[Posted 05/Aug/2022]

AUDIENCE: Infectious Disease, Ob/Gyn, Family Medicine

KEY FINDINGS: As of July 29, 2022, the Centers for Disease Control and Prevention (CDC) and state and local public health partners are reporting 5,189 cases of Monkeypox virus infections in the United States across 47 states, Washington, D.C., and Puerto Rico. CDC is also reporting multiple outbreaks of monkeypox that have been reported globally in 71 countries that do not normally report monkeypox activity. On Friday, July 22, CDC reported the first two cases of monkeypox in children in the United States during the current outbreak. This Health Alert Network (HAN) Health Update serves to alert clinicians to clinical considerations for preventing, diagnosing, and managing monkeypox in people with HIV, children, adolescents, and people who are pregnant or breastfeeding.

BACKGROUND: Since May 2022, CDC has been urging healthcare providers in the United States to be on alert for patients who have rash illnesses consistent with monkeypox. People with HIV, individuals who are immunocompromised, children, adolescents, and people who are pregnant or breastfeeding may be at risk for increased disease severity and adverse health outcomes associated with monkeypox infection. Clinicians should be familiar with unique clinical considerations for monkeypox in these patient populations. A broad diagnostic approach is encouraged to distinguish Monkeypox virus infection from other causes of fever and rash illness. Testing should be performed on persons for whom monkeypox is suspected based on clinical presentation or epidemiologic criteria. Clinicians should consult their state or territorial health department (State Contacts) or CDC through the CDC Emergency Operations Center (770-488-7100) as soon as monkeypox is suspected.

DETAILS: CDC has issued clinical considerations for monkeypox infection in multiple populations including: people with HIV, children and adolescents, and people who are pregnant or breastfeeding. These newly released clinical considerations complement existing clinical guidance for managing monkeypox and provide information on signs and symptoms of Monkeypox virus infection; pre- and post-exposure prophylaxis; treatment; and infection control in these populations.

Recommendations and Information for Healthcare Providers on Monkeypox in People with HIV

In the current outbreak, available international summary surveillance data in the CDC-issued clinical considerations for people with HIV indicate 30-51% HIV prevalence among persons with monkeypox for whom HIV status was known. It is currently unknown whether HIV infection affects a person's risk of acquiring Monkeypox virus infection and developing disease after exposure.

Persons with advanced and uncontrolled HIV might be at higher risk for severe or prolonged monkeypox disease. Therefore, prophylaxis (e.g., vaccination), medical treatment and close monitoring are a priority for this population. Compared with other persons with monkeypox, case reports among persons with inadequately treated HIV who have CD4 counts <=350 per mm³ reported higher rates of secondary bacterial infection, more prolonged illness (and thereby also longer period of infectiousness), as well as a higher likelihood of a confluent or partially confluent rash, rather than discrete lesions. In contrast, recent reports of patients with HIV infection and monkeypox who are on effective antiretroviral therapy (ART) have noted no deaths or evident excess hospitalizations to date. Providers should consider both viral suppression and CD4 count in weighing the risk of severe outcomes from monkeypox for any patient with HIV.

The rash of monkeypox can be confused with other rash illnesses that are considered in people with HIV, including herpes zoster (shingles), scabies, molluscum contagiosum, herpes, syphilis, chancroid, lymphogranuloma venereum, allergic skin rashes, and drug eruptions. Immunocompromised persons, including persons with advanced, untreated or inadequately suppressed HIV, may present with an atypical rash, including a disseminated rash that may make diagnosis more challenging.

Prevention of monkeypox and infection control practices in the home or healthcare setting are the same regardless of peoples' HIV status. Post-exposure prophylaxis (PEP) and antiviral treatments, including tecovirimat, are available for persons exposed to monkeypox or with Monkeypox virus infection. The safety and immunogenicity of JYNNEOS, a live, non-replicating viral vaccine, has been specifically established in people with HIV; however, immunogenicity among persons with HIV who have CD4 counts below 100 cells/mm³ or who are not virologically suppressed remains unknown. ACAM2000, a replicating viral vaccine, should not be given to people with HIV (regardless of immune status). Antiviral treatments for monkeypox have few interactions with antiretroviral therapy. ART and opportunistic infection prophylaxis should be continued in all people with HIV who develop monkeypox.

Recommendations and Information for Healthcare Providers on Monkeypox in Children and Adolescents

Limited pediatric data on infection with the Congo Basin clade of Monkeypox virus suggest increased risk of severe disease in children younger than 8 years of age. Rare complications of monkeypox include abscess, airway obstruction due to severe lymphadenopathy, cellulitis, corneal scarring, encephalitis, keratitis, pneumonia, and sepsis. The West African clade of Monkeypox virus involved in the current outbreak typically causes less severe disease than the Congo Basin clade.

Monkeypox virus can spread to children through contact with infectious body fluids (e.g., lesion exudates and respiratory secretions) of people or animals or through contact with fomites, as may occur in households and other close contact settings. The number of monkeypox cases among children in the United States is currently low; however, CDC acknowledges that the expanding U.S. outbreak and the possible risk for transmission in households and other settings may result in additional pediatric cases. Pediatric providers should be familiar with prevention, recognition, and testing considerations for monkeypox in children and adolescents.

Families should be counseled about preventing the spread of Monkeypox virus between children, caregivers, and household members in the home, including avoidance of contact with persons who have monkeypox, the body fluids of an infected person, and fomites (e.g., clothing, towels, bedding); wearing a well-fitting mask or respirator by the person with monkeypox and the contact (for children over 2 years of age) when interaction is unavoidable; and minimizing the number of caregivers for children with monkeypox. Particular attention should be made to keep children with monkeypox from scratching lesions or touching their eyes to prevent auto-inoculation and more severe illness. Caregivers should cover areas of broken skin with bandages to the extent possible and avoid direct skin-to-skin contact with the rash.

Children and adolescents who are close contacts of a person with monkeypox (e.g., household contact, other family member, caregiver, or friend) should be evaluated for illness and offered post-exposure prophylaxis with JYNNEOS or ACAM2000 (for children older than 12 months) or treatment when indicated. Monkeypox should be considered when children or adolescents present with signs or symptoms that could be consistent with the disease, especially if epidemiologic criteria are present. The rash of monkeypox can be confused with other rash illnesses that are commonly considered in children including varicella (chickenpox); hand, foot, and mouth disease; measles; scabies; molluscum contagiosum; herpes; allergic skin rashes and syphilis (including congenital syphilis); and drug eruptions.

Data are limited on the effectiveness of PEP for children who have been exposed to monkeypox or treatment for children with illness, and no vaccines or other products are currently licensed for monkeypox prevention or treatment in children or adolescents. However, PEP should not be withheld from children or adolescents who are otherwise eligible. Decisions about whether to offer PEP should take into account the patient's degree of exposure and the patient's individual risk of severe disease.

Prophylactic therapeutics that can be administered include vaccination, Vaccinia immune globulin, and antiviral medication. For almost all children and adolescents, vaccination is the preventive treatment that should be administered. Immune globulin or antivirals may also be considered for infants under 6 months of age, given their immature immune systems and possible decreased responses to vaccination.

Tecovirimat is currently being used as the first-line treatment for infection with Monkeypox virus, including for children and adolescents with severe disease or underlying medical conditions that may increase risk for severe disease and those with complications from monkeypox. Individual risks and benefits must be considered prior to initiating tecovirimat. Other treatments such as Vaccinia immune globulin may be considered in unusual circumstances.

In pediatric inpatient care settings, infection control procedures for children with monkeypox infection should also consider the child's age and caregiving needs; family and caregiver preferences; the extent, severity, and course of the child's illness; and risks for severe monkeypox disease in exposed caregivers (e.g., pregnancy or immunocompromising conditions).

Recommendations and Information for Healthcare Providers on Monkeypox in People who are Pregnant or Breastfeeding

Data regarding Monkeypox virus infection during pregnancy are limited. It is unknown if pregnant people are more susceptible to acquiring Monkeypox virus infection or if illness is more severe during pregnancy. Other poxviruses cause more severe infection during pregnancy. Monkeypox virus can be transmitted to the fetus during pregnancy and to the newborn by close contact during and after birth. There are few case reports of spontaneous pregnancy loss and stillbirth, preterm delivery, and neonatal monkeypox infection; the frequency and circumstances for these outcomes are unknown. Whether Monkeypox virus is present in breast milk is unknown; however, it may be transmitted through close contact during breastfeeding.

Prevention measures for monkeypox infection are similar for pregnant and non-pregnant people. Pre- or post-exposure prophylaxis should be offered to people who are pregnant or breastfeeding. When pre- or post-exposure prophylaxis by vaccination is chosen, JYNNEOS, a live, non-replicating viral vaccine, can be used. ACAM2000, a replicating viral vaccine, should not be used in people who are pregnant or breastfeeding.

During pregnancy, the cause of fever may be difficult to differentiate from other infections, such as intraamniotic infection (chorioamnionitis), until the monkeypox rash appears. Pregnant patients with rashes initially considered characteristic of dermatoses of pregnancy (e.g., polymorphic eruption of pregnancy) or of more common infections (e.g., varicella zoster or sexually transmitted infections) should be carefully evaluated for a monkeypox rash, and submission of specimens of lesions for monkeypox diagnosis should be considered, especially if the person has any epidemiologic risk factors for monkeypox infection.

While most adults with Monkeypox virus infection experience self-limiting infection and recover within 2-4 weeks, pregnant and breastfeeding people should be prioritized for medical treatment, if needed, due to the probable increased risk of severe disease during pregnancy, risk of transmission to the fetus during pregnancy or to the newborn by close contact during and after birth, and risk of severe infection in newborns. Treatment for Monkeypox virus infection should be offered to people who are pregnant or breastfeeding. The risks and benefits of treatment options should be discussed with the patient.

Recommendations for infection prevention and control of monkeypox in healthcare settings are the same for pregnant and non-pregnant patients. Newborns born to people with monkeypox should be placed in isolation, and healthcare personnel should follow infection prevention and control recommendations. Patients with monkeypox should be counseled about measures to prevent risk of transmission of Monkeypox virus to their newborn from close contact and breastfeeding.

Source: Centers for Disease Control and Prevention (U.S.) (2022). Update for Clinicians on Monkeypox in People with HIV, Children and Adolescents, and People who are Pregnant or Breastfeeding. Centers for Disease Control and Prevention. Published: July 30, 2022. DOI: CDCHAN-00472.

Three Dose Levels of a Maternal Respiratory Syncytial Virus Vaccine Candidate Are Well Tolerated and Immunogenic in a Randomized Trial in Nonpregnant Women

[Posted 12/Jul/2022]

AUDIENCE: Infectious Disease, Ob/Gyn, Internal Medicine

KEY FINDINGS: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life.

DETAILS: In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo. Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%-53.2%) versus placebo (0%-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one.

Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Schwarz, T. F., Johnson, C., Grigat, C., et al. (2022). Three Dose Levels of a Maternal Respiratory Syncytial Virus Vaccine Candidate Are Well Tolerated and Immunogenic in a Randomized Trial in Nonpregnant Women. The Journal of Infectious Diseases. 2022; 225(12): 2067-2076. Published: June 19, 2022. DOI: 10.1093/infdis/jiab317.

Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study

[Posted 14/Jun/2022]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

BACKGROUND: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis.

DETAILS: Analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (<=7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4).

Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Sonneveld, M. J., Hansen, B. H., Brouwer, W. P., et al. (2022). Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study. J Infect Disease. 2022; 225(11): 1967-1973. Published: June 6, 2022. DOI: 10.1093/infdis/jiaa192.

Comparative Bactericidal Activity Of Representative ß-Lactams Against Enterobacterales, Acinetobacter Baumannii and Pseudomonas Aeruginosa

[Posted 25/May/2022]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: ß-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of ß-lactam to another is not justified.

BACKGROUND: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of ß-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way. Purpose of this study is to describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

DETAILS: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu.h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded. Against E. coli and K. pneumoniae meropenem had a maximal ABE at >=MIC x 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at >=MIC x 4 and aztreonam at >=MIC x 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8x/16 x MIC. Other ß-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at >=MIC x 4, concentration changes in population profiles were least apparent with E. coli.

Copyright © Oxford University Press. All rights reserved.

Source: Noel, A. R., Attwood, M., Bowker, K. E., et al. (2022). Comparative Bactericidal Activity Of Representative ß-Lactams Against Enterobacterales, Acinetobacter Baumannii and Pseudomonas Aeruginosa. Journal of Antimicrobial Chemotherapy. 2022; 77(5): 1306-1312. Published: May, 2022. DOI: 10.1093/jac/dkac026.

Development and Validation of Bloomy Prediction Scores For 14-Day and 6-Month Mortality In Hospitalised Adults With Bloodstream Infections

A Multicentre, Prospective, Cohort Study.

[Posted 20/Apr/2022]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections.

BACKGROUND: The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. Study aimed to develop scores to predict short-term and long-term mortality in patients with bloodstream infections.

DETAILS: The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values. Between Feb 1, 2017, and Jan 31, 2019, 2568 (61.5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23.75% (95% CI 22.15-25.44; 610 of 2568 patients) and the 6-month mortality rate was 41.55% (39.54-43.59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0.873, 95% CI 0.849-0.896) and 6-month mortality (0.807, 0.784-0.831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9, 2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61.32% (95% CI 51.81-70.04), a specificity of 86.36% (83.80-88.58), a positive predictive value (PPV) of 37.57% (30.70-44.99), and a negative predictive value (NPV) of 94.35% (92.42-95.80). The BLOOMY 6-month score showed a sensitivity of 69.93% (61.97-76.84), a specificity of 66.44% (61.86-70.73), a PPV of 40.82% (34.85-47.07), and a NPV of 86.97% (82.91-90.18).

Copyright © Elsevier Ltd. All rights reserved.

Source: Tacconelli, E., Gopel, S., Gladstone, B. P., et al. (2022). Development and Validation of Bloomy Prediction Scores For 14-Day and 6-Month Mortality In Hospitalised Adults With Bloodstream Infections: A Multicentre, Prospective, Cohort Study. The Lancet. 2022; 22(5): 731-741.Published: May 1, 2022. DOI: 10.1016/S1473-3099(21)00587-9.

[Posted 27/Apr/2022]

AUDIENCE: Infectious Disease, Family Medicine, Ob/Gyn

KEY FINDINGS: RSVpreF formulations were safe, well tolerated, and induced robust neutralizing responses in adults. These findings support development of RSVpreF, which is being evaluated in a pivotal phase 3 study for maternal immunization.

BACKGROUND: Protection against human respiratory syncytial virus (RSV) remains an unmet need potentially addressable by maternal immunization. This phase 1/2 study evaluated a bivalent prefusion F vaccine (RSVpreF) with antigens from RSV subgroups A and B.

DETAILS: Adults 18-49 years old (N = 618) were randomized to receive placebo or 60, 120, or 240 µg RSVpreF with or without Al(OH)3. Safety and immunogenicity were evaluated. RSVpreF recipients more frequently reported local reactions and systemic events than placebo recipients; these were mostly mild or moderate. No vaccine-related serious adverse events occurred through 12 months postvaccination. All RSVpreF formulations induced 1-month postvaccination virus-neutralizing titers higher than those associated with protection of high-risk infants by palivizumab, the only prophylactic currently available for RSV. Geometric mean fold rises (GMFRs) across RSVpreF doses/formulations were 10.6-16.9 for RSV A and 10.3-19.8 for RSV B at 1 month postvaccination, greater than those historically elicited by postfusion F vaccines. GMFRs were 3.9-5.2 and 3.7-5.1, respectively, at 12 months postvaccination.

Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Walsh, E. E., Falsey, A. R., Scott, D. A., et al. (2022). A Randomized Phase 1/2 Study of a Respiratory Syncytial Virus Prefusion F Vaccine. J Infect Disease. 2022; 225(8): 1357-1366. Published: April 15, 2022. DOI: 10.1093/infdis/jiab612.