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Background Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). Methods In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen’s κ statistics. Results Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95–1.00), but less concordant for severe RSV-LRTI (κ: 0.47–0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. Conclusions Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. Clinical trial registration NCT01995175.

Background Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12–23-month-old RSV-seropositive children followed up for 2 years after vaccination. Methods Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti–RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. Results Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. Conclusions Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. Clinical Trials Registration NCT02927873.

BackgroundThe true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life.MethodsThis prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods.ResultsOf 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88–9.08), 5.50 (95% CI, 4.21–7.07), and 2.87 (95% CI, 2.18–3.70) cases/100 person-years in children aged 0–5, 6–11, and 12–23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0–5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0–2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs.ConclusionsA substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most.Clinical Trials Registration. NCT01995175.

Background Vaccine attitudes of healthcare providers (HCPs) influence patient vaccine acceptance. We sought to characterize vaccine knowledge, attitudes, and practices (KAP) among HCPs in NYS. Methods An electronic survey was developed to assess vaccine KAP among HCPs. The questionnaires were sent to members of various national medical organizations via local chapter administrators. Results 864 surveys were returned from 672 (78%) physicians and 192 (22%) mid-level practitioners (MLPs). 624/724 (86%) of HCPs report always recommending routine vaccines to eligible patients, yet only 76% recommend influenza vaccine (IV) and 77% strongly recommend HPV vaccine at 11-12 yrs. MLPs had a higher mean agreement level that recommending vaccines (4.6 vs 4.2 p < 0.01) or promoting HPV vaccine (4.2 vs. 3.9 p < 0.05) is within their scope of practice. Physicians had a higher mean agreement level that: vaccine benefits outweigh risks (4.9 vs 4.6 p < 0.01), HPV vaccine prevents cancer (4.7 vs 4.5 p < 0.01), and COVID-19 vaccine is safe (4.8 vs 4.5 p < 0.01) and effective (4.8 vs 4.7 p < 0.01). 82% (680/825) of HCPs knew that vaccines should not be deferred for mild illness. 14/836 (2%) believed that HPV vaccine could increase sexual activity, while 273/705 (39%) knew that the most common HPV associated malignancy is oropharyngeal cancer. HCPs who correctly answered ≥ 5/7 questions (462/507 91%) were more likely to recommend all vaccines to eligible patients than HCPs with lower scores (22/40 50% p < 0.05). Routine IV recommendation was more likely among HCPs who: strongly disagree that influenza is not serious enough for vaccination (292/397 (74%) vs 137/249 (55%) p < 0.01), strongly agree that it prevents severe disease (267/352 (76%) vs 162/294 (55%) p < 0.01), and receive annual IV (423/629 (67%) vs 6/17 (35%)) p < 0.01). HPV vaccine recommendation at 11-12 years was more likely among HCPs who strongly agree that the vaccine prevents cancer (273/326 (84%) vs 48/86, 56% p < 0.01) and those who stated that vaccination does not increase risk of unprotected sex (316/392 (79%) vs 3/12 (25%) p < 0.01). Conclusion Vaccine recommendation practices are influenced by HCP vaccine misperceptions and hesitancy. Interventions to reduce misperceptions and improve vaccine confidence are needed. Disclosures Manika Suryadevara, MD, Janssen: Grant/Research Support|Merck: Grant/Research Support|Roche: Grant/Research Support.

Background Data regarding respiratory pathogen epidemiology in the tropical country of Ecuador are limited. Here, we describe the temporal patterns and etiologies of medically attended acute respiratory infections among Ecuadorean children during the 20-month period preceding the onset of the 2020 SARS-CoV-2 pandemic. Methods Children < 5 years old presenting to a designated outpatient clinic with at least 2 new symptoms consistent with an acute respiratory infection are eligible for enrollment. Informed consent is obtained. Demographic and clinical details are collected. A nasopharyngeal sample is collected for diagnostic testing of 22 target pathogen groups using Biofire’s Respiratory Panel v1.7 multiplex polymerase chain reaction assay. Results Of the 820 subjects enrolled between July 15, 2018 and March 15, 2020, 655 (80%) tested positive for at least one pathogen. The detection of pathogens was more likely from samples collected from children enrolled in Quito (85%) compared to Machala (76%) (p < 0.05). The most frequently detected pathogen groups were rhinovirus/enterovirus (46%), parainfluenza virus (14%), respiratory syncytial virus (RSV) (12%), and influenza virus (10%). Two or more pathogen groups were co-detected in 174 (27%) of the respiratory samples. Pathogen specific seasonal patterns were not observed for rhinovirus/enterovirus, adenovirus, or atypical bacteria at either site. Samples collected in Quito were positive for the detection of RSV spanning a 32-week period between November and June. In contrast, detection of RSV from samples collected in Machala spanned only a 17- week period between February and May. In Quito, influenza viruses were detected between August and February, with influenza A activity preceding that of influenza B. In Machala, the detection of influenza B virus coincided with the dry season, while detection of influenza A virus was clustered in the rainy period between January and March. Conclusion The specific etiologies and seasonality of acute respiratory tract infections among Ecuadorean children < 5 years of age differ by site of enrollment. Such differences in regional data can be used to optimize regional implementation of existing and soon-to-be available public health prevention measures. Disclosures Manika Suryadevara, MD, Janssen: Grant/Research Support|Merck: Grant/Research Support|Roche: Grant/Research Support.

Implementation of respiratory virus prevention measures requires detailed understanding of regional epidemiology; however, data from many tropical countries are sparse. We describe etiologies of ambulatory pediatric acute respiratory tract infections (ARTI) in Ecuador immediately preceding the onset of the SARS-CoV-2 pandemic.Children 5 years presenting to a designated study site with an ARTI were eligible. Informed consent was obtained. Demographic and clinical data were recorded. A nasopharyngeal swab was collected, processed, and analyzed using multiplex polymerase chain reaction (PCR) for common respiratory pathogens. Rhinovirus/enterovirus positive samples were further characterized by genomic sequencing.A total of 820 subjects were enrolled in the study between July 2018 and March 2020. A total of 655 (80%) samples identified at least one pathogen. Rhinoviruses (44%) were most common, followed by enteroviruses (17%), parainfluenza viruses (17%), respiratory syncytial virus (RSV) (15%), and influenza viruses (13%). Enterovirus D68 was the most common enterovirus detected and was among the leading causes of bronchiolitis. Seasonal RSV and influenza virus activity were different along the coast compared with the highlands.Ongoing regional surveillance studies are necessary to optimize available and emerging pathogen-specific preventative measures.

Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing the F-, N- and M2-1 proteins, administered to 12-23-month-old RSV-seropositive children followed for 2 years post-vaccination.Children were randomized to receive 2 doses of ChAd155-RSV or placebo (1:1) (Day 1 and 31). Doses escalated from 0.5 × 1010 low (LD) to 1.5 × 1010 medium (MD) to 5 × 1010 high (HD) viral particles after safety assessment. Study endpoints included anti-RSV-A neutralizing antibody (Nab) titers through Year 1, and safety through Year 2.Eighty-two participants were vaccinated: 11 RSV-LD, 14 RSV-MD, 18 RSV-HD, 39 placebo. Solicited adverse events were similar across groups, except fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups post-dose 1 without further increase post-dose 2. RSV-A Nab titers remained higher than pre-vaccination levels at Year 1.Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed post-dose 1 with no observed booster effect post-dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted.clinicaltrials.gov NCT02927873, URL: https://www.clinicaltrials.gov/ct2/show/NCT02927873.Respiratory syncytial virus (RSV) is one of the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing three important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted over one year.

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose.In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose.From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions.A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).

Background Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. Methods A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-μg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. Results During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 μg, 20 μg, or 30 μg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 μg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). Conclusions A Covid-19 vaccination regimen consisting of two 10-μg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Objective The SENTINEL1 observational study characterized confirmed respiratory syncytial virus hospitalizations (RSVH) among U.S. preterm infants born at 29 to 35 weeks' gestational age (wGA) not receiving respiratory syncytial virus (RSV) immunoprophylaxis (IP) during the 2014 to 2015 and 2015 to 2016 RSV seasons. Study Design All laboratory-confirmed RSVH at participating sites during the 2014 to 2015 and 2015 to 2016 RSV seasons (October 1–April 30) lasting ≥24 hours among preterm infants 29 to 35 wGA and aged Results Results were similar across the two seasons. Among infants with community-acquired RSVH (N = 1,378), 45% were admitted to the intensive care unit (ICU) and 19% required invasive mechanical ventilation (IMV). There were two deaths. Infants aged Conclusion Among U.S. preterm infants 29 to 35 wGA not receiving RSV IP, RSVH are often severe with almost one-half requiring ICU admission and about one in five needing IMV.

Infections caused by respiratory syncytial virus (RSV) are a major cause of morbidity and mortality in young children worldwide. Understanding seasonal patterns of region-specific RSV activity is important to guide resource allocation for existing and future treatment and prevention strategies. The decades of excellent RSV surveillance data that are available from the developed countries of the world are incredibly instructive in advancing public health initiatives in those regions. With few exceptions, these developed nations are positioned geographically across temperate regions of the world. RSV surveillance across tropical regions of the world has improved in recent years, but remains spotty, and where available, still lacks the necessary longitudinal data to determine the amount of seasonal variation expected over time. However, existing and emerging data collected across tropical regions of the world do indicate that patterns of infection are often quite different from those so well described in temperate areas. Here, we provide a brief summary regarding what is known about general patterns of RSV disease activity across tropical Asia, Africa and South America, then offer additional country-specific details using examples where multiple reports and/or more robust surveillance data have become available.

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children, and older or immunocompromised adults. Although aerosolized ribavirin was licensed for RSV treatment on the basis of data demonstrating a reduced need for supplemental oxygen, ribavirin use is limited because of issues with efficacy, safety, and cost. Currently, the treatment of RSV is primarily supportive. New antiviral treatments for RSV are in the early stages of development, but it will be years until any of these may be licensed by the US Food and Drug Administration (FDA). Palivizumab, an RSV monoclonal antibody [immunoprophylaxis (IP)], has demonstrated effectiveness in disease prevention and is the only licensed IP for RSV disease in specific high-risk pediatric populations. Although its efficacy is well established, some challenges that may interfere with its clinical use include cost, need for monthly injections, and changing policy for use by the American Academy of Pediatrics (AAP). Preventing RSV disease would be possible through RSV vaccine development (e.g., live-attenuated, vector-based subunit, or particle-based). Alternatively, new long-acting monoclonal antibodies have demonstrated promising results in early clinical trials. Despite scientific advances, until new agents become available, palivizumab should continue to be used to reduce RSV disease burden in high-risk patients for whom it is indicated.

Immunizations are among the safest and most effective medical interventions available. Current US recommended immunization schedules show the age at which each vaccine series should begin and the ideal range for the time interval between each dose. An appreciation for the rationale behind these recommendations can be achieved through the careful study and understanding of key concepts from the disciplines of biochemistry, immunology, microbiology, and infectious disease epidemiology. By combining the relevant aspects from each of these fields of study, the specialized discipline known as vaccinology begins to take focus. To begin, it is first important to gain a general understanding of the immune response to infection, because the same principles apply to the protective immune responses that can be achieved with vaccination.

Tick-borne encephalitis is a serious infection of the central nervous system that is caused by the flavivirus tick-borne encephalitis virus. Between 8000 and 15,000 cases of central nervous system disease are reported from endemic areas each year; however, the total disease burden remains incompletely understood due to underdiagnosis. The natural reservoir of the virus includes several species of hard ticks and their small mammalian hosts. Disease is transmitted to humans via the bite of an infected tick. Human infections are more common in males and predictably more severe with advancing age. Disease is restricted geographically to Europe and Asia with the highest numbers of cases consistently reported from Russia and the Baltic nations. Infections caused by each of the three recognized virus subtypes differ in clinical severity and in geographic distribution. Inactivated whole virus vaccines have been shown to be safe and highly effective in preventing disease. Individuals at high risk for tick exposure who reside in or travel to endemic areas of the infection should be immunized. Those who continue to have risk factors should receive booster doses of vaccine every 5 years or as recommended by local health officials.

The active ingredient(s) included in vaccines are the pathogen-specific immunogens. Inactive ingredients are called excipients. A review of the long list of excipients included in any vaccine quickly reveals that the vast majority represent trace or residual concentrations of substances used during the manufacturing process. Residual substances include all components of the biologic culture medium used to support cell growth during amplification of the active vaccine components; any antibiotics used to prevent culture contamination; substances used to inactivate pathogens or toxins; and chemicals used to extract, purify, and concentrate the vaccine immunogen(s). All of these substances are essentially removed during subsequent manufacturing steps, leaving behind only trace amounts in the final vaccine product. A second group of vaccine excipients are the substances added to the vaccine during the final manufacturing steps. The precise amounts added remain in the final product to serve a specific purpose. Examples include agents used to stabilize the active vaccine component, substances called adjuvants that enhance vaccine immunogenicity, and vaccine preservatives. Every substance listed as an excipient in a vaccine plays a necessary role during manufacturing and production. Excipients necessary for manufacturing that do not serve a function in the final vaccine product are reduced to residual or trace concentrations in the final product.

The steps needed to bring an investigational vaccine candidate from the laboratory bench to the clinic are complex, highly regulated, costly, and time consuming. Years of preclinical effort are usually necessary before a candidate vaccine is ready to be studied in humans. Phase I, or “first in human,” clinical trials are organized first, involving only a small number of subjects. They are designed to evaluate the safety profile of the investigational vaccine to determine whether a larger Phase II trial should follow. Phase II studies continue to assess safety while beginning to assess “proof of concept.” For vaccine studies, this is most often a preliminary evaluation of the vaccine’s ability to induce the anticipated immune response. Investigational vaccines that pass Phase II safety and “proof of concept” criteria move into Phase III. Phase III trials are large multicenter studies designed to evaluate the immunogenicity and/or efficacy of candidate vaccine. When applicable, this is done as a comparison with the current standard of care to be sure that any newly approved vaccine meets or exceeds options already available. Upon successful completion of Phase III studies, an application for licensure is submitted to the appropriate regulatory body. In the USA, the Food and Drug Administration has responsibility for the review and disposition. Official vaccine recommendations are developed and published by the Center for Disease Control’s Advisory Committee on Immunization Practices. Post licensure, Phase IV trials to evaluate the vaccine’s safety and effectiveness in the “real world” context have become routine.

Human coronaviruses (HCoVs) cause respiratory tract infections during childhood manifesting as common colds, bronchiolitis, croup and pneumonia. In temperate geographies, HCoV activity peaks between December and March. The epidemiology and manifestations of HCoV infections have not been previously reported from Ecuador.Children5 years who presented with ≥2 symptoms consistent with an acute respiratory tract infection were eligible for enrollment. After obtaining informed consent, demographic data and details regarding the acute illness were recorded. Secretions collected with a nasopharyngeal swab underwent diagnostic testing using multiplex polymerase chain reaction.A total of 850 subjects were enrolled. A total of 677 (80%) tested positive for at least 1 pathogen, including 49 (7.2%) who tested positive for ≥1 HCoV type. HCoV-NL63 was the most frequent type detected (39%), followed by HCoV-OC43 (27%), 229E (22%) and HKU1 (12%). Nearly all subjects who tested positive for HCoV had nasal congestion or secretions (47/49; 96%). The most frequent syndromic diagnosis was common cold (41%), followed by bronchiolitis (27%). We found no association between the infecting HCoV type and subject's syndromic diagnosis (P0.05) or anatomic location of infection (upper vs. lower respiratory tract; P0.05). The 2018-2019 peak HCoV activity occurred from October to November; the 2019-2020 peak occurred from January to February.HCoVs were detected in ~7% of outpatient Ecuadorean children5 years of age with symptoms of acute respiratory tract infection. The most frequently detected HCoV types, and the period of peak HCoV activity differed for the 2018-2019 and 2019-2020 seasons.

Background In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. Methods This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6–12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. Results Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. Conclusion Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.

A single dose of either 30 µg or 60 µg of nonadjuvanted respiratory syncytial virus prefusion F protein antigen boosts humoral immune responses in women of childbearing age. The investigational vaccine was well tolerated and had a safety profile similar to that of the widely used combined Tdap vaccine., Background Respiratory syncytial virus (RSV) causes bronchiolitis and pneumonia in neonates and infants. RSV vaccination during pregnancy could boost preexisting neutralizing antibody titers, providing passive protection to newborns. Methods Two observer-blinded, controlled studies (RSV F-020 [clinical trials registration NCT02360475] and RSV F-024 [NCT02753413]) evaluated immunogenicity and safety of an investigational RSV vaccine in healthy, nonpregnant 18–45-year-old women. Both studies used a licensed adult formulation of combined tetanus toxoid-diphtheria toxoid-acellular pertussis (Tdap) vaccine as a control. RSV F-020 evaluated immunogenicity and safety: participants were randomized (1:1:1:1) to receive 1 dose of RSV–prefusion F protein (PreF) vaccine containing 30 µg or 60 µg of nonadjuvanted RSV-PreF, 60 µg of aluminum-adjuvanted RSV-PreF, or Tdap. RSV F-024 evaluated safety: participants were randomized 1:1 to receive 1 dose of 60 µg of nonadjuvanted RSV-PreF or Tdap. Results Both studies showed similar reactogenicity profiles for RSV-PreF and Tdap. No serious adverse events were considered vaccine related. In RSV F-020, geometric mean ratios of RSV-A neutralizing antibody levels at day 30 versus prevaccination were 3.1–3.9 in RSV-PreF recipients and 0.9 in controls. Palivizumab-competing antibody concentrations increased >14-fold in RSV-PreF recipients on day 30. RSV antibody titers waned after day 30 but remained well above baseline through day 90. Conclusions All formulations of RSV-PreF boosted preexisting immune responses in 18–45-year old women with comparable immunogenicity. The RSV-PreF safety profile was similar to that of Tdap vaccine.

A previously healthy 50-year-old man presents with a 4-day history of fevers to 39 °C, chills, night sweats, headache, and myalgias. He describes the headache as continuous, dull, and pounding. The illness began during his travel home to the United States after a 4-week stay in Ecuador for the purpose of Spanish language immersion. He stayed with a local family who owns a small, rural cacao and banana plantation. The family had dozens of domestic cats to help control the rodent population around their farm. The man noted that he attempted to avoid the cats because they were heavily flea infested but awoke one morning last week to find one of the cats on his bed and dozens of flea bites on his lower extremities. He does not recall seeing or being bitten by mosquitoes or other insects, attributing their scarcity to the lack of rainfall during “dry season.” On physical examination, the patient appears moderately ill. His temperature is 38.7 °C. Other vital signs are normal. His neck is supple. He has no conjunctivitis. His mucous membranes are slightly dry, but his oropharyngeal exam is otherwise normal. He has normal heart sounds, and his lungs are clear. His abdomen is soft, without organomegaly. A complete neurological exam is normal. Initial laboratory results show mild leukopenia and thrombocytopenia, elevated hepatic transaminases, and elevated biomarkers of inflammation. A full battery of diagnostic studies is sent to the laboratory searching for the cause of his illness. Based on the history and initial laboratory test results, you treat the patient empirically with doxycycline for possible rickettsial infection. When he returns for follow-up 2 days later, he reports that the fevers and night sweats have resolved and that the headache is no longer constant. Results of serologic testing for rickettsial infection are suggestive of infection with Rickettsia typhi, the cause of endemic typhus. When the patient is seen again 3 weeks later, his illness has completely resolved. Repeat serologic testing for R. typhi showed the expected fourfold rise in titer between the initial result (acute) and subsequent result (convalescent), thereby confirming the diagnosis of endemic typhus.

A 32-year-old woman presents with 3 days of crampy abdominal pain associated with frequent loose stools. She states that the diarrhea is now bloody and is occurring almost every hour. She was in good health until 2 weeks ago when she was diagnosed with pyelonephritis, treated with a 10-day course of ciprofloxacin. When she finished the antibiotic course a week ago, her urinary symptoms had completely resolved. On physical examination, she appears in moderate distress. Her temperature is 38.7°C and heart rate is 110 beats per minute. Her abdomen is not distended, but she has diffuse tenderness in all four quadrants. The remainder of her examination is normal. Several laboratory diagnostic tests are sent, including a complete blood count, comprehensive metabolic panel, urinalysis, urine and stool cultures, and stool for Clostridioides difficile toxin. You explain to the patient that she most likely has developed C. difficile infection as a complication related to the antibiotic therapy used to treat her kidney infection and give her a prescription for 10 days of p.o. vancomycin. The next day, the laboratory confirms the presence of C. difficile toxin in the stool sample. When seen in follow-up a week later, the patient reports that she is doing well. Her diarrhea has resolved, and she is no longer having abdominal cramps. Nine days later, she returns to the office because her symptoms have recurred. She explains that she is now experiencing moderate abdominal cramps associated with watery stools every 2–3 hours and would like to be tested again for C. difficile infection. She has not felt feverish and has not noted blood in her stool. Her physical examination reveals diffuse abdominal tenderness, without distension or guarding. She has very active bowel sounds. You explain that approximately one in every five people experiences a recurrence after C. difficile infection. While repeat testing is unnecessary, repeat treatment is. You explain that the vast majority of people who experience a recurrence of infection respond completely to a repeat course of treatment, but that a small number of individuals do develop more stubborn disease that requires a change in the therapeutic approach. The patient is re-treated with 10 days of p.o. vancomycin. During follow-up discussions in the office 2 weeks later, and then by phone a month after that, the patient indicates that she has responded well to the second treatment course without signs of additional recurrences.

A previously healthy 4-year-old female is seen at a local urgent care with 2 days of fever to 104 °F, fatigue, myalgias, runny nose, cough, hoarse voice, and pain with speaking. A nasopharyngeal swab is positive for influenza A virus. She is diagnosed with influenza infection with associated laryngitis and discharged home with supportive care. She slowly improves over the following 2 days. However, on day 5 of illness, her parents bring her to the Emergency Department for recurrence of high fevers and worsening lethargy, cough, and respiratory distress. Vital signs include a temperature of 40 °C, heart rate 150 beats per minute, respiratory rate of 35 breaths per minute, and a blood pressure of 90/50 mmHg. She is ill-appearing and in moderate respiratory distress, with inspiratory stridor and retractions. A dose of nebulized epinephrine is administered immediately for presumed laryngotracheobronchitis without any clinical improvement. The otolaryngology team is emergently consulted and performs an endotracheal intubation for airway stabilization. On laryngoscopy, exudative tracheitis is noted. Samples of the exudates are obtained and sent to the microbiology laboratory for culture. Empiric intravenous antibiotic therapy (vancomycin and ceftriaxone) for bacterial tracheitis are initiated. The bacterial cultures of the tracheal exudates isolate methicillin-susceptible Staphylococcus aureus. Her antibiotic regimen is then de-escalated to intravenous oxacillin.

A 9-year-old previously healthy, fully immunized female is seen in the pediatrician’s office for a 3 day history of fevers to 102 °F, cough, and right-sided abdominal pain. On examination, she has a temperature of 38.6 °C, heart rate of 120 beats per minute, respiratory rate of 20 breaths per minute, and oxygen saturations of 94% on room air. She is mildly ill-appearing, with crackles over the right lung base noted on auscultation. The remainder of her exam is benign. She is clinically diagnosed with right lower lobe community-acquired pneumonia (CAP). A 10-day course of oral amoxicillin is prescribed. Two days later, she is seen in the emergency department for persistent fevers, now up to 104 °F, worsening dyspnea, chest pain, abdominal pain, and vomiting. A chest x-ray at this time reveals a right lower lobe pneumonia with a large pleural effusion. She is admitted to the hospital for management of complicated CAP and treated with intravenous ampicillin. The pleural fluid is drained and sent to the microbiology lab for diagnostic evaluation. PCR of the pleural fluid is positive for Streptococcus pneumoniae, the most common cause of bacterial CAP. She continues receiving intravenous ampicillin during her hospital stay. By day 5, she has been afebrile for over 24 hours, tolerating oral intake, and has no supplemental oxygen requirement. She is discharged home to complete a course of oral amoxicillin for treatment of complicated CAP.

A 2-month-old male is brought to the emergency department via ambulance for evaluation of apnea. The mother states that he was previously well until a few days ago when he developed mild rhinorrhea and nasal congestion. He had no further symptoms until the day of presentation when he stopped breathing for 20–30 seconds and turned blue. EMS was called and brought him in for evaluation. He was born full term, via normal spontaneous vaginal delivery, with no complications. He was discharged home with the mother after 24 hours and has been healthy up until this illness. He lives at home with his parents, a 9-year-old brother and a 15-year-old sister. The mother states that she has had colds and allergies presenting as cough over the past few weeks. There have been no other exposures or sick contacts. The infant does not go to daycare. Due to persistent and worsening apnea, bradycardia, and desaturations in the emergency department, the patient is intubated and placed on mechanical ventilation. A complete blood count (CBC) shows a total leukocyte count of 44,000 cells/μL, with 90% lymphocytes and 10% neutrophils. The remainder of the CBC, electrolytes, and hepatic function panel are within normal limits. A chest radiograph is benign. Blood cultures are negative. A posterior nasopharyngeal swab is positive for Bordetella pertussis by polymerase chain reaction (PCR). A 5-day course of azithromycin is initiated. On further questioning, the 9-year-old brother last received a pertussis-containing vaccine at 4 years of age. The 15-year-old sister received her last pertussis-containing vaccine at 11 years of age. The mother had not received a pertussis-containing vaccine booster since childhood since she had declined the recommended Tdap vaccine during her third trimester of this pregnancy. Chemoprophylaxis with azithromycin is provided to all of the household contacts and to the attending physician who performed the intubation.

Lymphadenitis refers to any condition that results in an inflamed lymph node or group of lymph nodes. A careful medical history and physical examination are important when suspecting the diagnosis. Although infection is the most common cause of inflamed lymph nodes, noninfectious etiologies should also be considered. The history of the present illness, including the length of time the symptoms have been present, along with any associated systemic signs or symptoms can provide important clues about the underlying cause. A history of exposure to an infectious agent known to cause lymphadenitis and physical examination findings related to the anatomic location(s) of the affected lymph nodes can also be very useful in narrowing the broad differential diagnosis. By far, the most common causes of acute bacterial lymphadenitis are Staphylococcus aureus and Streptococcus pyogenes. As a group, subacute and chronic lymphadenitis is less common than acute infection but carries a much broader differential diagnosis with nontuberculous mycobacteria and Bartonella henselae, the cause of cat scratch disease, becoming the primary considerations. While tuberculosis (TB) is generally considered an infection of the lungs, one of the well-described clinical presentations of extrapulmonary TB is chronic lymphadenitis. Less common microbiologic causes of lymphadenitis include other bacteria, a variety of viruses, several fungi, and at least one parasite. Acute lymphadenitis is often treated empirically with antimicrobial agents effective against S. aureus and S. pyogenes. When the illness is atypical, prolonged, or severe, a diagnostic evaluation that includes blood tests, imaging studies, and screening for TB should be performed. If the diagnosis remains enigmatic despite those efforts, fine needle aspiration, lymph node biopsy, or complete surgical excision of the inflamed lymph node may be necessary. Surgically obtained tissue should be sent for microbiologic studies and for histologic evaluation. Definitive medical treatment depends on the identified underlying cause.

A 13-month-old immunized female is seen in the pediatrician’s office for evaluation of fever. She was well until one week prior to the office visit, when her illness began with a runny nose and mild cough. Three days prior to the office visit, she developed fevers to 103 ° F, increased fussiness, and difficulty sleeping. On physical examination, she is tired and fussy but not toxic in appearance. Rhinorrhea is present. Her right tympanic membrane is erythematous and bulging, with an effusion present. Pneumatic otoscopy reveals reduced mobility of the tympanic membrane. She is diagnosed with a right acute otitis media and prescribed amoxicillin to cover for the most common causes of AOM including Streptococcus pneumoniae.

A previously healthy boy 6 year old is seen in the pediatrician’s office with a 2-day history of fever, sore throat, and rash. There are no sick contacts at home. On physical exam, he has a temperature of 38.4 °C and appears tired but nontoxic. The remainder of his vital signs is normal for age. His oropharynx is erythematous. He has enlarged tonsils with exudates. Petechiae are noted on his palate. Tender anterior cervical lymphadenopathy is present bilaterally. There is a diffuse sandpaper-like rash present on his trunk. Rapid testing for group A streptococcus performed on a throat swab is positive. He is treated for scarlet fever with 10 days of oral amoxicillin.

During hospital rounds with the inpatient team, a medical student asks the attending “How do you decide what empiric antibiotic therapy to start for a patient hospitalized with a presumed infection?” The attending physicians explains the principles for deciding on empiric antibiotic therapy: (1) Identify the site(s) of infection. (2) Identify the most common infecting pathogens for the site(s), taking into account the patient’s immune status, medical history, and recent exposures. (3) Initiate antimicrobial treatment based on local susceptibility patterns of these pathogens and drug penetration at the site(s) of infection.

A 19-year-old university freshman is found unconscious lying on the floor of the shared bathroom in his residence hall. Emergency medical services are called. When they arrive, the student is breathing spontaneously, his heart rate is 130 beats per minute, and his blood pressure is 75/40. He moans briefly when two large bore intravenous catheters are placed. No clinical change is noted following an injection of naloxone. His fingerstick blood glucose is 180 mg/dl. A normal saline bolus is administered during his transfer to the hospital by ambulance, accompanied by his roommate.

A 9-year-old girl presents with fevers and myalgias for the past 3 days. Earlier today, her father noted that her left eyelid appeared “puffy.” The girl and her parents just returned from a 3-week trip to Peru, exploring the coastline and visiting the Incan ruins at Machu Picchu. For much of the visit, they stayed as guests in the home of their guide family, a three-room thatched structure with a dirt floor and makeshift tin roof. They report being diligent about taking malaria prophylaxis as prescribed and only drinking water treated with iodine. On physical examination, the girl is febrile. Her left eyelid and periorbital soft tissues are slightly swollen, and her left bulbar conjunctiva is injected. Shotty lymphadenopathy is present along the left anterior cervical chain. Three nontender pea-sized mobile lymph nodes are also palpable just anterior to her left ear. The remainder of her physical exam is normal. Laboratory test results show a normal complete blood count. Thick and thin “malaria smears” were negative for the presence of Plasmodium species but clearly demonstrated the presence of several extracellular, flagellated protozoa identified by the laboratory parasitologist as Trypanosoma cruzi, the etiologic agent of South American trypanosomiasis (aka Chagas disease). After conferring with the experts at the US Centers for Disease Control and Prevention, the patient was treated with the antiparasitic medication benznidazole. During treatment, complete blood counts and serum hepatic transaminases were monitored weekly as recommended. The patient made a full recovery.

A group of 10 young adults attended a summertime beach barbeque together. Each couple contributed to the food served during the picnic. It was a hot summer day, but everything was stored in coolers, on ice, until they were ready to eat. The par-boiled chicken was kept in a cooler separate from the other items. All ten people ate the BBQ chicken served right off the grill. All five women and four of the men ate the macaroni and fruit salads. All ten drank beer with the meal. After they finished eating, they played volleyball on the beach for an hour and then enjoyed cooling down in the lake. On return to the picnic area, the man who had not eaten any macaroni or fruit salad earlier grabbed the salads from the table, where they had been left (covered) and finished the contents of both bowls, while the others enjoyed cold beer and chips. Two hours later, as the group packed up their belongings to head home, then man who had finished off the salads complained of feeling nauseous and began vomiting. When it was suggested that he may have developed food poisoning, he questioned the possibility because he ate the same things that everyone else had eaten. When reminded that he was the only one who had eaten the macaroni salad after it had been sitting unrefrigerated at temperatures over 90°F for several hours, he realized his mistake. He continued to vomit for 3 more hours and then began to feel better. He slept well that night and awoke the next day feeling fine. He called his sister, a public health nurse, later that afternoon to recount his miserable experience. She informed him that he very likely developed staphylococcal food poisoning from a toxin that was being made by the bacteria present in the salad as it sat in the heat all afternoon. The others did not fall ill because the toxin was not present in the salad at the time they ate it. Both were glad that he was the only one from the group who was foolish enough to eat the salad after it had gone unrefrigerated for so long. He has paid closer attention to careful food handling practices ever since.

A 41-year-old female with breast cancer presents to the outpatient infusion center for her scheduled weekly dose of intravenous chemotherapy. She states that she’s been more fatigued than usual since her last dose 1 week ago, but otherwise feels well. Her temperature is 37.2°C, pulse 82 beats per minute, respirations 16 per minute, blood pressure 112/80 mmHg, and pulse oximetry 99%. The skin overlying the location of the implanted venous access “port” device appears normal. Using aseptic technique, her nurse inserts a 90° Huber needle percutaneously into the reservoir, verifying good blood return. She collects blood to send to the laboratory for a complete blood count and comprehensive metabolic panel and then flushes the catheter with 5 ml of saline. As she finishes, the patient develops shaking chills. Her temperature is now 39.4°C, pulse 128 beats per minute, and blood pressure 132/86. Blood cultures of equal volume are collected from the line and from a peripheral vein, and empiric treatment with vancomycin and piperacillin plus tazobactam is started via a peripheral intravenous catheter. The chemotherapy is postponed, and the patient is admitted to the hospital. Results from the complete blood count show an absolute neutrophil count of 1900 cells/μl. Six hours later, the laboratory reports that the blood culture collected from the central line shows growth of Gram-positive cocci in clusters. The organism is further identified the next day as Staphylococcus epidermidis, susceptible to vancomycin. The laboratory report is further updated indicating that the blood culture collected from the peripheral vein was now also positive for growth of Gram-positive cocci in clusters, lagging the time to positivity of the central line culture by 21 hours. The peripheral blood culture isolate was subsequently identified to be S. epidermidis, with the same antibiotic susceptibility profile as the isolate growing from the central line culture.

A 12-year-old female was evaluated in the emergency department (ED) for a swelling on her right leg. She is previously healthy; however, she has several mosquito bites on her leg which she has been scratching. Over the past 12 hours, she has had worsening redness and swelling around one of the mosquito bites, with associated fevers and vomiting. In the ED, she is febrile to 39 °C. Her physical examination is significant for a 10-cm tender area of redness, induration, warmth, and fluctuance on her right leg just above her knee. Incision and drainage of the abscess are performed at the bedside. The evacuated purulent material is sent for Gram stain and bacterial culture. She is admitted to the hospital and treated with intravenous vancomycin and cefazolin to target the most likely causes of the infection: Streptococcus pyogenes and methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Culture results reveal Staphylococcus aureus, a catalase-positive, coagulase-positive gram-positive coccus typically seen as purple grape-like clusters on Gram stain. Rapid latex agglutination testing is positive for the detection of penicillin-binding protein (PBP) 2A. Expression of this protein further identifies the organism as methicillin-resistant S. aureus (MRSA). IV cefazolin was discontinued. Vancomycin is continued while awaiting the full antimicrobial susceptibility report. On hospital day 2, antimicrobial susceptibilities reveal that the isolate is susceptible to clindamycin. At this time, the patient is afebrile, showing signs of clinical improvement, and tolerating oral intake without vomiting. Her treatment is switched from IV vancomycin to oral clindamycin, and she is discharged home with a diagnosis of MRSA skin abscess. Her infection resolves completely after treatment with a 10-day course of clindamycin.

A previously healthy 6-year-old girl is seen in the pediatrician’s office with complaints of pain with urination, urinary frequency, urgency, and blood in her urine. She is afebrile in the office. Her physical examination is benign with the exception of tenderness to palpation of her suprapubic region. A midstream clean catch urine sample is sent to the laboratory for diagnostic studies. In the office, a urine dipstick reveals the presence of leukocyte esterase, nitrites, hemoglobin, and protein. Since she is well-appearing and maintaining oral intake, empiric treatment for a lower urinary tract infection is initiated with oral cephalexin. The unspun urine Gram stain reveals 3+ white blood cells and 3+ Gram-negative rods. The urine culture grows E. coli, susceptible to cephalexin. The pediatrician calls the mother to discuss the culture results on day 2 of antibiotic treatment. The mother states the child is feeling much better. The pediatrician explains that the child does not need any imaging studies of her kidneys or bladder since this is an uncomplicated UTI and she has not had prior urinary tract infections. Oral cephalexin is continued for a total of 10 days. Follow-up urine cultures are only necessary if she fails to improve or develops symptoms again after her treatment is complete.

A previously healthy 17-year-old girl is seen in the emergency department with complaints of left lower quadrant abdominal pain, vomiting, and fevers for the last 2 days. She does not have a prior history of urinary tract infections. Her appendix was removed when she was 6 years old. She states that she is sexually active and has had three male partners over the past 3 months, with intermittent condom use. Her temperature is 38 °C, with normal vital signs otherwise. On physical examination, she has tenderness of the left lower quadrant of her abdomen, without rebound or guarding. On pelvic exam, her cervix is friable with motion tenderness. On bimanual exam, she has moderate left adnexal tenderness. Results of laboratory studies include a total white blood cell count of 26,000 cells/μL with 85% neutrophils and 15% lymphocytes, an elevated erythrocyte sedimentation rate, and an elevated C-reactive protein. Swabs of the cervix, taken during the pelvic exam, were sent to the laboratory for a wet mount, KOH prep, and nucleotide acid amplification testing for gonorrhea, chlamydia, and trichomonas. The laboratory calls with positive results for both gonorrhea and chlamydia. A screening blood test for syphilis and a fourth-generation HIV test are negative. The girl is hospitalized for treatment of pelvic inflammatory disease. After 4 days of treatment with intravenous cefoxitin and oral doxycycline, her pain is well-controlled, and she is fever free for 48 hours. Results of a repeat erythrocyte sedimentation rate and C-reactive protein are improved. The girl is discharged home to complete a 14-day course of doxycycline. Her sexual partners are contacted by the local health department and advised to seek medical attention and treatment for chlamydia and gonorrhea.

A previously healthy 38-year-old man presents with progressive somnolence and feeling off balance when walking. During the last 2 weeks, he has had difficulty concentrating at work, unable to complete even simple tasks. He feels very sleeping, especially during the daytime, despite sleeping up to 15 hours each day. The man is a university mathematics professor who had been spending semester breaks visiting different regions of West Africa on safari for 2–3 week trips over the last 3 years. He reports “dozens” of insect bites during each trip but states that he is always careful to take prescribed malaria prophylaxis as instructed. He was hospitalized 2 months ago to be evaluated for fever, chills, and somnolence. Further discussion with the man and his spouse reveals that his symptoms began more than 8 months ago. He describes several episodes of memory problems such as losing his way while driving to his son’s school function. His spouse has noticed that he has become increasingly irritable, preferring to “sleep the day away.” The patient also notes problems with balance and coordination. On two occasions, he has fallen while walking to his car. These events have been occurring more frequently during the last month. The patient is sleepy and confused. His vital signs are normal. His physical examination reveals abnormal memory and cognition, generalized hypertonia, hyperreflexia, and ataxia. He is unable to walk without assistance. An extensive diagnostic evaluation was performed including laboratory and neuroimaging studies. Evaluation of the cerebrospinal fluid revealed a cell count of 65/μl with 90% lymphocytes and 10% neutrophils, a protein concentration of 987 mg/dL, and glucose 47 mg/dL. CSF studies for bacteria, mycobacteria, fungi, and viruses were negative. Giemsa stain of concentrated cerebrospinal fluid revealed a single trypanosome parasite by microscopy. Treatment for neurologic stage West African sleeping sickness, caused by infection with Trypanosoma brucei gambiense, is initiated with eflornithine. After 7 days of treatment, the patient is noted to be more alert and much less confused, although he remains unsteady on his feet. He completes 14 days of treatment followed by a month of inpatient physical therapy. He now walks without assistance and has been able to work part time. He undergoes repeat lumbar puncture every 2–3 months for the next 2 years to monitor for relapse of infection.