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The Role of Blood Viscosity in Infectious Diseases
review-article
Author(s):
Gregory D Sloop
1
,
,
Quirijn De Mast
2 ,
Gheorghe Pop
3 ,
Joseph J Weidman
4 ,
John A St. Cyr
5
Publication date (Electronic, pub):
24 February 2020
Publication date (Electronic, collection):
February 2020
Journal:
Cureus
Publisher:
Cureus
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Abstract
Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood.
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Most cited references44
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Cardiac Complications in Patients with Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Observational Studies
Introduction Community-acquired pneumonia (CAP) is a common and deadly condition. In the United States alone, it is estimated that each year CAP affects 5–6 million people, results in about 1.1 million hospital admissions, and causes the death of over 60,000 Americans, representing the most frequent cause of infectious disease–related mortality and, along with influenza, the overall eighth leading cause of death in this country [1],[2]. CAP occurs more frequently in the middle aged and the elderly, a population that is also at the highest risk for cardiac diseases [3],[4]. Not surprisingly, more than half of elderly patients who present to the hospital with CAP in the United States have preexisting chronic cardiac conditions, and as the population continues to age, this association will become more important [3],[5]. Acute infections, including CAP, can affect the cardiovascular system in various ways and have been recognized as precipitants of acute cardiac events [6]–[8]. Although the possibility of major cardiac complications occurring in a considerable proportion of CAP patients is very plausible, systematic data on the magnitude of this problem are remarkably scant [9]. Given the burden of CAP in North America and other western societies [1],[2], a careful characterization of the risk of cardiac complications in patients with this infection can have important implications for health policy-making and direct patient care. This systematic review examines the literature published on cardiac complications in patients with CAP in an attempt to characterize the nature and significance of this association, and to identify areas in this field that require further investigation. Methods The PRISMA checklist is provided in Text S1. Search Strategy Our systematic search strategy was developed to capture all articles of prognosis of CAP in which cardiac complications had been reported and is presented in Text S2. We included articles reporting in English, French, or Spanish languages. We searched the following databases: MEDLINE (from 1950 to June 13, 2010), Scopus (from 1960 to June 13, 2010), and EMBASE (from 1980 to June 13, 2010). Reference lists of selected papers were also screened for additional articles of interest. Outcomes Our outcomes consisted of the incidence of cardiac complications as a combined endpoint, incident (new or worsening) heart failure, acute coronary syndromes (ACS; acute myocardial infarction or unstable angina), and incident cardiac arrhythmias within 30 d of CAP diagnosis. Eligibility Criteria To ensure that the literature reviewed dealt with CAP rather than other conditions, we included only studies in which the definition of CAP was supported by radiographic evidence of acute airspace disease (new or progressing infiltrate within 48 h of presentation), and clinical signs or symptoms of pulmonary infection. Only observational studies reporting the occurrence of any of the cardiac complications of interest in their results or stating the evaluation of these outcomes in their methods were considered. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria in their methodological section, enrol their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. We excluded studies with focus on nosocomial or health care–associated pneumonia, case series (defined as studies with ≤25 participants), articles without original data, antibiotic efficacy trials (because they are usually restricted to highly selected patients), and articles dealing primarily with pediatric patients or patients infected with the human immunodeficiency virus. We also excluded studies in which the inception time of their cohorts was beyond 48 h from the diagnosis of pneumonia. Selection of Studies All titles and abstracts of the citations identified by our literature search were independently screened by two investigators (VFC-M and KNS). Relevant articles were reviewed in their entirety. Each investigator made a recommendation for inclusion or exclusion of single articles and if discordant, a third investigator solved the discrepancy (GR). When two or more articles had overlap of their populations and reported on the same cardiac outcomes, only the most inclusive article was considered. Data Extraction, Synthesis, and Analyses We systematically collected data on the incidence of the cardiac complications of interest, the characteristics of the populations studied, and several aspects of the study setting and methodological design (Table S1). We contacted (by e-mail) the corresponding authors of those papers that offered no details of the methodology followed for the ascertainment of the cardiac complications of interest, and asked them to provide us with copies of the study protocols (or similar) in which this information would be available. Given the aim of our analyses, we focused on how rigorously the evaluation of medical and/or cardiac complications was established in the methodological considerations of these studies as an indicator of their risk of bias in the ascertainment and reporting of these outcomes and their quality relevant to our work. Publication bias was assessed by preparing a funnel plot for the outcome of overall cardiac complications. Pooled incidence rates of cardiac complications were calculated separately for studies dealing with outpatients, inpatients as a whole, low-risk inpatients (e.g., inpatients with no indication for hospital admission, low-risk pneumonia severity index categories, not requiring admission to intensive care units, etc.), and high-risk inpatients (i.e., patients admitted to intensive care units). We took this approach to prevent heterogeneity in our estimates since these categories represent distinct populations of CAP patients. We performed prespecified subgroup analyses for studies of CAP inpatients by characteristics of their study setting and design, quality indicators of potential bias (see above), and attributes of their populations. Because of the limited number of studies available, these analyses are presented in a descriptive format only. Pooled event rates and their confidence intervals (CIs) were estimated using a random effects model weighted by the inverse variance. When only one study was available, the Agresti-Coull method was used. All analyses were conducted in comprehensive meta-analysis version 2.2. Results Our search strategy yielded 2,176 articles for review. A flow summary of the selection process is provided in Figure 1. Table 1 presents a summarized description of the 25 ultimately selected articles [10]–[34]. Two studies had overlapping study populations [30],[34], but since the smaller study reported on each of the four cardiac complications of interest [30], while the larger one reported only data on ACS [34], we kept both but considered only the latter for analyses related to ACS. One article reported on outpatients and inpatients as separate groups [19], and for purposes of comparative and pooled analyses, each group was treated as a distinct study. Table S1 provides the most detailed information on the setting, methodology, population, and findings of the included studies. 10.1371/journal.pmed.1001048.g001 Figure 1 PRISMA flow diagram: selection process. 10.1371/journal.pmed.1001048.t001 Table 1 Studies of cardiac complications in patients with CAP. Reference Year n Population Design Incidence of Cardiac Complications (%) Overall Cardiac Complicationsa Incident Heart Failure Incident Cardiac Arrhythmiasb ACSc Allen et al. [10] 1984 502 Inpatients Prospective single-center — — 65 5 17.2 (13.0–22.4) 4 14.3 (6.9–27.4) 4 7.1 (4.5–10.8) 3 5.1 (2.1–11.7) Not reported 1 19.4 (14.1–26.0) 1 14.7 (10.1–20.9) — — 1 5.9 (3.1–10.6) Gender: 50%+ Male 2 18.0 (15.1–21.4) 6 12.5 (8.1–18.8) 6 5.3 (3.2–8.6) 6 4.7 (2.4–8.9) Preexisting cardiac/cardiovascular disease: <25% — — — — — — — — 25–50% — — — — — — — — 50%+ — — — — — — — — Not reported 6 17.7 (13.9–22.2) 8 14.1 (9.3–20.6) 6 5.3 (3.2–8.6) 6 4.7 (2.4–8.9) Coronary artery disease: <25% — — 1 12.0 (7.1–19.2) 1 0.9 (0.0–5.2) 1 4.3 (1.6–9.9) 25–50% 2 23.0 (20.7–25.5) 3 13.9 (7.8–23.5) 3 5.8 (2.8–11.3) 1 9.5 (8.1–11.2) 50%+ — — — — — — — — Not reported 4 14.5 (10.4–19.8) 4 15.0 (7.5–27.9) 2 6.5 (3.5–11.7) 4 3.8 (1.5–9.2) Congestive heart failure: <25% 4 18.8 (14.3–24.3) 2 16.3 (9.5–26.5) 3 6.4 (3.0–13.3) 2 5.4 (1.6–16.8) 25–50% — — 1 12.0 (7.1–19.2) 3 4.1 (1.9–8.5) 1 4.3 (1.6–9.9) 50%+ — — — — — — — — Not reported 2 15.9 (10.6–23.1) 5 13.5 (7.4–23.5) — — 3 4.2 (1.1–14.1) Diabetes mellitus: <25% 3 21.3 (17.9–25.1) 5 11.6 (6.8–19.0) 3 6.4 (3.0–13.3) 2 5.4 (1.6–16.8) 25–50% 1 5.5 (2.1–12.5) 1 12.0 (7.1–19.2) 2 2.9 (0.5–16.0) 1 4.3 (1.6–9.9) 50%+ — — — — — — — — Not reported 2 15.6 (10.6–23.1) 2 23.5 (9.0–48.8) 1 4.0 (1.2–10.2) 3 4.2 (1.1–14.1) Chronic obstructive pulmonary disease: <25% 4 15.2 (10.0–22.4) 3 9.1 (5.8–14.2) 1 7.9 (5.6–11.1) 1 2.8 (1.5–5.0) 25–50% 1 22.0 (18.9–25.5) 2 15.6 (8.4–27.2) 3 5.8 (2.8–11.3) 1 9.5 (8.1–11.2) 50%+ — — 1 12.0 (7.1–19.2) 2 2.3 (0.5–9.5) 1 4.3 (1.6–9.9) Not reported 1 19.4 (14.1–26,0) 2 23.5 (9.0–48.8) — — 3 4.2 (1.1–14.1) Smoking: <25% 1 24.1 (20.8–27.7) — — — — — — 25–50% — — 2 11.1 (8.9–13.9) 1 5.8 (4.0–8.2) 1 11.0 (5.4–20.4) 50%+ — — — — 2 7.2 (2.7–17.7) — — Not reported 5 16.2 (12.2–21.1) 6 15.4 (9.3–24.3) 3 3.9 (1.6–9.2) 5 3.9 (1.8–8.4) One study reporting the incidence of ACS and incident cardiac arrhythmias on outpatients and low-risk inpatients without making distinction between them was not included in this table [15]. Incident heart failure, incident cardiac arrhythmias, and ACS tended to be more common in studies with older populations and higher rates of preexisting coronary artery disease, but not in those with higher prevalence of preexisting congestive heart failure. Studies of predominantly female populations had higher incidences of incident heart failure, whereas the opposite was observed for overall cardiac complications. Rates of all cardiac complications but incident heart failure were lower in studies of patients with higher prevalence of diabetes mellitus. While overall cardiac complications, incident heart failure and incident cardiac arrhythmias were more common in studies with higher prevalence of chronic obstructive pulmonary disease, the opposite was observed for ACS. Finally, ACS occurred more commonly in studies of patients with higher rates of smoking. Risk Factors and Impact of Cardiac Complications on CAP Outcomes Only three studies [31],[33],[34], all dealing with CAP and ACS, attempted to analyze risk factors for the occurrence of cardiac complications. Possible risk factors identified included older age, preexisting congestive heart failure [34], severity of pneumonia [33], and the use of insulin by glucose sliding scales in hospitalized patients [31]. No study analyzed the association of cardiac complications with the development of other medical complications (i.e., acute renal failure, respiratory failure, shock, etc.), or the impact of these events on other CAP outcomes (i.e., mortality). Discussion Our main finding is that major cardiac complications occur in a significant proportion of patients with CAP, especially in those requiring hospitalization for this infection. The pooled incidence rates of overall cardiac complications, incident heart failure, ACS, and incident arrhythmias in hospitalized patients with CAP were 17.7%, 14.1%, 5.3%, and 4.7%, respectively. Given the burden of CAP in North America and other western societies [1],[2], these pooled findings have important implications. Firstly, clinicians need to realize the significance of this association for appropriate clinical alertness and to better inform CAP patients about the risk of cardiac complications once the diagnosis of pneumonia is made. Secondly, physicians and health officials need to increase efforts to optimize the rates of influenza and pneumococcal vaccination among the elderly and those with chronic cardiac conditions to reduce the incidence of CAP in these high-risk populations. Thirdly, attention needs to be directed to the potential impact of cardiac complications in the mortality and cost associated with CAP. Finally, the research community needs to urgently direct more efforts to the study of this area. Our results expand on the findings of Fine et al. [9], who in the only previous systematic review on this topic reported four CAP cohorts (232 patients total) with a pooled incidence of heart failure of 8.6%. Our study not only confirms that incident heart failure is common in the course of CAP but suggests that its occurrence in patients hospitalized with this infection may be much higher than previously realized, and that ACS and cardiac arrhythmias are also remarkably frequent in this population. Incident heart failure can be precipitated by CAP by several mechanisms [7],[30]. Acute inflammation can not only depress myocardial function, as it is well described in septic states [35],[36], but it can also increase large artery stiffness and the pulse wave reflections from peripheral middle-sized and small arteries that return to the heart in late systole, increasing left ventricular afterload and raising oxygen consumption [37]. Hypoxemia associated with CAP can raise pulmonary arterial pressure and right ventricular afterload while impairing myocardial oxygen delivery [7]. Tachycardia, common in acute infections, increases myocardial oxygen needs but shortens the diastolic period in which coronary perfusion occurs [38]–[40]. The net result of these effects is a shift in the metabolic supply/demand ratio of the myocardium and further impairment of its function. These changes are presumed to be of greater significance in patients with preexisting cardiac disease. In addition, incident heart failure in CAP can result from myocardial inflammation (myocarditis), a complication well described in patients with pneumonia mainly of viral origin, and that could have been underrepresented in previous investigations because of a lack of adequate noninvasive techniques for its identification (i.e., cardiac magnetic resonance imaging) [41]. Finally, we realize that acute renal impairment, common in hospitalized CAP patients [19], can also play a role in this setting [42]. Acute infections, including CAP, can also trigger the occurrence of ACS, and clinical studies have shown a significant temporal increase in the risk of ACS soon after the development of respiratory infections [34],[43],[44]. Surges of biomechanical stress, as a result of increased sympathetic activity and other hemodynamic changes (i.e. alterations of the circulatory volume and the systemic and coronary vascular tone), can prompt plaque rupture [7]. Acute infections can also promote plaque disruption by increasing intraplaque inflammatory activity [7]. In this setting, thrombus formation over a disrupted coronary plaque—a key step in the development of ACS—would be favoured by infection-induced prothrombotic changes in the blood and endothelium [7]. In addition, preexisting coronary artery disease that doesn't produce myocardial ischemia under baseline conditions can result in significant ischemia in the face of increased metabolic demands associated with CAP (i.e., demand ischemia; see above). Most of the cardiac arrhythmias reported in the reviewed studies represented atrial tachyarrhythmias, particularly atrial fibrillation. Abnormalities in the cardiac conduction system in the setting of acute pneumonia have been recognized since the early 20th century and consistently confirmed thereafter [45],[46]. More recently, a study of more than 800,000 patients admitted to the hospital with atrial fibrillation as a secondary condition found that in patients 65 y of age or older, the second leading primary diagnosis was pneumonia (7%), after only congestive heart failure (13%), and before acute myocardial infarction (6%) [8]. While incident heart failure, ACS, and cardiac arrhythmias constitute distinct clinical entities, they share many pathophysiological bases and risk factors, and the occurrence of one of them can as well trigger the development of the others. While only one study in our review clearly documented the frequent concomitant occurrence of more than one cardiac complication in CAP patients [30], we think that this scenario is likely to be rather common. Our study highlights several shortcomings of the medical literature on this area, which might influence our interpretations. Only a small proportion of studies primarily focused on cardiac outcomes and very few provided a definition for them, raising concerns for potential bias in the ascertainment and/or reporting of these events in those studies that did not. This is relevant especially for incident heart failure and ACS since their manifestations can overlap with those of CAP and other associated conditions (i.e., lung injury). Nevertheless, the few studies that provided clear definitions for the cardiac complications of interest consistently reported substantial incidences of these outcomes, providing reassurance for the validity of our findings. Only three studies of CAP and ACS looked at possible risk factors for the occurrence of these events but their analyses were largely underpowered and limited [31],[33],[34]. While it seems intuitive to think that the presence of preexisting cardiac conditions should have an important effect on the risk of cardiac complications in patients with CAP, further research will be needed to delineate their significance in this setting. As well, the association of cardiac complications with the development of other medical complications (i.e., acute renal failure, respiratory failure, shock, etc.), or the impact of these events in other CAP outcomes (i.e., mortality) is yet to be established. Finally, little is known about the timing of these complications, and only one study suggested that ACS in CAP patients tend to occur within few days after hospital admission [34]. Our work has limitations beyond the methodological shortcomings of the individual analyzed studies. We cannot rule out potential publication bias against studies that found no significant occurrences of cardiac complications. Additionally, we can only assume that the diagnostic evaluations in individual studies were performed in a uniform manner and the ascertainment of cardiac events was correct. The small number of studies dealing with CAP populations other than inpatients as a whole prevents us from drawing firm conclusions on the incidence of cardiac complications in these groups; and the finding of a counter-intuitively lower incidence of overall cardiac complications in high-risk CAP inpatients could be explained by this factor. The implied differences in the management of inpatients and outpatients may have led to the under-reporting of cardiac events in studies dealing with the latter group. Although studies of cardiac complications in CAP inpatients were the most common in our review, their number was still underpowered for performing adequate analyses (i.e., meta-regression) of factors that could account for the heterogeneity in their findings, and any appreciable difference observed in our subgroup analyses should be viewed in this context. Our review was limited to cardiac complications occurring within 30 d from presentation with CAP because it is assumed that the influence of the infection on patients' comorbid conditions is maximal during this time [47]; however, it is plausible that this influence can go beyond this period as it has been suggested by recent studies [44],[48]. Likewise, many of the mechanisms implicated in the development of cardiac complications in patients with CAP could account for similar occurrences in other infectious and noninfectious acute inflammatory states [7]. In fact, evidence suggests that acute infections of the urinary and gastrointestinal tract are also associated with increased risk of ACS in the short term [7],[44],[49]. However, exploring the magnitude of these associations was beyond the scope of our review. Our findings highlight the urgent need for prospective, well-designed, and adequately powered studies of cardiac complications in patients with CAP. Investigations should focus on identifying risk factors for the occurrence of cardiac complications in this population and developing strategies to identify those CAP patients at high risk for developing these events. These strategies may include clinical scoring systems, biomarker-based approaches, noninvasive cardiac imaging, or a combination of these. Studies are also needed to characterize the impact of cardiac complications on the mortality and resource utilization associated with CAP. Careful mechanistic studies of the pathophysiology of cardiac complications in the course of CAP and the role of preexisting heart disease in their development should serve for the appropriate design of interventions aimed at preventing their occurrence in high-risk groups. As an example, discriminating between acute plaque rupture versus demand ischemia as the factor driving the occurrence of ACS in this population will have important and obvious therapeutic implications. Such interventions will need to be tested in randomized clinical trials. The ultimate goal will be to improve the outcomes of patients with CAP and to decrease the burden that this disease imposes on our health care systems through recognition of risk, prevention, and intervention on acute cardiac complications. Supporting Information Figure S1 Funnel plot for studies of CAP that reported the incidence of overall cardiac complications. (TIF) Click here for additional data file. Table S1 Details of the setting, design, and population of studies of cardiac complications in patients with CAP. (DOC) Click here for additional data file. Table S2 Definitions of cardiac complications used in studies of CAP. (DOC) Click here for additional data file. Text S1 PRISMA checklist. (DOC) Click here for additional data file. Text S2 Search strategy. (DOC) Click here for additional data file.
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Recommendations of the Advisory Committee on Immunization Practices for Use of a Hepatitis B Vaccine with a Novel Adjuvant
Sarah F. Schillie, Aaron Harris, Ruth Link-Gelles … (2018)
Hepatitis B (HepB) vaccination is the primary means of preventing infections and complications caused by hepatitis B virus (HBV). On February 21, 2018, the Advisory Committee on Immunization Practices (ACIP) recommended Heplisav-B (HepB-CpG), a yeast-derived vaccine prepared with a novel adjuvant, administered as a 2-dose series (0, 1 month) for use in persons aged ≥18 years. The ACIP Hepatitis Vaccines Work Group conducted a systematic review of the evidence, including data from four randomized controlled trials assessing prevention of HBV infection and six randomized controlled trials assessing adverse events in adults. Seroprotective antibody to hepatitis B surface antigen (anti-HBs) levels were achieved in 90.0%–100.0% of subjects receiving HepB-CpG (Dynavax Technologies Corporation), compared with 70.5%–90.2% of subjects receiving Engerix-B (GlaxoSmithKline Biologicals). The benefits of protection with 2 doses administered over 1 month make HepB-CpG an important option for prevention of HBV. Introduction Vaccination is the primary means for preventing hepatitis B virus (HBV) infection and its complications. Existing hepatitis B (HepB) vaccines use an aluminum adjuvant. On November 9, 2017, Heplisav-B (HepB-CpG), a single-antigen HepB vaccine with a novel immunostimulatory sequence adjuvant, was approved by the Food and Drug Administration for the prevention of HBV in persons aged ≥18 years. The vaccine is administered as 2 doses, 1 month apart ( 1 ). On February 21, 2018, the Advisory Committee on Immunization Practices (ACIP)* recommended HepB-CpG for use in persons aged ≥18 years. HepB-CpG contains yeast-derived recombinant HepB surface antigen (HBsAg) and is prepared by combining purified HBsAg with small synthetic immunostimulatory cytidine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) motifs (1018 adjuvant). The 1018 adjuvant binds to Toll-like receptor 9 to stimulate a directed immune response to HBsAg ( 1 ). HepB-CpG is available in single-dose 0.5 mL vials. Each dose contains 20 μg of HBsAg and 3,000 μg of 1018 adjuvant. HepB-CpG is formulated without preservatives and is administered as an intramuscular injection in the deltoid region of the upper arm ( 1 ). HepB-CpG is the fifth inactivated HepB vaccine currently recommended for use in the United States. This report contains ACIP guidance specific to HepB-CpG and augments the 2018 ACIP recommendations for the prevention of HBV infection ( 2 ). This report does not include new guidance for populations recommended to receive HepB vaccination or immunization management issues other than those that pertain specifically to HepB-CpG. The intended audience for this report includes clinical and public health personnel who provide HepB vaccination services to adults. These recommendations are meant to serve as a source of guidance for health care providers; health care providers should always consider the individual clinical circumstances of each patient. Methods From February 2016 to January 2018, the ACIP Hepatitis Vaccines Work Group † participated in three teleconference meetings to review the quality of evidence for immunogenicity and safety of HepB-CpG and implementation issues. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for evaluating evidence was adopted by ACIP in 2010 (https://www.cdc.gov/vaccines/acip/recs/grade/). The Work Group identified critical and important outcomes for inclusion in the GRADE tables, conducted a systematic review of the evidence, and subsequently reviewed and discussed findings and evidence quality ( 3 ). Key outcomes were designated as critical (hepatitis B infection, severe adverse events, and cardiovascular safety) or important (mild adverse events). Factors considered in determining the recommendation included benefits and harms and evidence type. Values and preferences and economic factors were not systematically considered. The scientific literature was searched through a systematic review of Medline (Ovid), CAB Abstracts, Embase, Global Health (Ovid), Scopus, and Cochrane databases. Search terms included “Heplisav,” “HBV-ISS,” “HBsAg-1018,” “1018 immunostimulatory sequence,” and “hepatitis B surface antigen-1018 ISS.” To qualify as a candidate for inclusion in the review, a study had to present immunogenicity or disease endpoints or safety data on HepB-CpG. Studies were excluded if they were basic science, a secondary data analysis, immunogenicity outcomes for a nonlicensed formulation or use of HepB-CpG, a general review or opinion perspective, conducted on nonhuman primates, or if data could not be abstracted. Supporting evidence for the Work Group’s findings is available online (https://www.cdc.gov/vaccines/acip/recs/grade/hepb.html). A summary of Work Group discussions was presented to ACIP on October 25, 2017, and February 21, 2018. At the February 2018 meeting, a proposed recommendation was presented to the committee, and, after a public comment period, was approved by the voting ACIP members as follows: HepB-CpG is recommended as an option for HepB vaccination for persons aged ≥18 years (14 voted in favor, with none opposed, none abstained, and none recused). This report summarizes the data considered, the quality of evidence, and the rationale for the recommendation. Summary of Key Findings The body of evidence consisted of four randomized controlled trials assessing prevention of HBV infection and six randomized controlled trials assessing adverse events (mild adverse events, serious adverse events, and cardiovascular adverse events) in adult subjects. Outcomes compared HepB-CpG with Engerix-B. Data from these studies informed HepB-CpG licensure. Studies assessing prevention of HBV infection used antibody to hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL as a serologic correlate of protection. Protection among 7,056 subjects receiving 2 doses of HepB-CpG was compared with protection among 3,214 subjects receiving 3 doses of Engerix-B. Seroprotective anti-HBs levels were achieved in 90.0%–100.0% of subjects receiving HepB-CpG, compared with 70.5%–90.2% of subjects receiving Engerix-B ( 4 – 7 ). The body of evidence for the benefits of protection against HBV infection was deemed to be GRADE evidence type 2 (i.e., evidence from randomized controlled trials with important limitations, or exceptionally strong evidence from observational studies). The evidence type was downgraded for indirectness because immunogenicity was used as a surrogate for protection. Safety profiles among 9,871 subjects receiving 2 or 3 doses of HepB-CpG were compared with those among 4,385 subjects receiving 3 or 4 doses of Engerix-B. Among subjects receiving HepB-CpG, 45.6%, 5.4%, and 0.27% experienced a mild adverse event, serious adverse event, or cardiovascular event, respectively. Among subjects receiving Engerix-B, 45.7%, 6.3%, and 0.14% experienced a mild adverse event, serious adverse event, or cardiovascular event, respectively ( 1 , 4 – 9 ). The body of evidence assessing adverse events was deemed to be GRADE evidence type 1 (evidence from randomized controlled trials, or overwhelming evidence from observational studies). Rationale Based on the available immunogenicity evidence, a 2-dose schedule (0, 1 month) of HepB-CpG will be efficacious for the prevention of HBV infection. The risk for adverse events, including cardiovascular adverse events, was reviewed and will be monitored. The benefits of protection with 2 doses administered over 1 month make this an important option for prevention of HBV. ACIP Recommendations HepB-CpG may be used as a HepB vaccine in persons aged ≥18 years recommended for vaccination against HBV (Box) ( 2 ). BOX Adults who are recommended to receive hepatitis B vaccine Persons at risk for infection through sexual exposure Sex partners of hepatitis B surface antigen (HBsAg)–positive persons Sexually active persons not in a long-term, mutually monogamous relationship Persons seeking evaluation or treatment for a sexually transmitted infection Men who have sex with men Persons with a history of current or recent injection drug use Persons at risk for infection by percutaneous or mucosal exposure to blood Household contacts of HBsAg-positive persons Residents and staff of facilities for developmentally disabled persons Health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids Hemodialysis patients and predialysis, peritoneal dialysis, and home dialysis patients Persons with diabetes mellitus aged <60 years and persons with diabetes mellitus aged ≥60 years at the discretion of the treating clinician International travelers to countries with high or intermediate levels of endemic HBV infection (HBsAg prevalence ≥2%) Persons with hepatitis C virus infection, persons with chronic liver disease (including, but not limited to, those with cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal) Persons with human immunodeficiency virus infection Incarcerated persons Other persons seeking protection from hepatitis B virus infection (even without acknowledgment of a specific risk factor) CDC Guidance for Use Interchangeability and dosing schedule. Data are limited on the safety and immunogenicity effects when HepB-CpG is interchanged with HepB vaccines from other manufacturers. When feasible, the same manufacturer’s vaccines should be used to complete the series ( 10 ). However, vaccination should not be deferred when the manufacturer of the previously administered vaccine is unknown or when the vaccine from the same manufacturer is unavailable ( 10 ). The 2-dose HepB vaccine series only applies when both doses in the series consist of HepB-CpG. Series consisting of a combination of 1 dose of HepB-CpG and a vaccine from a different manufacturer should consist of 3 total vaccine doses and should adhere to the 3-dose schedule minimum intervals of 4 weeks between dose 1 and 2, 8 weeks between dose 2 and 3, and 16 weeks between dose 1 and 3. Doses administered at less than the minimum interval should be repeated. However, a series containing 2 doses of HepB-CpG administered at least 4 weeks apart is valid, even if the patient received a single earlier dose from another manufacturer. Special populations. There are no clinical studies of HepB-CpG in pregnant women. Available human data on HepB-CpG administered to pregnant women are insufficient to inform assessment of vaccine-associated risks in pregnancy. Until safety data are available for HepB-CpG, providers should continue to vaccinate pregnant women needing HepB vaccination with a vaccine from a different manufacturer. Postvaccination serologic testing. To assess response to vaccination and the need for revaccination, postvaccination serologic testing 1–2 months after the final dose of vaccine is recommended for certain persons following vaccination (e.g., hemodialysis patients, HIV-infected and other immunocompromised persons, health care personnel, and sex partners of HBsAg-positive persons) ( 2 ). Postvaccination serologic testing should be performed using a method that allows determination of the protective level of anti-HBs (≥10 mIU/mL) ( 2 ). Persons with anti-HBs <10 mIU/mL following receipt of 2 doses of HepB-CpG should be revaccinated. Revaccination may consist of administration of a second complete HepB vaccine series followed by anti-HBs testing 1–2 months after the final dose. Alternatively, revaccination may consist of administration of an additional single HepB vaccine dose followed by anti-HBs testing 1–2 months later (and, if anti-HBs remains <10 mIU/mL, completion of the second HepB vaccine series followed again by anti-HBs testing 1–2 months after the final dose) ( 2 ). Administration of more than two complete HepB vaccine series is generally not recommended, except for hemodialysis patients ( 2 ). HepB-CpG may be used for revaccination following an initial HepB vaccine series that consisted of doses of HepB-CpG or doses from a different manufacturer ( 11 ). HepB-CpG may also be used to revaccinate new health care personnel (including the challenge dose) initially vaccinated with a vaccine from a different manufacturer in the distant past who have anti-HBs <10 mIU/mL upon hire or matriculation ( 2 ). Precautions and contraindications. Before administering HepB-CpG, health care providers should consult the package insert for precautions, warnings, and contraindications. Adverse events occurring after administration of any vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). Reports can be submitted to VAERS online, by fax, or by mail. Additional information about VAERS is available by telephone (1-800-822-7967) or online (https://vaers.hhs.gov). Future Considerations Postlicensure surveillance studies and additional data pertaining to the use of HepB-CpG will be reviewed by ACIP as they become available, and recommendations will be updated as needed. Future economic analyses might inform cost-effectiveness considerations of HepB-CpG, including its use among persons at an increased risk for vaccine nonresponse.
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- Abstract: found
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Red blood cell deformability as a predictor of anemia in severe falciparum malaria.
Robert Angus, Alexander White, K. Chotivanich … (1999)
Decreased erythropoiesis and increased clearance of both parasitized and noninfected erythrocytes both contribute to the pathogenesis of anemia in falciparum malaria. Erythrocytes with reduced deformability are more likely to be cleared from the circulation by the spleen, a process that is augmented in acute malaria. Using a laser diffraction technique, we measured red blood cell (RBC) deformability over a range of shear stresses and related this to the severity of anemia in 36 adults with severe falciparum malaria. The RBC deformability at a high shear stress of 30 Pa, similar to that encountered in the splenic sinusoids, showed a significant positive correlation with the nadir in hemoglobin concentration during hospitalization (r = 0.49, P < 0.002). Exclusion of five patients with microcytic anemia strengthened this relationship (r = 0.64, P < 0.001). Reduction in RBC deformability resulted mainly from changes in unparasitized erythrocytes. Reduced deformability of uninfected erythrocytes at high shear stresses and subsequent splenic removal of these cells may be an important contributor to the anemia of severe malaria.
Author and article information
Journal
Journal ID (nlm-ta): Cureus
Journal ID (iso-abbrev): Cureus
Journal ID (issn): 2168-8184
Title:
Cureus
Publisher:
Cureus
(Palo Alto (CA)
)
ISSN
(Electronic):
2168-8184
Publication date
(Electronic, pub):
24
February
2020
Publication date
(Electronic, collection):
February
2020
Volume: 12
Issue: 2
Electronic Location Identifier: e7090
Affiliations
Author notes
Gregory D. Sloop
bigdaddypathologist@
123456gmail.com
Article
DOI: 10.7759/cureus.7090
PMC ID: 7096068
PubMed ID: 32226691
SO-VID: a1cc2916-4e3b-4800-a1c7-b1a03d1d6056
Copyright © Copyright © 2020, Sloop et al.
License:
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 9
February
2020
Date
accepted
: 24
February
2020
Categories
Subject:
Cardiology
Subject:
Infectious Disease
Subject:
Hematology
Data availability: