases of treated plague reported from 1937 to 2019. Fifty-nine percent were male; median age was 22 years (range, 8 days-80 years). The case fatality rate was 20% overall. Most patients had primary bubonic (63%), pneumonic (21%), or septicemic (5%) plague, with associated case fatality rates of 17%, 27%, and 38%, respectively. Among those treated with an aminoglycoside (n = 407 [53%]), the case fatality rate was 13%. Among those treated with a sulfonamide (n = 322 [42%]), tetracycline (n = 171 [22%]), or fluoroquinolone (n = 61 [8%]), fatality was 23%, 10%, and 12%, respectively. Case fatality rate did not substantially differ between patients treated with 1 vs 2 classes of antimicrobials considered to be effective for plague. CONCLUSIONS: In addition to aminoglycosides, other classes of antimicrobials including tetracyclines, fluoroquinolones, and sulfonamides are effective for plague treatment, although publication bias and low numbers in certain treatment groups may limit interpretation.

Intervention To Stop Transmission of Imported Pneumonic Plague - Uganda, 2019.

Plague, an acute zoonosis caused by Yersinia pestis, is endemic in the West Nile region of northwestern Uganda and neighboring northeastern Democratic Republic of the Congo (DRC) (1-4). The illness manifests in multiple clinical forms, including bubonic and pneumonic plague. Pneumonic plague is rare, rapidly fatal, and transmissible from person to person via respiratory droplets. On March 4, 2019, a patient with suspected pneumonic plague was hospitalized in West Nile, Uganda, 4 days after caring for her sister, who had come to Uganda from DRC and died shortly thereafter, and 2 days after area officials received a message from a clinic in DRC warning of possible plague. The West Nile-based Uganda Virus Research Institute (UVRI) plague program, together with local health officials, commenced a multipronged response to suspected person-to-person transmission of pneumonic plague, including contact tracing, prophylaxis, and education. Plague was laboratory-confirmed, and no additional transmission occurred in Uganda. This event transpired in the context of heightened awareness of cross-border disease spread caused by ongoing Ebola virus disease transmission in DRC, approximately 400 km to the south. Building expertise in areas of plague endemicity can provide the rapid detection and effective response needed to mitigate epidemic spread and minimize mortality. Cross-border agreements can improve ability to respond effectively.

Public Health Responses to COVID-19 Outbreaks on Cruise Ships - Worldwide, February-March 2020.

An estimated 30 million passengers are transported on 272 cruise ships worldwide each year* (1). Cruise ships bring diverse populations into proximity for many days, facilitating transmission of respiratory illness (2). SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) was first identified in Wuhan, China, in December 2019 and has since spread worldwide to at least 187 countries and territories. Widespread COVID-19 transmission on cruise ships has been reported as well (3). Passengers on certain cruise ship voyages might be aged ≥65 years, which places them at greater risk for severe consequences of SARS-CoV-2 infection (4). During February-March 2020, COVID-19 outbreaks associated with three cruise ship voyages have caused more than 800 laboratory-confirmed cases among passengers and crew, including 10 deaths. Transmission occurred across multiple voyages of several ships. This report describes public health responses to COVID-19 outbreaks on these ships. COVID-19 on cruise ships poses a risk for rapid spread of disease, causing outbreaks in a vulnerable population, and aggressive efforts are required to contain spread. All persons should defer all cruise travel worldwide during the COVID-19 pandemic.

Francisella opportunistica sp. nov., isolated from human blood and cerebrospinal fluid.

Two isolates of a Gram-negative, non-spore-forming coccobacillus cultured from the blood and cerebrospinal fluid of immunocompromised patients in the United States were described previously. Biochemical and phylogenetic analyses revealed that they belong to a novel species within the Francisella genus. Here we describe a third isolate of this species, recovered from blood of a febrile patient with renal failure, and formally name the Francisella species. Whole genome comparisons indicated the three isolates display greater than 99.9 % average nucleotide identity (ANI) to each other and are most closely related to the tick endosymbiont F. persica, with only 88.6-88.8 % ANI to the type strain of F. persica. Based on biochemical, metabolic and genomic comparisons, we propose that these three isolates should be recognized as Francisella opportunistica sp. nov, with the type strain of the species, PA05-1188T, available through the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSM 107100) and the American Type Culture Collection (ATCC BAA-2974).

Direct Diagnostic Tests for Lyme Disease.

Borrelia burgdorferi was discovered to be the cause of Lyme disease in 1983, leading to seroassays. The 1994 serodiagnostic testing guidelines predated a full understanding of key B. burgdorferi antigens and have a number of shortcomings. These serologic tests cannot distinguish active infection, past infection, or reinfection. Reliable direct-detection methods for active B. burgdorferi infection have been lacking in the past but are needed and appear achievable. New approaches have effectively been applied to other emerging infections and show promise in direct detection of B. burgdorferi infections.

Advances in Serodiagnostic Testing for Lyme Disease Are at Hand.

The cause of Lyme disease, Borrelia burgdorferi, was discovered in 1983. A 2-tiered testing protocol was established for serodiagnosis in 1994, involving an enzyme immunoassay (EIA) or indirect fluorescence antibody, followed (if reactive) by immunoglobulin M and immunoglobulin G Western immunoblots. These assays were prepared from whole-cell cultured B. burgdorferi, lacking key in vivo expressed antigens and expressing antigens that can bind non-Borrelia antibodies. Additional drawbacks, particular to the Western immunoblot component, include low sensitivity in early infection, technical complexity, and subjective interpretation when scored by visual examination. Nevertheless, 2-tiered testing with immunoblotting remains the benchmark for evaluation of new methods or approaches. Next-generation serologic assays, prepared with recombinant proteins or synthetic peptides, and alternative testing protocols, can now overcome or circumvent many of these past drawbacks. This article describes next-generation serodiagnostic testing for Lyme disease, focusing on methods that are currently available or near-at-hand.

Zika virus as a sexually transmitted pathogen.

PURPOSE OF REVIEW: Zika virus has recently emerged from an obscure mosquito-borne pathogen to an international public health concern. It is the first viral agent newly demonstrated to cause birth defects in several decades, and it is the only arbovirus now known to be transmitted sexually. The purpose of this review is to provide an overview of current understanding of sexual transmission of Zika virus and its possible clinical and public health consequences. RECENT FINDINGS: Sexual transmission of Zika virus has been reported from at least 13 countries without simultaneous mosquito-borne transmission; it is undoubtedly also occurring in countries with active arthropod transmission. Most published cases involve transmission from symptomatically infected men to women partners. Nevertheless, transmission from a symptomatic man to another man, from a symptomatic woman to a man, and from an asymptomatic man to a woman has also been reported. Sexual transmission has occurred before symptom onset, during illness, and after resolution of the source partner's symptoms. With the exception of a woman who developed symptomatic infection 44 days after onset of her husband's illness, nearly all instances reported to date have occurred within 20 days of the source partner's illness. Zika virus RNA has been detected in semen, saliva, blood, urine, and vaginal and cervical secretions; the length of time during which RNA can be detected varies widely across different body fluids but is especially lengthy in semen. Although semen has been found to contain ZIKV RNA for more than 180 days after illness onset, only a small proportion of samples with detectable RNA yield replicative virus whenever cultured. SUMMARY: Public health agencies have promulgated interim recommendations to prevent sexual transmission of Zika virus; however, much remains unknown regarding the duration of contagiousness and risk factors for transmission. Given the risk for birth defects, the greatest concern is for transmission of the virus to women who are pregnant or attempting to become pregnant. To prevent sexual transmission in general, couples are advised to use condoms or not have sex for at least 6 months from the start of the male partner's symptoms or the date he was diagnosed with Zika or after he has returned from an area with risk of ZIKV infection. Women who have symptomatic ZIKV infection or have traveled to an area of risk are advised to use condoms or avoid sex for 8 weeks from the start of the woman's symptoms or the date she was diagnosed with Zika or after the woman returns from the area of risk.

Vital Signs: Trends in Reported Vectorborne Disease Cases - United States and Territories, 2004-2016.

INTRODUCTION: Vectorborne diseases are major causes of death and illness worldwide. In the United States, the most common vectorborne pathogens are transmitted by ticks or mosquitoes, including those causing Lyme disease; Rocky Mountain spotted fever; and West Nile, dengue, and Zika virus diseases. This report examines trends in occurrence of nationally reportable vectorborne diseases during 2004-2016. METHODS: Data reported to the National Notifiable Diseases Surveillance System for 16 notifiable vectorborne diseases during 2004-2016 were analyzed; findings were tabulated by disease, vector type, location, and year. RESULTS: A total 642,602 cases were reported. The number of annual reports of tickborne bacterial and protozoan diseases more than doubled during this period, from >22,000 in 2004 to >48,000 in 2016. Lyme disease accounted for 82% of all tickborne disease reports during 2004-2016. The occurrence of mosquitoborne diseases was marked by virus epidemics. Transmission in Puerto Rico, the U.S. Virgin Islands, and American Samoa accounted for most reports of dengue, chikungunya, and Zika virus diseases; West Nile virus was endemic, and periodically epidemic, in the continental United States. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Vectorborne diseases are a large and growing public health problem in the United States, characterized by geographic specificity and frequent pathogen emergence and introduction. Differences in distribution and transmission dynamics of tickborne and mosquitoborne diseases are often rooted in biologic differences of the vectors. To effectively reduce transmission and respond to outbreaks will require major national improvement of surveillance, diagnostics, reporting, and vector control, as well as new tools, including vaccines.

Patterns of Human Plague in Uganda, 2008-2016.

Plague is a highly virulent fleaborne zoonosis that occurs throughout many parts of the world; most suspected human cases are reported from resource-poor settings in sub-Saharan Africa. During 2008-2016, a combination of active surveillance and laboratory testing in the plague-endemic West Nile region of Uganda yielded 255 suspected human plague cases; approximately one third were laboratory confirmed by bacterial culture or serology. Although the mortality rate was 7% among suspected cases, it was 26% among persons with laboratory-confirmed plague. Reports of an unusual number of dead rats in a patient's village around the time of illness onset was significantly associated with laboratory confirmation of plague. This descriptive summary of human plague in Uganda highlights the episodic nature of the disease, as well as the potential that, even in endemic areas, illnesses of other etiologies might be being mistaken for plague.

Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States.

The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks.

Effectiveness of Residential Acaricides to Prevent Lyme and Other Tick-borne Diseases in Humans.

BACKGROUND: In the northeastern United States, tick-borne diseases are a major public health concern. In controlled studies, a single springtime application of acaricide has been shown to kill 68%-100% of ticks. Although public health authorities recommend use of acaricides to control tick populations in yards, the effectiveness of these pesticides to prevent tick bites or human tick-borne diseases is unknown. METHODS: We conducted a 2-year, randomized, double-blinded, placebo-controlled trial among 2727 households in 3 northeastern states. Households received a single springtime barrier application of bifenthrin or water according to recommended practices. Tick drags were conducted 3-4 weeks after treatment on 10% of properties. Information on human-tick encounters and tick-borne diseases was collected through monthly surveys; reports of illness were validated by medical record review. RESULTS: Although the abundance of questing ticks was significantly lower (63%) on acaricide-treated properties, there was no difference between treatment groups in human-tick encounters, self-reported tick-borne diseases, or medical-record-validated tick-borne diseases. CONCLUSIONS: Used as recommended, acaricide barrier sprays do not significantly reduce the household risk of tick exposure or incidence of tick-borne disease. Measures for preventing tick-borne diseases should be evaluated against human outcomes to confirm effectiveness.