Factors Associated With Severe Illness in Patients Aged <21 Years Hospitalized for COVID-19.

OBJECTIVES: To describe coronavirus disease 2019 (COVID-19)-related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness. METHODS: We abstracted data from medical charts to conduct a cross-sectional study of patients aged <21 years hospitalized at 6 United States children's hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation. RESULTS: Of 947 hospitalized patients, 759 (80.1%) had COVID-19, of whom 287 (37.8%) had severe illness. Factors associated with severe illness included coinfection with respiratory syncytial virus (RSV) (PR 3.64) and bacteria (PR 1.88) in infants; RSV coinfection in patients aged 1 to 4 years (PR 1.96); and obesity in patients aged 5 to 11 (PR 2.20) and 12 to 17 years (PR 2.48). Having ≥2 underlying medical conditions was associated with severe illness in patients aged <1 (PR 1.82), 5 to 11 (PR 3.72), and 12 to 17 years (PR 3.19). CONCLUSIONS: Among patients hospitalized for COVID-19, factors associated with severe illness included RSV coinfection in those aged <5 years, obesity in those aged 5 to 17 years, and other underlying conditions for all age groups <18 years. These findings can inform pediatric practice, risk communication, and prevention strategies, including vaccination against COVID-19.

Characteristics and Clinical Outcomes of Children and Adolescents Aged <18 Years Hospitalized with COVID-19 - Six Hospitals, United States, July-August 2021.

During June 2021, the highly transmissible† B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating strain in the United States. U.S. pediatric COVID-19-related hospitalizations increased during July-August 2021 following emergence of the Delta variant and peaked in September 2021.§ As of May 12, 2021, CDC recommended COVID-19 vaccinations for persons aged ≥12 years,¶ and on November 2, 2021, COVID-19 vaccinations were recommended for persons aged 5-11 years.** To date, clinical signs and symptoms, illness course, and factors contributing to hospitalizations during the period of Delta predominance have not been well described in pediatric patients. CDC partnered with six children's hospitals to review medical record data for patients aged <18 years with COVID-19-related hospitalizations during July-August 2021.†† Among 915 patients identified, 713 (77.9%) were hospitalized for COVID-19 (acute COVID-19 as the primary or contributing reason for hospitalization), 177 (19.3%) had incidental positive SARS-CoV-2 test results (asymptomatic or mild infection unrelated to the reason for hospitalization), and 25 (2.7%) had multisystem inflammatory syndrome in children (MIS-C), a rare but serious inflammatory condition associated with COVID-19.§§ Among the 713 patients hospitalized for COVID-19, 24.7% were aged <1 year, 17.1% were aged 1-4 years, 20.1% were aged 5-11 years, and 38.1% were aged 12-17 years. Approximately two thirds of patients (67.5%) had one or more underlying medical conditions, with obesity being the most common (32.4%); among patients aged 12-17 years, 61.4% had obesity. Among patients hospitalized for COVID-19, 15.8% had a viral coinfection¶¶ (66.4% of whom had respiratory syncytial virus [RSV] infection). Approximately one third (33.9%) of patients aged <5 years hospitalized for COVID-19 had a viral coinfection. Among 272 vaccine-eligible (aged 12-17 years) patients hospitalized for COVID-19, one (0.4%) was fully vaccinated.*** Approximately one half (54.0%) of patients hospitalized for COVID-19 received oxygen support, 29.5% were admitted to the intensive care unit (ICU), and 1.5% died; of those requiring respiratory support, 14.5% required invasive mechanical ventilation (IMV). Among pediatric patients with COVID-19-related hospitalizations, many had severe illness and viral coinfections, and few vaccine-eligible patients hospitalized for COVID-19 were vaccinated, highlighting the importance of vaccination for those aged ≥5 years and other prevention strategies to protect children and adolescents from COVID-19, particularly those with underlying medical conditions.

Coronavirus Disease 2019 (COVID-19) Prevalences Among People Experiencing Homelessness and Homelessness Service Staff During Early Community Transmission in Atlanta, Georgia, April-May 2020.

BACKGROUND: In response to reported coronavirus disease 2019 (COVID-19) outbreaks among people experiencing homelessness (PEH) in other US cities, we conducted multiple, proactive, facility-wide testing events for PEH living sheltered and unsheltered and homelessness service staff in Atlanta, Georgia. We describe the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and associated symptoms, and review shelter infection prevention and control (IPC) policies. METHODS: PEH and staff were tested for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) during 7 April-6 May 2020. A subset of PEH and staff was screened for symptoms. Shelter assessments were conducted concurrently at a convenience sample of shelters using a standardized questionnaire. RESULTS: Overall, 2875 individuals at 24 shelters and 9 unsheltered outreach events underwent SARS-CoV-2 testing, and 2860 (99.5%) had conclusive test results. The SARS-CoV-2 prevalences were 2.1% (36/1684) among PEH living sheltered, 0.5% (3/628) among PEH living unsheltered, and 1.3% (7/548) among staff. Reporting fever, cough, or shortness of breath in the last week during symptom screening was 14% sensitive and 89% specific for identifying COVID-19 cases, compared with RT-PCR. Prevalences by shelter ranged 0-27.6%. Repeat testing 3-4 weeks later at 4 shelters documented decreased SARS-CoV-2 prevalences (0-3.9%). Of 24 shelters, 9 completed shelter assessments and implemented IPC measures as part of the COVID-19 response. CONCLUSIONS: PEH living in shelters experienced a higher SARS-CoV-2 prevalence compared with PEH living unsheltered. Facility-wide testing in congregate settings allowed for the identification and isolation of COVID-19 cases, and is an important strategy to interrupt SARS-CoV-2 transmission.

Current trends in translational research in leptospirosis.

PURPOSE OF REVIEW: In the past years, the importance of studying leptospirosis in a translational context has become more evident. This review addresses recent findings in the study of leptospirosis infection, focusing on those applicable to public health, or that will affect management and diagnosis of cases of leptospirosis. RECENT FINDINGS: We review here recent findings regarding translational aspects of leptospirosis research. Briefly, PCR or a combination of serology and PCR seem to have a higher sensitivity than the current gold standard (microagglutination test). More clinical trials are needed to determine the best treatment for mild and severe leptospirosis. Dendritic cells and γδ T cells seem to have an important role in the immune response to leptospirosis. Environmental assessment is emerging as a very useful tool. SUMMARY: In order to understand leptospirosis, multiple aspects need to be considered, including host, pathogen and environment. In this review, we will address newer diagnostics, current advances in immunology and treatment and the growing role of environmental assessment.

Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths.

Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergillosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)(3/4). The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)(3/2), an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.).

Utilization of omeprazole to augment subtherapeutic voriconazole concentrations for treatment of Aspergillus infections.

Voriconazole is the preferred antifungal agent for Aspergillus infections. Therapeutic drug monitoring is recommended to achieve target concentrations and prevent toxicity. However, variable pharmacokinetics, cytochrome P450 polymorphisms, and extensive drug-drug interactions can contribute to subtherapeutic concentrations. We report a voriconazole "boosting" effect of omeprazole to achieve target concentrations for the treatment of Aspergillus in a patient who had persistently subtherapeutic trough concentrations.

Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people.

We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m(2), who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)(3/4) and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.

Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people.

The majority of Americans are overweight, and the incidence of obesity continues to increase. This trend predisposes people to a number of deleterious consequences, including the metabolic syndrome and other conditions that lead to a greater number of hospital admissions. Invasive candidiasis is an important nosocomial infection that results from these admissions. Echinocandins such as micafungin are indicated for treatment. We have previously demonstrated that overweight patients exhibit higher micafungin systemic clearance (SCL) than leaner patients. We hypothesized that obese and extremely obese people would show even higher SCL than merely overweight patients. To test this, we performed a prospective study of 36 adult volunteers randomized to receive a single dose of either 100 mg or 300 mg of micafungin whose body mass index fell within one of the following categories: <25, 25 to 40, and >40 kg/m(2). The male-to-female ratio was 1:1. The minimum weight was 43 kg, the median 97 kg, and the maximum weight 155 kg. A two-compartment model was examined using the maximum likelihood solution via the expectation-maximization algorithm. Men had a higher median SCL of 1.53 liters/h versus 1.29 liters/h (P = 0.01) in the Mann-Whitney U-test. The typical SCL was 1.04 liters/h but increased by a factor of (weight/66)(0.75) as weight increased above 66 kg. Thus, the relationship between micafungin SCL and weight in adults is best described by fractal-geometry-based laws. Furthermore, micafungin SCL continues to increase as weight increases, with no obvious plateau. This leads to a requirement for strategies to determine individualized dosing levels for obese and extremely obese patients.

Gonococcal meningitis diagnosed by DNA amplification: case report and review of the literature.

We report a case of gonococcal meningitis diagnosed by DNA amplification. A 47-year old man presented with a 4-day history of asymmetric painful swelling of his ankles and wrists, and skin rash. He had sex with men only but was HIV negative. Headache and photophobia led to a cerebrospinal fluid (CSF) examination that revealed meningitis. Cultures were negative but we detected Neisseria gonorrhoeae in his urine and CSF using a GC/chlamydia DNA amplification assay. The patient was discharged without sequela after 14 days of intravenous ceftriaxone.

Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden.

The roles of innate immune responses in protection from or pathogenesis of severe leptospirosis remain unclear. We examined the role of Toll-like receptors (TLRs) in mouse infection and macrophage responses to Leptospira. C3H/HeJ mice (TLR4 deficient) and C3H/HeJ-SCID mice, but not C3H/OuJ mice (TLR4 intact), died after intraperitoneal infection with Leptospira interrogans serovar Icterohaemorrhagiae. Death in both C3H/HeJ mouse strains was associated with jaundice and pulmonary hemorrhage, similar to the patient from whom the isolate was obtained. In chronic sublethal infection, TLR4-deficient mice harbored more leptospires in liver, lung, and kidney than control mice. Heat-killed Leptospira stimulated macrophages to secrete proinflammatory cytokines, tumor necrosis factor alpha, interleukin-6, and macrophage inflammatory protein 2 not inhibited by polymyxin B, suggesting that leptospiral lipopolysaccharide (LPS) did not drive these responses. Anti-TLR4 and anti-MD-2 but not anti-CD14 monoclonal antibodies inhibited cytokine production. Peritoneal macrophages from CD14-/- and TLR2-/- mice exhibited no defect in cytokine responses to Leptospira compared to controls. Macrophages from C3H/HeJ, TLR4-/-, and MyD88-/- mice secreted far-lower levels of cytokines than wild-type macrophages in response to Leptospira. TLR4 plays a crucial role in protection from acute lethal infection and control of leptospiral burden during sublethal chronic infection. Cytokine responses in macrophages correlated with leptospiral clearance. These TLR4-dependent but CD14/TLR2-independent responses are likely mediated by a leptospiral ligand(s) other than LPS.

Mild, self-resolving acute leptospirosis in an HIV-infected patient in the Peruvian Amazon.

We report a case of acute, self-resolving leptospirosis presenting in a HIV-positive patient from the Peruvian Amazon. The patient presented with an undifferentiated acute febrile illness that resolved without treatment, diagnosed retrospectively as leptospirosis by serology and real-time polymerase chain reaction. Five months later, he was admitted because of a febrile illness with jaundice, hepatosplenomegaly, peripheral edema, and oral candidiasis. Because of the clinical suspicion of AIDS, stored sera of the previous admission were tested, and HIV seropositivity was confirmed, proving that the condition was present at the first admission. Acute leptospirosis in HIV coinfection is not inevitably severe, and there is probably a wide variation in clinical manifestations similar to what occurs in immuno-competent hosts.

Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden.

BACKGROUND: Pulmonary involvement in leptospirosis remains poorly recognized in regions where it is endemic, despite reports of recent outbreaks and epidemic disease. METHODS: A prospective, population-based study was carried out to identify febrile patients exposed to Leptospira in urban and rural contexts in Iquitos, Peru. Evidence of exposure to Leptospira was obtained by serologic testing, and diagnosis of leptospirosis was confirmed in pulmonary cases by culture or quantitative real-time PCR assay. RESULTS: Of 633 consecutively enrolled febrile patients, 321 (50.7%) had antileptospiral IgM antibodies or high titers of antileptospiral antibodies. Seven patients with histories of only urban exposure to leptospires had severe pulmonary manifestations; of these, 5 patients died; 4 of the deaths were caused by pulmonary hemorrhage, and 1 was caused by acute respiratory distress syndrome and multiorgan failure. Real-time, quantitative PCR assay showed high levels of leptospiremia (>or=10(4) leptospires/mL) in most fatal cases; 1 patient, from whom tissue specimens were obtained at autopsy, had >or=10(5) leptospires/g of lung, kidney, and muscle tissue. DISCUSSION. This study demonstrates the underdiagnosis of leptospirosis in a region of high endemicity and the underrecognition of grave pulmonary complications. Pulmonary involvement in leptospirosis was present in urban but not rural areas. Presumptive treatment for leptospirosis should be initiated immediately in the appropriate epidemiological and clinical context.

The role of lipopolysaccharide binding protein in resistance to Salmonella infections in mice.

Polymorphonuclear leukocytes (PMN) and LPS-binding protein (LBP) are both components of the innate immune system. LBP is a plasma protein that binds to lipid A and enhances the biological activity of LPS 100- to 1000-fold. Recently it was reported that LBP-deficient mice are more susceptible to Salmonella typhimurium infection. Here we report that LBP KO mice are more susceptible to Salmonella peritonitis, but not to oral or i.v. infection. LBP knockout (KO) mice responded normally to i.p. injections of Staphylococcus aureus and casein, but not to i.p. injection of S. typhimurium or Salmonella LPS. Mice with a mutation in Toll-like receptor 4 (C3H/HeJ) have a similar defect in PMN chemotaxis. In normal mice S. typhimurium stimulated production of the CXC chemokines macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant, but levels of cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein-2 were greatly reduced in the LBP KO mice. LBP KO mice pretreated with casein to attract PMN in an LBP-independent manner were more resistant to Salmonella infection, but neutropenic mice were not protected by casein. Splenic TNF-alpha mRNA levels were also lower in LBP KO than in control mice infected with Salmonella. Since TNF-alpha can activate PMN, LBP KO mice may have both fewer and less active PMN in the first few hours after Salmonella are injected, making LBP KO mice more susceptible. This work confirms the importance of PMN in resistance to Salmonella infections and shows that this is facilitated by LBP.