Abstract

Purpose: To evaluate the structure, processes, and outcomes of a Community Health Team (CHT) intervention for high-risk/high-cost patients of patient-centered medical homes (PCMHs).

Methods: A mixed-methods evaluation wherein survey, interview, and focus group questions were developed from validated measures, Affordable Care Act (ACA) concepts, a literature review, and intervention goals were used. CHT service documentation data was also reviewed.

Results: 334 PCMH patients were identified as high-risk/high-cost and deemed eligible for CHT services. CHTs were successful in connecting patients with diverse services, enhancing patient health self-management and improving quality of life. The CHT intervention was highly valued by patients and PCMH practice providers. The need for explicit policies and protocols, data use agreements, and centralized data warehouse and case management systems was highlighted as potential facilitators of successful CHT implementation.

Conclusion: Areas of excellence, and areas of improvement, were identified and target the CHTs’ ability to address the complex needs of high-risk/ high-cost patients through collaboration with PCMH practices and the broader medical neighborhood. As states develop CHTs to help manage care for chronically ill patients within primary care practices, PCMHs, and medical neighborhoods, we provide recommendations to guide future implementation efforts.

Introduction

In 2001, the Institute of Medicine (IOM) called for a commitment to improve the organization and delivery of healthcare in the United States (US). [1] The IOM report notes that, due to advances in medical science and technology, Americans are living longer and an increase in the incidence and prevalence of chronic conditions has emerged. Despite these changes in the public’s healthcare needs, much of the healthcare system today focuses on acute needs and rewards quantity of services delivered at the expense of higher quality care. [2] As a result, the US has fallen behind other countries in amenable mortality (being the worst of sixteen industrialized nations), [3] ranks poorly on access and safety, [4] and outspends any other nation on healthcare. [5]

A small group of healthcare utilizers consumes a majority of healthcare resources in the US. In 2013, about 1% of the US population accounted for 21% of all US health expenses, and 5% accounted for almost half of all US health expenses. [6] Often patients in that 1% or 5% bracket have complicated health regimens and multiple healthcare providers. For instance, in 2012, of the top 1% of Medicaid health care utilizers, 83% had at least three chronic conditions, and more than 60% had five or more conditions. [7]

Since its passage in March of 2010, the Patient Protection and Affordable Care Act (ACA) [9] has guided healthcare reform. The Patient-Centered Medical Home (PCMH) model for delivery of primary care and collaboration of medical office staff with a Community Health Team (CHT) are important components of healthcare transformation in the US. The CHT, particularly when in concert with the PCMH, has been discussed as holding great promise in addressing the complex needs of these high utilizing patients. [8] The CHT model was designed to provide seamless coordination of preventive health and primary health care with community services to improve patient health outcomes while reducing healthcare costs. CHTs are typically comprised of an integrated group of multidisciplinary staff to address the spectrum of medical and non-medical psychosocial needs of patients with chronic disease conditions using community-clinical linkages. [8] Despite the increasing adoption of CHTs, there is limited information describing CHTs operations or implementation challenges.

Care Transformation Collaborative-Rhode Island (CTC-RI), the oversight organization for the state’s all-payer PCMH initiative, determined that creating a CHT pilot intervention could add needed resources to PCMHs to help meet the complex, multi-faceted needs of high-risk, high-cost patients. CTC-RI received funding from health plans and Rhode Island Foundation, chose a community-based model, and contracted with two RI health care organizations to each host and manage a regional CHT to serve multiple PCMH practices. The goal of CHT services was to improve patient health and quality of life, enhance appropriate use of health care services, decrease use of inappropriate medical services such as ambulatory sensitive emergency department visits, and, ultimately, decrease costs.

This contractual arrangement and corresponding CHT pilot intervention were implemented in Fall 2014. Under this contractual arrangement, each host organization directly hired or contracted for staff, and was responsible for oversight of all CHT staff and functions. Supervisors from each CHT were responsible for their CHT program development and management. Each regional CHT coordinated with PCMH primary care practices to provide services outside of the medical offices for patients who have been identified by health plans to be high-risk and/or high-cost. CTC-RI monitored CHT performance through bi-monthly meetings that were attended by the CHT program managers, health plan representatives, and other key stakeholders. CHT operational issues were presented to this group for problem solving. CTC-RI received monthly invoices from each entity enumerating their activities.

A mixed-methods evaluation of this CHT pilot intervention commenced in Spring of 2015, covering the first year of implementation. This evaluation consisted of a literature review of CHTs and similar programs in the United States and an analysis of quantitative and qualitative data collected from CHT staff, patients served by the CHTs, and participating PCMH practice providers. A primary purpose of this evaluation was to assess the structure, processes, and outcomes of the CHT intervention to inform the consideration of future CHT expansion and implementation efforts. This paper fills a research to practice gap through the presentation of results from the analysis of quantitative and qualitative data collected for evaluation of this CHT pilot intervention.

Methods

The evaluation design consisted of both quantitative and qualitative methods in order to benefit from data using multiple means of inquiry. The Memorial Hospital of RI Institutional Review Board reviewed and approved this study.

Quantitative methods

Service documentation

Prior to commencement of evaluation efforts, CHT administrators and staff documented team outreach and service provision efforts. These data were provided to the authors to better understand the structure, processes, and outcomes of the CHT intervention.

Survey instruments

Drawing from existing surveys, the literature, and our knowledge of the CHT program goals, we created surveys for CHT patients, CHT administrators and staff, and practice staff. Survey items were adapted from validated [10] [11] [12]. Additional items not previously validated were included to address factors unique to the CHT service, and to reflect ACA recommendations for CHT interventions. Subscale scores were created by averaging responses to survey items in a manner consistent with the validated measures [10].

Data management and analysis

Participant consent and survey data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted in the Department of Biostatistics Center for Statistical Sciences of Brown University. Descriptive statistics were analyzed for patient demographics, CHT outreach and service provision efforts, and survey responses. A repeated-measures Analysis of Variance (ANOVA) was conducted to assess differences in survey subscale scores between patients, CHT staff, and practices, while addressing within-participant variability.

Qualitative methods

Instrument development

Qualitative, open-ended question guides were developed for interviews with patients, CHT staff, and NCMs at the participating practices. Interview guides were informed by a literature review targeting the processes identified in other CHT-like programs, and discussions about goals of this CHT intervention with CTC-RI directors, CHT staff, and CHT planning committee meetings.

Data collection

All participants in qualitative interviews and group discussions provided written informed consent. Interviews and group discussions were digitally audio recorded and transcribed verbatim. The evaluation team (MS, MC, RG) attended and facilitated group discussions with each CHT, and two authors (MC, RG) conducted the interviews. A contact referral form was offered to patients currently being seen by the CHT staff. Patients who were interested in participating in an interview provided their name, telephone number and address which were given to the interviewers who then called the patients to schedule an interview. Patients were offered their location of choice for the interview and most of the interviews occurred in patients’ homes.

Analysis of qualitative data

Qualitative data were analyzed using traditional qualitative analysis processes that have, in recent years, been labeled “immersion/ crystallization.” [13] This process entailed individually listening to the audio recordings, reading the transcripts, and taking analytic notes throughout the process followed by group discussion among the authors to explore divergent interpretations and to arrive at final presentation of the findings.

Comparing best practices

We used emerging best practices described by the 2013 Commonwealth Fund Brief, Care Management for Medicaid Enrollees through Community Health Teams [14] to provide a framework for our qualitative findings and recommendations (Table 4).

Results

Quantitative findings

Of 886 patients initially identified by health plans as high-risk/ high-cost, 334 patients were deemed eligible for, and received, CHT services. Across both CHTs, the majority of patients were female, and between the ages of 45 and 64 years. Across both CHTs, the majority of activities the CHT staff engaged in per patient were case management. At the time of evaluation, 152 patients were actively participating in the CHT intervention. Patient recruitment and characteristics by CHT is presented in Table 1. CHT activity by activity category and team is presented in Table 2.

Table 1. Patient recruitment and characteristics, by team.

Table 2. CHT activity by activity category and team.

A sample of patients served by CHTs (n = 22), and all staff from the two CHTs (n = 8) completed surveys to assess their perceptions of the structure, processes, and outcomes of the CHT intervention. Survey response options ranged from 0-4, with greater scores indicating stronger agreement. Response options were identical between participants. Four subscales were created by averaging responses to survey items to reflect Access, Service, Respect, and Outcomes. These subscales are consistent with the Vermont 2013 Mental Health Consumer Satisfaction Survey [10].

A repeated-measures ANOVA was conducted to assess differences in survey subscale scores between patients and CHT staff, while addressing within-participant variability. Subscale means are presented in the results that follow and are displayed in Figure 1. Results suggest average ratings of agreement were significantly greater on the Access (x = 3.53, F(1, 27) = 48.75, p < .001), Service (x = 3.51, F(1, 27) = 49.63, p < .001), and Respect (x = 3.46, F(1, 27) = 39.50, p < .001) subscales when compared to the Outcomes (x = 2.80) subscale. Ratings did not differ between patients and CHT staff (F(3, 81) = 1.150, p = .334).

Figure 1. Subscale scores for patients and CHT staff

Twenty-one clinicians from 9 PCMH practices completed the survey to assess their perception of the structure, processes, and outcomes of the CHT intervention. Survey response options ranged from 0-4, with greater scores indicating stronger agreement. Response options were identical to those used on the patient and CHT staff survey. The same Outcomes subscale that was used for patients and CHT staff surveys was included in the practice survey.

Results from a repeated-measures ANOVA indicate significant differences in survey item scores (F(49,539) = 3.487, p < .001). Generally speaking, practice survey participants “agreed” with survey items (x =2.94 on 0-4 scale). However, there were 14 survey items for which the practice survey participants rated significantly greater, and/or significantly less than average. Similar to what was found with patients and CHT staff survey results, the Outcomes subscale score was less than other items, though not a statistically significant difference.

Qualitative findings: Patient interviews

We conducted 27 in-person patient interviews—12 served by one CHT in the north of the state and living in urban areas, and 15 served by the CHT in the south of the state living in suburban or rural areas. The majority (56%) of patients interviewed were male, between 46-55 years old (41%), non-Hispanic white (70%), with less than 12th grade education (37%).

Referral for CHT services. The referral process was not clearly evident to patients. Most did not know how they were referred for CHT services, though some knew the referral came from a provider at the PCMH. As one patient noted, “[The NCM] was trying to get me help that I needed.” However, another asserted, “I don’t know. It certainly wasn’t my doctor. My doctor is too overwhelmed to. . .”

Differentiating among sources of services. Patients who received psychosocial services from the CHT as well as from other entities (e.g. health plan case worker; visiting nurse) were confused about the etiology of the services, and whether these services interconnected. While no patient complained about being contacted by too many social service workers, they noted redundancy in service offerings, and appreciated communication between the service providers.

“So I have to make sure the information they have is right. Especially if they’re going to give me more meds they need to know the current meds I have. So a lot of problems I’ve have, with [the CRS] being in touch with some of the other people who work at the hospital as well as my visiting nurses . . . it really helps if they talk all the time and then advise me the next step.”

Services patients received directly from the CHT or with help from the CHT. Patients described commonly delivered services falling into two categories – services provided directly by the CHT, and services that the CHT helped the patients obtain. See Table 3 for details regarding these services.

Table 3. Services provided directly by the CHTs.

Patients’ attitudes towards interacting with the CHT staff. All patients were pleased with their interactions with the CHT staff. They found staff to be “pleasant”, “friendly”, “helpful”, “motivated”, “energetic”, and to go to great lengths to locate and secure the resources that the patients needed. Many described the CHT staff to be informative, providing guidance without being too “directive” or “pushy”. Along with logistical help with critical problems that patients received from the CHT staff, patients placed high value on the moral support they experienced from interacting with CHT staff. All patients felt they could call upon the staff whenever they felt it to be necessary. In addition to the concrete provision and referral for services, CHT staff filled a gap in many patients’ lives in terms of having someone who will listen to them and who cares about them. This was evident even for patients who described having good relationships with nearby family members who also helped them. Patients stated, “She [CHT staff person] cares about me;” “It helps me feel a little secure and stuff like that because I know [CHT staff person] is right there to help me if I need help.” “They give me some new point of view too. That’s important. I didn’t think of that – my problems are not unique which we all think they are.” “She’ll come out. She’ll sit here. She’ll talk to me. We laugh together and everything.”

“The best thing is to still know that somebody would listen to you, and that you’re not alone, that even though . . . no one cares about what you’re going through, but then all of a sudden [CHT staff] walk in the door asking you how you are, asking you ‘What can we do to help you because you’re not happy?’ And to have them appear at your doorstep is just something to show that there’s somebody out there that still cares, that’s willing to help you. And if they can’t help you they’re going to find somebody that will.”

Qualitative findings: CHT staff and PCMH practice nurse care managers (NCMs)

Each CHT participated in focus groups at the beginning and end of the evaluation. From the two CHTs combined, data were collected from 8 non-manager staff, 1 data analyst, 1 CHT manager, and 1 CHT consultant manager. We also conducted individual qualitative interviews with 4 NCMs working at PCMH practices participating in the CHT pilot intervention. These qualitative findings are outlined using practices described in the 2013 Commonwealth Fund Brief, Care Management for Medicaid Enrollees through Community Health Teams [14] as a structure. Table 4 provides a summary of these findings.

Table 4. CHT pilot intervention features as outlined according to the 2013 Commonwealth Fund Brief, Care Management for Medicaid Enrollees through Community Health Teams.

Multidisciplinary teams coordinate services, promote patient self-management and help patients manage medications. CHT staffing totaled 7.5 FTEs and included team managers/coordinators, community resource specialists (CRS), behavioral health staff that included a behavioral health nurse and a licensed clinical social worker, and a data analyst. CHTs stated the primary care physician and nurse care manager (NCM) oversee and coordinate the patient’s healthcare. NCMs reported believing it was their responsibility to provide health education to encourage patient self-management, and indicate such in the patient’s care plan. The CHTs described efforts to support this patient health self-management. CHTs stated they reconciled medication by ensuring medications in the home match the patient’s health record medication list. As needed, CHTs also helped patients to obtain prescriptions. Respondents also noted the CHT behavioral health staff was crucial in helping patients locate and receive appropriate behavioral health services. In turn, the receipt of behavioral health services helped patients become more capable of addressing their health issues.

“Well one thing that might be helpful is now that we’ve done it for a while…the specific roles…to outline those specifically because when we first started it was kind of a generalized concept. But to have the specific role such as the social worker can do this, this and this; the community outreach worker can do this, this and this. These are their resources. These are services that they can offer your patients at no cost to theyou know, those kinds of things. It was generalized for us, but it wasn’t in detail.”

CHTs and NCMs expressed confusion about roles and responsibilities. Some NCMs stated it would be helpful to have roles and responsibilities clearly defined through written materials.

Sustained continuous relationships with patients. CHTs noted the assessment and care planning process formed the basis for developing long-term relationships with patients. CHT CRS and/or the Behavioral Health staff stated having initial face-to-face contact with patients who agreed to participate in the CHT service. Although CHTs developed a care plan and goals with the patient at initial meeting, they described completing follow-up assessments for only a minority of patients. Once care plan goals were met, CHTs reported calling patients periodically for follow-up. CHTs reported most ongoing contact with the patient occurred through encouraging patients to call.

Communication mechanisms are in place to routinely send and receive information about patients. CHTs noted regular communication with NCMs by phone, email, monthly meetings, and notes in the patient record (where permitted) to understand the patient’s needs, to provide updates, and to address crises that arise. Additionally, CHTs regularly held clinical team meetings with the NCMs and other practice staff to discuss patient progress and readiness for discharge. CHTs claimed NCM buy-in was crucial for effectively working with the practice. One NCM described a successful collaborative effort to help a patient avoid an emergency department visit:

“That CHT person was checking in. And [the patient] had multiple clinical issues that she thinks she should go to the ER for. And [the CHT] communicated with us again. They said, ‘Well, this is what’s happening now.’ And so we were able to bring her in [to the clinic]. So kind of like a back and forth we’re working here to advocate for [patients] with the clinic, but they’re out there in the field, and they can see what’s going on in the home. And that communication piece is pretty crucial with keeping [patients] out of the hospital.”

CHTs asserted a barrier to communication was the lack of appropriate authorization allowing the sharing of patient protected health information (PHI). As a result, the CHTs could not receive or discuss patient PHI directly with the health plans. Additionally, CHT staff could not access patients’ electronic health records. CHTs described this as problematic for getting patient contact information, understanding the scope of the patient’s health problems, and in communicating with practices. Business associate agreements were later established in 2016 to authorize the sharing of patient PHI.

CHTs provide whole-person care when patients are identified as high-risk, high-need, or high-cost. All respondents described this is an area of strength for the CHT pilot intervention. One NCM stated, “somebody in healthcare taking the time to listen, to hear and to help that patient set their own agenda as opposed to agenda that the physician or even myself might have.” However, there were varying definitions for what constituted high-risk, high-need, or high-cost. Since practices work with multiple payers, and payers used different patient identification algorithms, there was some confusion about what constituted a high-risk, high-cost patient. NCMs at times referred patients with immediate needs, such as referral for food stamps, rather than patients who met the CHT program guidelines. Some respondents hoped practices could make referrals, rather than using health plan generated high-risk lists. These respondents reported believing doing so could prevent patients from becoming high-risk/high-cost.

There is a focus on transitions in care, especially between hospital and home. CHTs reported relying on NCMs, or the patient, for notification regarding a patient’s pending, current, or recent past hospitalization or emergency department use. Upon receiving notification, CHT staff worked with the patient to ensure s/he understood the discharge care plan, and helped arrange for needed services. CTC-RI implemented a formal alert system in 2016.

Team members routinely connect patients with relevant community-based services. All respondents stated this is an area of strength and high performance. NCMs reported CHTs were skilled at ferreting out resources, though both CHTs described difficulty with referrals due to a lack of affordable housing, reliable transportation systems, and limited detox beds and/or sober housing placements. The CHT behavioral health staff was described as crucial in helping patients locate and receive appropriate mental health or substance use disorder services. Respondents noted as patients’ behavioral health needs stabilized, patients became more capable of addressing their health issues.

“I would say that certainly some of our users [patients] have behavioral health issues. And the direct interaction with the CHT has been the impact. Some of those patients have gotten the behavioral health interventions that they needed—counseling, hospitalization, medications. So without the CHT we were, I personally was, failing at addressing the needs of these patients. I could not do it.”

However, CHTs reported needing more in-home behavioral health resources, particularly for remote portions of the state or for homebound patients.

CHTs provide care coordination and care management services. CHT staff noted it was sometimes difficult to facilitate coordination since state and local agencies often did not know about the CHT service. CHTs reported this difficulty often resulted in service redundancy and confusion for the patient.

Discussion

Survey results suggest that patients and CHTs feel that patients have access to CHT services, the CHT intervention is helpful, and patients are treated with respect. While ratings on the Outcomes subscale were generally strong, patients and CHTs did not feel as strongly that the CHT pilot intervention resulted in improvements in physical/mental health, symptom distress, or functioning. PCMH practice providers similarly rated the Outcomes subscale items less than other items, though this was not a statistically significant difference.

Results from patient interviews indicated patients are universally satisfied with their interactions with the CHTs, and with the services CHTs provide for them. The scope of services that CHTs help patients with is broad, addressing a variety of psychosocial needs. Satisfaction was also often linked to CHT’s presence for listening to patient problems, providing support, and discussing a myriad of issues that directly impact patients’ health, emotional stability and quality of life.

Focus groups and interviews with CHT staff and PCMH practice NCMs highlighted the CHT pilot intervention’s positive impact on patients by helping to stabilize their physical/mental health, psychosocial needs, and access their relevant entitlements such as disability benefits or food stamps. Some also noted a reduction in inappropriate healthcare use. We found many areas of excellence, including the quality of CHT and NCM relationships, CHT’s ability to address patients’ multiple challenges, and the case review process. Structural and procedural targets for improvement include the need for clear policies and protocols, data use agreements, a data warehouse or repository, and a centralized case management system. There also appears to be opportunities to consider leveraging the motivation, skills and enthusiasm of the CHT staff and expand CRS’ responsibilities.

A primary purpose of this evaluation was to assess the structure, processes, and outcomes of the CHT intervention to inform the consideration of future CHT expansion and implementation efforts. As states to develop CHTs to help manage care for chronically ill patients within primary care practices, it is worthwhile to consider lessons learned from this CHT pilot intervention to guide future local and national implementation efforts. See Appendix 1 for lessons learned and recommendations for CHT program design based upon this evaluation of the pilot CHT intervention with regard to CHT structure, patient identification and selection for CHT services, CHT functioning, and collaboration between the CHT, PCMH primary care practices, and health plans.

Conclusion

The CHT pilot intervention has achieved numerous successes and overcome a variety of obstacles since its inception. Considering lessons learned from this pilot will allow the design of an expanded CHT intervention that effectively leverages CHT staff members’ skills, experience, and commitment to achieve improved patient health and experience at reduced cost.

Appendix

Recommendations for Community Health Team
Program Design and Implementation

Below we discuss lessons learned and recommendations for CHT program design based upon this evaluation of the pilot CHT intervention with regard to CHT structure, patient identification and selection for CHT services, CHT functioning, and collaboration between the CHT, PCMH primary care practices, and health plans.

CHT structure

Findings from this evaluation identified confusion experienced by CHTs, PCMH practice providers, and patients regarding the roles and responsibilities of the CHT program. Participants stated it would be helpful to have roles and responsibilities clearly defined through written materials. As a result, we recommend clearly detailed roles and responsibilities be established and disseminated prior to implementation. Specifically, we recommend universal, detailed, transparent policies and procedures for all aspects of the oversight entity’s and CHTs’ workflow and functioning, and that these policies and procedures be communicated to all relevant stakeholders prior to implementation of CHT services. Additionally, we recommend the creation of CHT services and outreach documentation procedures and categories for use across multiple CHTs. This process has been started in this pilot; we suggest building upon previous work to create a systematic approach to be used consistently across CHTs.

Best practices from successful care management programs call for establishment of a central program office to coordinate activities, monitor progress, and help stakeholders reach their goals. While this pilot rolled out with a focus on regional development to meet regional needs, it is recommended that centralized coordination be reinforced, and a staff person dedicated to this role would be identified.

To facilitate consistency across CHTs, centralized coordination, as well as enhanced communication between appropriate stakeholders, we also suggest the establishment of a centralized data warehouse or data repository, a single electronic care management system to be utilized across CHTs, as well as the establishment of business associate agreements to authorize the sharing of patient PHI. The absence of these features was discussed by many evaluation participants as a significant barrier to effectively providing coordinated care for CHT patients. Inconsistent access to the patient record served as a barrier to routinely sending and receiving information about patients, and a barrier to facilitating transitions in case especially between the hospital and home.

With regard to the development of CHTs, this pilot intervention evaluation highlighted the appreciation for behavioral health staff in addressing the many mental health needs of their patients. Many CHTs nationally include a broader range of staff that include health educators, dieticians, pharmacists, etc. The inclusion of staff members on CHTs from a variety of disciplines can enhance the CHTs reach to better address the needs of their patients.

Patient identification and selection for CHT services

For this CHT pilot intervention, CHTs and PCMH practices worked with multiple payers. Each payer used a different algorithm for identifying high-risk, high-cost, patients. At times, PCMH practice providers referred patients to the CHT program with immediate needs, rather than adhering to the payers’ high-risk, high-cost, lists of patients. Evaluation participants hoped PCMH practices could make referrals to the CHT program in prevent patients from becoming high-risk/high-cost. As a result, we recommend a standardized identification of eligible, appropriate, and impactable patients for CHT services, with mechanisms for practice NCMs and other providers to be integral to the referral process.

CHT functioning

To limit confusion patients’ confusion regarding the CHT program’s roles and responsibilities, several recommendations emerged from evaluation participants. These recommendations include enhanced efforts to increase patients’ understanding of the role of the CHT and care planning through repeated conversations about available and appropriate CHT services, and to communicate to patients how contact will be maintained with the CHT at each stage of service. Additionally, enhanced coordination between CHTs and other sources of case management provided to patients by different stakeholder organizations is recommended to reduce redundancy in services, and better define responsibilities of each source of service to the patient.

In this CHT pilot intervention, CHTs reported having developed care plans and goals with patients at an initial meeting, but only completing follow-up assessments for a minority of patients. Typically, once care plan goals were met, minimal communication continued between CHT staff and patients. As a result, we recommend the institution of a protocol for follow-up with patients after initial critical issues are addressed. This can better ensure ongoing recognition of patients’ conditions over time.

Participants in this CHT pilot intervention evaluation also expressed a desire to enhance communication and collaboration between CHT teams. They reported beliefs that CHTs have much to learn from each other, and having a format such as all-staff CHT meetings could facilitate the sharing of best practices, as well as the identification and resolving of issues common to all teams. Additionally, having a forum in place for all CHT staff members across teams to attend can also facilitate the creation, maintenance, and sharing of geographic and language-specific community resource lists.

Collaboration between the CHT, PCMH primary care practices, and health plans

Results from this evaluation highlighted the importance of ongoing collaboration between PCMH practice NCMs and CHTs. Strong relationships were reported to contribute successful coordination and delivery of care. As such, we recommend the establishment of explicit mechanisms to ensure optimal ongoing communication between CHTs and NCMs and other providers in participating practices. Similarly, we recommend the establishment of a forum for CHTs to regularly communicate patient successes back to the practices.

Results from this evaluation also highlighted the importance of ongoing communication between CHTs and the health plans. Insurers need to know which beneficiaries are receiving CHT services, and CHTs need access to patient PHI. Appropriate authorizations allowing the sharing of patient PHI between the CHTs and the health plans were not in place during this evaluation, but established later in 2016. Quarterly reports to health plans on CHT performance have also been planned to enhance communication. We recommend ensuring that these authorizations are established prior to implementation.

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Abstract

Background: Iron is a pro-oxidant and an essential nutrient for different bacteria. Experimental animal studies have demonstrated exacerbating sepsis episodes. Intravenous iron treatment has been implicated, at least theoretically in increasing infection episodes. However, these studies did not obtain any conclusion in this respect. Therefore, the aim of our study was to evaluate whether there is a risk between intravenous iron treatment and infection episodes following iron treatment.

Methods: In our study, 186 patients who received intravenous iron treatment were included. The biochemical parameters included “pre and post iron treatment” (e.g., ferritin, serum iron, transferring saturation, and hemoglobin) and the later emergence of infections. Moreover, we evaluated all possible risk factors that could interfere with the subsequence appearance of infection.

Results: Infectious complications were reported in 24 patients (12.8%) after the iron treatments began, and no infection was reported in 87.15% (n=162) of the patients. The most common infections were urinary (33%) and respiratory infections (25%). The most common infectious agents were enterobacteriae (e.g., E coli, E faecalis, and E faecium). Notably, we did not observe any intracellular pathogens. In our statistical survey, we did not find a relationship between infection onset and intravenous iron treatment. To analyze the baseline disease, comorbidities, such as diabetes and other treatment (e.g., corticosteroids or anti-TNF) were evaluated, and, no association was found.

Conclusion: In our study, intravenous iron was an effective treatment to correct anemia, and it did not appear to correlate with the development of secondary infections.

Key words

iron therapy; intravenous iron; iron infection

Abbreviations

IV – intravenous; HD – hemodialysis infection

Introduction

Iron is an important nutrient for many bacteria, and in laboratory animals, it was shown to exacerbate sepsis. [1] It has been postulated that increased plasma iron is responsible for the association of hemochromatosis with infections by Vibrio vulnificus, Yersinia enterocolitica, and Escherichia coli. [2] Accordingly, there are host defense mechanisms that tend to restrict the available iron from invading pathogens. [3] For example, the transferrin receptor is the major pathway for delivery of iron to peripheral tissues through endocytosis of its ligand, transferrin, which binds to iron and circulates in the plasma. Down regulation of the transferrin receptor limits the cell’s ability to acquire transferrin-bound iron and concomitantly reduces the endosomal pool of iron that can be accessed by intracellular pathogens, such as L. pneumophila, Mycobacterium tuberculosis, and Mycobacterium avium, and thus restricts their growth. [4, 5] Iron repletion with oral iron has been associated with adverse outcomes for certain infections. In a study of 137 iron-deficient Somali nomads, who were treated with placebo or oral iron (71 subjects), Murray et al. noted seven infection episodes in the placebo group and 36 in the oral iron group (including reactivation of preexisting malaria, brucellosis, and tuberculosis). [6] A large iron supplementation trial of young children on Pemba Island, was prematurely terminated as a result of an excess of serious adverse events (including deaths) in those receiving iron. [7] Ferric iron (Fe)–carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. [8] Intravenous (IV) Fe is generally well tolerated and effective in correcting Fe-deficient states. However, complexing Fe to carbohydrate polymers does not block its potent pro-oxidant effects; therefore, systemic free radical generation and, possibly, tissue damage may result. [9] On the other hand, excessive iron administration may lead to oversaturation of transferrin and the release of free, catalytically active iron into circulation (NTBI) [10] which could be readily utilized by bacteria, leading to their multiplication and the possibility of an overwhelming infection. [11, 12] The aim of the present work was to determine the short-term infection rate associated with IV iron treatment and the possible risk factors that can predict these infections in a contemporary patient cohort.

Material and methods

Patient enrollment A retrospective, longitudinal study was carried out at Marqués de Valdecilla University Hospital (Santander, Spain). The hospital records of patients who underwent ambulatory treatment with IV iron at the hospital day center between January 2011 and December 2012 were reviewed.

Patient parameter evaluation The medical records of these patients were searched after institutional review board approval was obtained for the following data fields: a) demographic features; b) principal diagnosis; c) comorbid factors, such as diabetes mellitus, arterial hypertension, and dislipemia; d) concomitant treatment as potential infection causes, such as corticosteroids, immunosuppresive therapy, and anti-TNF treatment; e) previous infection, and; f) laboratory data prior to and after IV iron treatment, such as hemoglobin concentration, mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), red cell volume distribution width (RDW), serum iron, transferrin saturation, and serum ferritin.

Intravenous iron treatment One thusand mg (50 mg/ml) of ferric carboxymaltose was administered in an ambulatory regimen to the subjects at the hospital day center. The doses of this treatment were adapted subsequently according to the Ganzoni equation and their efficacy.

Case definitions We used a retrospective cohort design with a 1-month baseline period. After IV iron treatment was started, all of the patients were followed for 3 months. We looked for any infectious diseases, and we differentiated the subjects by bacterial, viral and fungal infections, as well as by gastrointestinal, genitourinary, respiratory and other diseases. If a single blood culture was positive for coagulase-negative staphylococci, Corynebacteria, or Bacillus sp., the culture was considered contaminated or representative of a transient bacteremia but not of a bacteremic episode. All other situations in patients in whom at least one blood culture was positive were defined as bacteremic episodes.

Statistical Analysis The results were analyzed with the SPSS 15.0 computer software package (Statistical Package for Social Sciences, Inc., Chicago. IL). Continuous variables were summarized as the means or as the medians and ranges. Categorical variables were compared with the chi-square and Fisher´s exact tests. Correlations between the data sets were examined using the Pearson (r) or Spearman rank (rs) correlation coefficients. Any differences were considered significant for all statistical tests at p values of less than 0.05.

Results

A total of 186 adult patients (70 men and 116 women; mean age, 63 yrs; range, 18 to 80 yrs) were enrolled. The principal diagnosis of the patients included in the study were cardiac diseases (n=41, 22%), neoplasm diseases (n=32, 17.2%), renal diseases (n=31, 16.7%), malnutrition due to bariatric surgery (n=19, 10.2%), hepatic diseases (n=15, 8.1%), and lung diseases (n=15, 8.1%) (Table 1). A comorbid condition known to increase the infection risk was found in 88 patients (47.3%), which included diabetes mellitus (n = 53), current malignancy (n = 32) (under treatment and/or not cured), being a transplant recipient (n= 3), and having both a malignancy and diabetes mellitus (n= 5). Twelve patients were treated with corticosteroids and six were treated with anti-TNF therapy. The pretreatment median hemoglobin level was 9.5 gr/dL (5.6- 12.6 gr/ dL) and after the treatment it was 11.8 gr/dL (7.4-14.1 gr/dL) (Table 2). Additionally, we found a statistically significant difference between the baseline biochemical iron metabolism parameters pre-and post IV iron treatment (Table 2). Thus, we corroborated that IV iron was an effective therapy in our patients.

Table 1. The principal diagnosis of the patients included in the study

Table 2. The baseline laboratory iron metabolism parameters pre-and post-intravenous iron treatment

MCH – mean cell hemoglobin;
MCHC – mean cell hemoglobin concentration;
RDW – red cell volume distribution width.

No patients had more than one bacteremic episode within the month prior to treatment. Twenty-four patients (12.9%) suffered from one infection episode after the IV iron treatment, and 162 patients (87.1%) did not have any infection episodes. The majority of these infections were from bacterial microorganisms (75%, n=18) followed by unknown etiologies (16.7% n=4) and viral episodes (8.3%, n=2). There were no fungal infections. The urinary tract was involved in 33.3% of the cases (n=8); 25% of the cases involved therespiratory system (n=6), which was similar to the unknown focus case percentage; and 16.7% of the cases involved the gastrointestinal system (n=4). The infectious agent was unknown in 63.5% of the cases (n=15). The pathogens responsible for these episodes were E coli (16.7%, n=4) followed by E faecalis, E faecium, Lysteria and Proteus mirabilis, which all occurred in 4.2% of the cases (n=1). No intracellular microorganisms or non-capsulated bacteria were found in our series. Additionally, no serious diseases and no mortality cases were reported three months after the treatments began.

The main characteristics of the patients with and without infection episodes are shown in Table 3. More patients with an infection episode had a comorbidity (diabetes or malignancy) and ongoing immunosuppressive therapy than the patients without infections. However, this was not statistically significant. Furthermore, when we analyzed the relationship between infections with other comorbidities, such as diabetes, cancer, transplantation or treatments such as steroids or anti-TNF we did not find any association.

Table 3. Comorbidity incidences in the infection or no infection groups

NS – Non-Significant

Discussion

Almost all life forms require iron because of its involvement in basic cellular processes. Free iron was shown to potentiate bacterial growth in vitro. [13] In fact, during infections, pathogens use various means to acquire iron from their hosts, whereas hosts attempt to withhold it from pathogens. [14, 15] Iron therefore represents a point of conflict between the host and the pathogen, and an altered iron balance associated with poor outcomes in several infectious diseases, including malaria, [7] tuberculosis, [16] and HIV-1 infection. [17] Furthermore, certain bacterial species, including E. Coli, Klebsiella spp., and Salmonella spp., use unbound iron in the blood to enhance their growth. These organisms release siderophores, which are iron chelators, into the blood. Once these siderophores are released, bacteria can compete with proteins, such as transferrin for unbound iron in the serum. [18, 19] Staphylococcus aureus and Haemophilus influenzae do not possess siderophore; however, they do have transferrin receptors, which allow these bacteria to use iron for growth. [18] Vibrio vulnificus cannot grow if there is no iron available, and their virulence depends on the ability to obtain iron combined with transferrin. Hepcidin, which is produced during innate immune responses to infections, reduces the iron availability in the serum by inhibiting ferroportin function in macrophages and enterocytes and potentially limits extracellular pathogen growth therein. [20] Intravenous iron may also impair immune function and increase infection susceptibility. [21] Gupta et al. [22] found that exposure of mononuclear cells to IV iron agents induced significant intracellular oxidative stress and shortened CD4+ T lymphocyte survival. High doses of IV iron agents impaired the phagocytic activity and microbial killing capability of polymorphonuclear leukocytes [23-25]. Furthermore, in a recent in vitro study, iron sucrose led to impaired phagocytic function and increased polymorphonuclear leukocyte apoptosis. [26] However, the current evidence in clinical practice cannot determine whether iron supplementation increases the risk of infection or worsens outcomes due to infection. [27, 28] There is increasing data to suggest that infective and adverse-event risks may be related to the intensity and frequency of IV iron dosing. [29-31] Brookhart et al. [32] studied iron dosing patterns in a retrospective cohort of 117.050 prevalent hemodialysis (HD) patients and found that administration of large boluses of IV iron for repleting iron deficiency was associated with increased infection-related hospitalization or death compared with smaller doses of IV iron maintenance therapy. The risk of infection-related hospitalization was increased further in patients who experienced infections within the past month. Similarly, the DOPPS study showed a trend towards an increase infection.related mortality in prevalent HD patients treated with > 300 mg of IV iron. [33] A recent meta-analysis of randomized controlled trials evaluating IV iron use (often administered as frequent boluses) in patients with varying infective risk profiles found IV iron to be associated with a 30% greater risk of infection compared with oral or no iron therapy. [34] Conversely, a prospective observational study of 985 patients failed to demonstrate a relationship between infection and serum ferritin or IV iron dosing. [35] In our study, large IV iron boluses were an effective treatment for anemia that was caused by different etiologies, because hemoglobin increased at 2 or 3 points at the end of the treatment and we found any relationship between IV iron administration and infection, which was similar to the previously published data. Furthermore, in our study, transferrin saturation increased to 23.5%, thereby leaving little to no unbound iron available for bacterial utilization, as shown in previous in vitro studies. [10] For example, in the K. pneumonia case, bacterial suppression occurred throughout its incubation until the transferrin saturation exceeded 60%, at which time bacterial growth occurred. [19] Another in vitro study showed that the inhibition of Staphylococcus epidermidis growth was lost once the transferrin saturation exceeded 80%. [18] Subsequent studies had ambiguous results that left the relationship somewhat unclear. [36, 37] In a retrospective observational cohort study of 23.000 adult patients on HD hospitalized for bacterial infection, Ishida et al. found no association between iron treatment and readmission for infection. [38] Feldman’s group, in a re-analysis of their HD cohort using multivariable analysis, showed no statistically significant association between any level of iron administration and mortality. [39] Moreover, a French multicenter prospective study regarding bacteremia risk factors in HD patients (EPIBACDIAL) did not find any correlation between parenteral iron or ferritin and bacteremia. [40] Furthermore, in the Anker study, quality of life and functional status improved in heart failure (a relatively high-risk group) without an increase in infections [41].

Our study had limitations due to its retrospective nature. However, of the patients who were analyzed, we found a 12.8% infections after the beginning of iron therapy. Notably, an important difference in our study compared with the previously published studies was that we did not find any association between IV iron treatment and intracellular pathogens.

In conclusion, based on our study, iron treatment is safe and it does not associate with the development of new infections. However, the infection relationship is not clear and many studies are treating to investigate the different mechanisms regarding this issue. It is important to verify this result with other studies to improve the care and future treatment of patients because iron treatment is frequently used worldside. This knowledge can improve anemia management and avoid side effects. Thus, large multi-centered randomized controlled trials designed to evaluate both the short- and long-term safety of different IV iron dosing regimens are still required to determine the optimal iron therapy.

Conflict of interests

No conflict of interest exists and all authors had full access to all the data used in the study and take full responsibility for the decision to submit the manuscript for publication.

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Abstract

Asthma is an important chronic disease affecting a lot of people worldwide. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This manuscript emphasizes on new generation monoclonal human (ized) antibodies in asthmatics and off-label use. The first developed biologic agent is the anti- immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma.

Introduction

Asthma is an important chronic disease affecting a lot of people worldwide [1]. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This special issue emphasizes on new generation monoclonal human (ized) antibodies in asthmatics [2-4].

The pathophysiological mechanisms underlying asthma, which is a heterogeneous disease, are characterized by interactive responses among various cell types and the hematopoietic cells of the adaptive and innate immune systems. Frequently is conventional therapy like inhaled steroids and beta-agonists sufficient for asthma symptoms. However, a little minority of the asthmatics is not controlled with conventional therapy. Therefore, are new treatment options essential for severe asthmatic patients [5].

Anti-IL-5 Molecules

Interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells play an important role in the pathogenesis of asthma. Monoclonal antibodies targeting these cytokines as treatment for severe asthma are expected to be beneficial [6]. Eosinophilic inflammation is an important event in the pathogenesis of asthma. IL-5 is a key cytokine that arranges eosinophil production, survival, maturation and recruitment of eosinophils to the inflammation [7]. Mepolizumab, reslizumab, and benralizumab are new developed monoclonal antibodies that target the cytokine IL-5. Mepolizumab and reslizumab have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with severe asthma with an eosinophilic phenotype [8,9]. Mepolizumab and reslizumab binds directly to IL-5 ligand. These molecules effectively decreased circulating and sputum eosinophil counts, but they failed to improve airway mucosal eosinophilia, acute exacerbation rates, lung function and symptom scores in several studies. These disappointing results may be affected from inappropriate selection of the patients. In order to overcome the probable mechanistic limitations of early anti-IL-5 agents, an anti-IL5R monoclonal antibody was developed and called as benralizumab. Benralizumab, previously known as MEDI-563, is a humanized recombinant IgG1-k isotype monoclonal antibody. It was constructed from the mouse anti-human IL-5Rα mAbs generated by mice immunized with recombinant human IL- 5Rα [10]. Clinical studies revealed that anti-interleukin 5 monoclonal therapies for asthma could be safe for slightly improving FEV1 (or FEV1% of predicted value), quality of life, and reducing exacerbations risk and blood and sputum eosinophils. However these drugs have no significant effect on PEF, and SABA rescue use. These may be a result of patient selection. Further trials are required to clarify the optimal antibody for different patients [7].

Anti-IL-4/IL-13 Molecules

Another investigated cytokine important in the inflammatory pathways in the pathogenesis of asthma is anti-IL-4. IL-4 is a pleiotropic cytokine secreted mainly by activated T cells. Mast cells, basophils, and eosinophils can also secret IL-4 [10,11]. IL-4 is important in inducing IgE isotype switching, T cell polarization into Th2 cells, and generation of IL-4, IL-5, and IL-13 by Th2 cells. IL-4Rα is expressed on CD4+ and CD8+ T cells, B cells, macrophages, lung epithelial cells, airway goblet cells, and smooth muscle cells [11]. There is a functional homogeniety between IL-4 and IL-13. IL-4 can activate a heterodimeric receptor complex consisting of the IL-4 receptor α- subunit (IL-4Rα) and a γC subunit. IL-13 can activate the IL-4Rα and the IL-13 receptor α1-subunit (IL-13Rα1) [5]. Both IL-4 and IL-13 can bind to heterodimeric combination of the α-subunit of the IL-13 receptor and the α-subunit of the IL-4 receptor. And this leads to signaling of both IL-4 and IL-13. Therefore, will blocking IL-4R α with an antibody of this receptor chain expected to block the effects of both IL-4 and IL-13 [6].

Pascolizumab and VAK694 are anti-IL-4 neutralizing monoclonal antibodies. Also, IL-4 receptor antagonist drugs like dupilumab, pitrakinra and AMG-317 have been discovered. Even a recombinant IL-4Rα that captures soluble IL-4 and prevents their binding to IL-4 receptors, has been developed. It is called altrakincept. However, further research on this drug was discontinued by its manufacturer, since the phase 3 clinical trial failed to confirm its earlier promising results. Since there is a high redundancy of IL-4 and IL-13 signaling, blocking of both IL-4 and IL-13 has been expected to be more efficient [11]. Dupilumab is a drug that inhibits signaling from IL- 4 and IL-13 concomitantly. It is a molecule that binds to the alpha subunit of the IL-4 receptor. Phase II trials for dupilumab showed that asthma exacerbations were decreased in patients using this drug [12,13]. Dupilumab also improved lung function. It reduced the inhaled corticosteroid dose in the patient group. There was also an associated reduction in fractional exhaled nitric oxide with reduced serum concentrations of Th2-associated inflammatory markers such as CCL17 (TARC), CCL26 (eotaxin-3), and IgE [6]. These results are promising and further clinical trials will us show us the long-term efficacy of dupilumab [11].

Another similar drug that targets IL-4 is pitrakinra. It is a recombinant human IL-4 variant that competitively inhibits IL-4Ra to interfere with the actions of both IL-4 and IL-13. Studies on this competitive antagonist called pitrakinra revealed that it leads to significant reduction in asthma exacerbations and improves asthma symptoms in patients with eosinophilia [14]. Pitrakinra also attenuated the late-phase asthmatic response to allergen challenge in patients with mild atopic asthma [6]. The other drug called AMG317 was evaluated in another phase II trial in approximately 300 patients with moderate to severe asthma. Weekly injections over 12 weeks were well tolerated but did not have significant effects on the Asthma Control Questionnaire score (ACQ score; the primary outcome) [14].

Interleukin 13 shares 30% homology with interleukin 4. IL-13 is secreted by Th2 cells, ILC2s, mast cells, basophils, and eosinophils. IL-13 has the potential to increase goblet-cell differentiation, and activation of fibroblasts. IL-13 production can induce an increase in bronchial hyperresponsiveness, and switching of B-cell antibody production towards IgE [6]. IL-13 is similar to IL-4 and uses the same signaling pathways. The high-affinity receptor of IL-13 is a heterodimer of IL-4Rα/IL- 13Rα1. IL-13Rα1 is present on eosinophils, B cells, monocytes, macrophages, smooth muscle cells, lung epithelial cells, airway goblet cells, and endothelial cells. Biologicals that target IL-13 are anti-IL-13 mAbs: anrukinzumab, dectrekumab, GSK679586, IMA-026, lebrikizumab, RPC-4046, and tralokinumab [11].

Patients with severe asthma often have elevated levels in sputum despite therapy with high dose inhaled or oral corticosteroids. Lebrikizumab is one of the many humanized monoclonal antibodies that have been developed to specifically bind to IL-13 and inhibit its function [14]. In a randomized, double-blind, placebo- controlled study were 219 asthma patients observed and evaluated whether the drug lebrikizumab could alter the course of asthma. Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab. This therapy needs futher evaluation before being utilized in clinics [15]. Another monoclonal antibody called tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, has been evaluated in adults with moderate to severe uncontrolled asthma despite controller therapies. Patients were randomly assigned to receive tralokinumab or placebo subcutaneously every 2 weeks for 13 weeks. Although it had an acceptable safety and tolerability, it did not reduce asthma exacerbations [16].

Antithymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine that may trigger allergic inflammation and, thus, play a role in allergic asthma [17]. It is an epithelial-derived cytokine and makes its effect through its receptor, TSLP-R, which is a heterodimeric receptor that consists of the IL-7 receptor alpha chain (IL-7Rα) and the TSLP receptor alpha chain 1 (TSLPRα). In hematopoietic cells, TSLP-R is mainly expressed in DCs, monocytes, B cells, T cells, NK cells, invariant natural killer T (iNKT) cells, eosinophils, basophils, and mast cells [11].

A human anti TSLP monoclonal immunoglobulin G2 lambda (AMG 157) that binds human TSLP and prevents receptor interaction was assessed in a trial. Randomly assigned 31 patients with mild allergic asthma received AMG 157 (700 mg) or placebo intravenously, once a month for three doses. The primary outcome, the maximum percentage decrease in the FEV during the late asthmatic response was 45.9 percent less in the AMG 157 group than the placebo group on day 84. AMG 157 reduced allergen induced bronchoconstriction and airway inflammation. No serious adverse effects were reported. Further studies on this drug are planned to clarify its use in clinical practice [17].

Anti-IL-9 Monoclonal Antibody

IL-9 is a Th2 cytokine and a T cell and mast cell growth factor. Anti-IL-9 antibody-treatment has been shown to protect from allergen-induced airway remodeling, with a concomitant reduction in mature mast cell numbers and activation. It can also decrease expression of the profibrotic mediators transforming growth factor (TGF)-b1, vascular endothelial growth factor (EGF), and fibroblast growth factor-2 (FGF-2) in the lung. The function of IL-9 in allergy has been investigated for its pleiotropic activities on cell types associated with allergic diseases including Th2 lymphocytes, mast cells, B cells, eosinophils, and airway epithelial cells. An anti-IL-9 monoclonal antibody (MEDI-528) has been studied in a clinical trial on 327 asthmatic subjects. Patients were randomized to receive placebo or one of three doses of MEDI-528 (dosage 30, 100, or 300 mg s.c. twice weekly for 4 weeks) in addition to their usual asthma medications. The addition of MEDI-528 to existing asthma controller medications did not improve ACQ-6 scores, asthma exacerbation rates, or FEV1 values. Further clinical trials are needed to explore this drug for altering the course of asthma. Thus, the potential clinical benefit of targeting IL-9 or its receptor in the treatment of asthma remains to be shown in further studies [5].

Anti-IL-2 antibody

Allergen exposure can stimulate IL-2 and its receptor expression (IL -2R) a chain (sCD25) in airways of patients with severe asthma. Daclizumab is a humanized monoclonal antibody that binds specifically to a subunit (CD25) of the high-affinity IL-2R, and inhibits IL-2 binding and its biological activity. Daclizumab can inhibit various T cell functions, including T cell proliferation and cytokine production. It has been investigated in a randomized controlled study. The drug has the potential to improve pulmonary function and asthma control in patients moderate to severe chronic asthma [18]. The risk of immunosuppression in clinical practice needs to be clarified.

Anti-GATA3-spesific DNAzyme

Approximately half of the asthmatic patients exhibit a Th2 type in response to allergen exposure. This Th2 endotype is characterized by a predominant activation of Th2 cells that produce cytokines such as interleukins 4, 5, and 13. The expression and production of all these Th2 cytokines have been shown to be controlled by the zinc finger transcription factor GATA3, which is essential for Th2-cell differentiation and activation. It is considered to be the master transcription factor of the Th2 pathway of immune activation. Therefore, could be interventions to disrupt this immune network, a synthetic DNA molecule (DNAzyme), that binds to GATA3 messenger RNA and cleaves it, a solution. This synthetic molecule called SB010 could significantly attenuate both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis after this drug showed an attenuation of Th2-regulated inflammatory responses [19].

Anti-IL-17 antibody

Although half of the asthma patients exhibit a Th2 type endotype, some remaining patients exhibit a Th17 driven endotype. This subpopulation is characterized with a Th17 driven inflammation. Th17 cells can contribute to airway hyperresponsiveness by recruiting both eosinophils and neutrophils. Therefore, has been IL-17 receptor blocking suggested to beneficial in asthma treatment [20]. Biologicals targeting IL-17 include an anti-IL-17A mAb: secukinumab and an anti-IL- 17 receptor mAb: brodalumab. Although the inhibition of IL-17 receptor A had no effect on subjects with asthma as a whole, a subgroup analysis showed an effect with uncertain significance. Further studies are needed to determine the role of secukinumab in asthma [11]. Brodalumab (AMG 827) is a human, anti–IL-17RA immunoglobulin G2 (IgG2) monoclonal antibody that binds with high affinity to human IL-17RA, blocking the biologic activity of IL- 17A, -17F, -17A/F heterodimer, and -17E (IL-25). Brodalumab can block IL-25 activity and IL-17A and IL-17F. In a randomized controlled study were 302 patients taking this drug evaluated and at the end of the study there was no evidence for an effect of brodalumab in these patients. Further studies may clarify the potential of this drug [20].

Anti TNF antibodies

In addition, human(ized) monoclonal antibodies (HMA) evaluated for the treatment of severe persistent asthma (SPA), but not approved after Phase II trial are as follows; Infliximab (Recombinant human–murine chimeric anti-TNFα monoclonal antibody Infliximab), etanercept (Soluble TNFα receptor fusion protein), and golimumab (Fully human TNFα-blocking antibody) [5]. The expression of TNF alfa is increased in asthma in association with airway neutrophilia. Berry and colleagues have demonstrated that the TNF-α axis is upregulated in patients with refractory asthma, as evidenced by the increased expression of membrane-bound TNF-α, TNF receptor 1, and TNF-α– converting enzyme by peripheral-blood monocytes [21]. Treatment with golimumab did not demonstrate a favorable risk-benefit profile in patients with severe persistent asthma [22]. A study with etanercept showed a small decrease in asthma exacerbations was observed in a randomized placebo controlled study [23]. In a case-series report was it told that in severe, uncontrolled, steroid-dependent asthma infliximab could reduce exacerbations and hospitalizations [24]. In some severe refractory asthma endotypes anti-TNFα therapy may have a role. However, it should be kept in mind that these agents have some safety concerns and should use carefully only in some severe refractory asthma endotypes [5].

ANTI-IgE

The first developed biologic agent is the anti-immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma [5].

The other human(ized) promising monoclonal antibody drug developed, but not approved yet is ligeluzimab. Ligeluzimab binds with very high affinity to the Cε3 domain of IgE. Ligeluzumab may provide longer supression of IgE. Trials with this biologic agent are ongoing [5].

Anti-ige: off-label use non-atopic asthma

The off-label use of omalizumab in patients with uncontrolled non-atopic asthma has resulted in a decrease in exacerbation rates and improvement in asthma symptom scores. In a study conducted in 2013, omalizumab was administered to 266 patients with severe allergic asthma and 29 patients with non-atopic severe asthma for two years, and the study found a decline in the exacerbation rate, increase in the quality of life, and significantly improved disease control in both groups [25-27]. In two studies which used omalizumab in a group of patients with non-atopic severe asthma, the authors observed downregulation of FcRI expression in the basophils and increased FEV1.

Nasal polyposis, allergic rhinitis, and allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis affects 7 to 9% of patients with cystic fibrosis (CF) and 1 to 2% of patients with asthma, posing a diagnostic challenge [28,29]. Cases series related to ABPA were first published in 2007. In a series of eight cases with cystic fibrosis and ABPA published by Tanou et al. [30] in 2014, the authors reported increased FEV1, improved respiratory symptoms, and reduced steroid consumption. In a series of six cases with CF diagnosed with ABPA published by Lehman et al. [31], the authors reported improved symptoms in patients receiving omalizumab, whereas the efficacy of the treatment was less pronounced in patients diagnosed with ABPA and long disease duration and in patients who developed progressive lung problems [31]. In a series of 14 patients with severe asthma and ABPA in 2015, Aydın et al. [32] showed that 11 patients achieved complete and three patients achieved partial response. The authors also reported an overall improvement in the pulmonary functions and respiratory symptoms with a statistically significant reduction in the use of oral corticosteroids (OCS) and number of disease episodes. Also, the patients with a total immunoglobulin E (IgE) level of <1,000 IU showed a better response to omalizumab, compared to those with a total IgE level of >1,000 IU. However, this finding was found to have a low-evidence level, considering the lack of large-scale, prospective case series and randomized and placebo- controlled studies.

Efficacy and safety of omalizumab were first evaluated in a randomized, double-blind, placebo-controlled study of 221 patients with seasonal allergic rhinitis in 2002 [33]. This study reported a significant symptomatic relief up to 48% in the combination treatment group (specific immunotherapy [SIT]+omalizumab), compared to SIT group alone. A randomized study in Japan reported a significant improvement in daily nasal and eye symptoms in patients with seasonal allergic rhinitis receiving omalizumab [34].

In 2007, a randomized placebo-controlled study of eight patients was the first to report reduced rates of postoperative polyp recurrence in patients with atopic asthma and nasal polyps (NP) [35]. In a study of 19 patients with severe asthma and NP in 2011, Vennera et al. [36] reported symptom reduction and disease stabilization with the use of omalizumab treatment. In addition, Tajiri et al. [37] evaluated omalizumab in patients with severe asthma and NP, and reported significant improvements in nasal symptoms, asthma control, and sinus tomography results. However, not all studies were able to show the beneficial effects of the treatment. In a randomized, double-blind, placebo-controlled study of patients with chronic rhinosinusitis receiving omalizumab, Pinto et al. [38] showed improvement in the Sino-Nasal Outcome Test (SNOT-20) scores at three, five, and six months, although there was no significant difference in the scores compared to the control group. The aforementioned study did not observe any changes in the quality of life, symptom scores, cellular inflammation, nasal passage, and olfactory test parameters.

Atopic Dermatitis And Food Allergy

In a series of three patients published in 2005, the authors reported no response after four months of treatment [39], while Lane et al. [40] published a series of three patients in the same study period and reported successful treatment outcomes of severe AD using omalizumab [40]. In addition, a pilot study of 21 patients published in 2009 found a statistically significant clinical improvement in all patients [41]. Another series of three patients published in 2011 reported significant improvement in the Eczema Area and Severity Index (EASI) and itching severity score in patients with severe AD unresponsive to conventional treatment and those with elevated IgE levels [42]. A study of 11 patients published in the same year reported reduced SCORing Atopic Dermatitis (SCORAD) scores, reduced symptoms, and significant improvement in the quality of life (3). The efficacy of omalizumab was also evaluated in 20 adults with severe AD in a prospective, 28-week, open-label study conducted by Hotze et al. [43] in 2014. The authors reported no response to treatment in seven patients harboring filaggrin gene mutation (FLG), while there was a significant improvement in the remaining eight patients. The authors also concluded that the patients with FLG gene mutation were prone to achieve lower response to omalizumab.

Furthermore, in food-related immunotherapy (IT) studies, omalizumab initiated before or received simultaneously with the treatment facilitated the development of tolerance. In a series of 11 patients with cow milk allergy scheduled for IT, 10 patients tolerated daily intake of 8 g cow milk after the initiation of omalizumab, nine weeks before IT, and combination with IT treatment, thereafter [44]. Another use of this treatment is to facilitate a rapid and safe transition to the maintenance phase in patients with food allergy receiving oral IT [45]. Another use of the treatment in food allergy is eosinophillic esophagitis developing in association with multiple food allergies. Also, in a study administered omalizumab to patients with eosinophillic esophagitis, the authors found reduced allergic symptoms and improved quality of life, although there was no change in endoscopic and histologic characteristics of the disease [46].

Food Allergy and Anaphylaxis

Anaphylaxis can occur as a result of exposure to various allergens such as food, drug, and venom; however, no triggering factor can be shown in some cases, of which the latter is known as idiopathic anaphylaxis. The patients with elevated baseline tryptase levels or those diagnosed with mastocytosis are expected to have higher rates of anaphylaxis with a more aggressive course of disease. In particular, patients with venom allergy on IT may experience some difficulties in switching to maintenance dose. Severe anaphylactic episodes can be observed in patients diagnosed with mastocytosis on IT due to venom allergy. In addition, IT combined with omalizumab has enabled a safe transition to the maintenance phase in this group of patients [47-49]. Addition of omalizumab to rush and ultra-rush venom IT protocols has increased the success of IT and enabled a safer transition to the maintenance phase. Another use of omalizumab is to prevent recurrent anaphylactic episodes in patients who are unable to be controlled with conventional therapies [50- 55]. There are case reports on the role of this treatment in preventing idiopathic anaphylactic episodes [56-58].

Several studies have reported asthma symptom control, improved quality of life, and development of tolerance to aspirin in two patients with the use of omalizumab in patients with aspirin-induced airway disease, nasal polyps, and severe asthma [59, 60]. Two patients with recurrent insulin allergy, despite the use of desensitization protocols, and one patient of carboplatin allergy during carboplatin therapy due to ovarian cancer successfully continued their treatment with the addition of omalizumab to the treatment [61-63].

In conclusion, although omalizumab has been approved for the treatment of severe allergic asthma and chronic idiopathic urticaria, it offers an off-label use as a final resort in many allergic diseases. Recent studies have shown that omalizumab is effective in treating bullous pemphigoid, Stevens-Johnson syndrome (SJS)/toxic
epidermal necrolysis (TEN, Type-III/IV reaction, such as graft versus host disease), Netherton syndrome, asthma and chronic obstructive pulmonary disease overlap syndrome (ACOS). Its effects on soluble inflammatory markers, such as sCD200, sTRAIL, hematopoietic cells, Th1/2 cytokines (CXCL8; IL-1β; IL-4; IL-5; IL17A), total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations were demonstrated in several studies [64-70].

Monoclonal antibodies are a candidate for use in several indications with the contribution of large-scale studies to the literature in the near future.

Declaration of Interest

All authors declare that they have no conflict of interest.

Acknowledgements

Prof.Dr. Tse Wen Chang, Prof.Dr.Saadet Gumuslu, Prof.Dr. Fatih Uz, Prof.Dr Arzu Mirici.

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Introduction

The autonomic nervous system (ANS) is an arm of the nervous system surrounded by the peripheral nervous system (PN) and the central nervous system (CNS). It is responsible for the regulation of involuntary bodily functions such as the beating of the heart to the way in which food is digested [1-4]. This system further separates into two division: the sympathetic nerves (SNs) and the parasympathetic nerves (PNs) with each carrying efferent (motor) signals to the heart and afferent responses to the brain [2,3]. In maintaining the body’s homeostasis, each nerve fibre triggers internal or external stimulus. Stimulations coming from the SNs releases epinephrine and norepinephrine prepare the body for stressful or emergency situations or what is best known as the fight or flight state [2]. SNs activities increase heart rate, cardiac output, contractility, conduction velocity and blood pressure during physical stimuli such as exercise [2]. SNs also makes the palm of the hand sweat, the pupils to dilate, and causes the hair on the body to stand on end [2].

In contrast, the PNs which originate from the brain stem and the sacral portion of the spinal cord releases acetylcholine to conserve energy during normal relaxed situations [2]. The efferent outflow termed the vagus nerve operates the parasympathetic to transmit nerves fibres to the lung, heart and other organs [2, 3,]. These nerves work to lower blood pressure (BP), to slow the heart rate (HR) down and to control digestive functions [2].

The SNs and PNs work in opposite direction of each other and as such the SNs enhance automaticity, while the PNs inhabit it [5]. A good demonstration of SNs and PNs operating in opposed action would be if the heart receives a neural stimulus from the parasympathetic branch; it would slow the heart down whereas sympathetic activities would speed up the heart. There is a wide consent suggesting that any changes between the systems play a role in pathological dysfunctions of the ANS [3-5]. For example, a cascade of adverse cardiac events takes place if parasympathetic vagal tone decreases [3, 5-6]. Hypertension-related diseases, coronary heart disease, heart failure and myocardial ischemia are various heart conditions caused by chronic SNs activation [5-8]. The shifts to a more sympathetic overdrive are a catastrophe for ANS impairment. As such any treatment whether by drug action or with exercise training that tilts the autonomic balance toward greater parasympathetic dominance and less sympathetic activity significantly improve prognosis [3].

Moreover, cardiovascular autonomic functions or dysfunctions are clinically evaluated by measuring resting heart rate (RHR), heart rate (HR), BP or heart rate recovery (HRR) [6]. Whether done directly or indirectly these autonomic parametres are good indicators in determining how the heart is working during conditions like exercise or stress [6,7,5,9]. In clinical practices, more specifically in cardiac rehabilitation (CR), several autonomic parametres are used in assessing patients ANS function and their physical capacity. Unfortunately, because of the difficulties and the lack of experience to perform some tests, and the time it takes to do the test, some methods are not applicable in CR setting [4].

In looking at different nerve simulations, clinical research studies found that ANS parametres were risk markers for cardiovascular diseases [5,7,9]. A decline in heart rate variability (HRV), for example, was associated with many cardiac conditions including sudden death [9]. Indeed clinical procedures like HRV in monitoring autonomic processes are necessary with patients. They are practical to check if the ANS is operating normally or to see if a disease or disorders are attacking the system. In this paper, we briefly look at the RPP and how the usefulness of this autonomic test is to CR. The RPP has been quoted in the literature, but it is now accepted as a reliable tool for making clinical decisions for exercise prescription.

Cardiac Rehabilitation and Exercise Testing (ET)

Cardiac rehabilitation is an outpatient health programme delivered by a multidisciplinary team of health professionals (i.e. physicians, nurses, exercise physiologist, dieticians) following cardiac incidents [10-13]. The plan typically provides a multifaceted offering of health services such as low to moderate exercise training, health education, risk factor modifications, counselling and social services [10-12]. The objective of CR is to enhance secondary prevention by lessening cardiac symptoms thereby reducing cardiac mortalities and morbidities for patients with cardiovascular disease [13]. Evidence demonstrate the efficacy of CR interventions where these schemes have improved patient’s quality of life (i.e. reduce depression, better risk profile, enhanced functional status) [12-14]. In one study a CR exercise-based programme was safe to improve cardiopulmonary function with patients who had preserved left ventricular ejection fraction (LVEF) and reduced LVEF [15]. In another research, the authors suggested following coronary artery bypass surgery exercise has the potential to better the long-term prognosis and lower the need for hospital care in cardiac patients [16]. CR is indicative in supporting cardiac autonomic functions to improve the long-term health and well-being of cardiac patients and their families.

Exercise prescription in CR is a determinant on patient’s ET results. Before the start of a CR programme, it is standard practice for all patients to undergo clinical assessments which include ET [11]. With a goal to boost patient’s clinical outcome, ET is done by evaluating left ventricular function (LVF) using an echocardiography or with a maximal exercise test limited by symptoms [11,17-20]. Before the beginning and ending of the programme, ET is the most critical testing component in CR. It provides plenty of information about patients’ functional capacity, their hemodynamic adaptation to maximal and submaximal levels of exercise HR and BP, their residual myocardial ischemia, and their cardiac arrhythmias which can be either induced or worsens with activity [20]. CR exercise testing also let us knows the amount needed to calculate patients training heart rate (THR) for the aerobic exercise [20].

The cardiopulmonary graded test or CPX is the gold standard and approved method used for CR exercise testing. Testing is conducted by treadmill walking, ergometre cycling, stepping, or performing a 12 minute timed walking test [11, 18-20]. During the CPX, patient’s peak oxygen uptake (VO2peak), their anaerobic threshold, their VE/VCO2 and O2 are observed as well as other parametres such as their maximal workload, and their resting and exercised BP and HR [20]. VO2peak is the most frequently analysed CPX parametre as it determines patients’ functional capacity, and it is the strongest prognostic for cardiovascular disease [20]. VO2peak provides information on exercise intensity with a percentage of 50% to 70% the most acceptable [18, 20]. Under the supervision of a healthcare professional patient’s workload is monitored at various exercise stage [18, 20]. They are asked about the perception of exercise intensity using the well-known Borg Rating of Perceived Exertion Scale (RPE) [11, 20]. Furthermore, it is advisable the patient completes each stages of exercise [11]. However, with their discretion, the physician or cardiologist could terminate the test at a particular heart rate or at the request of the patient [11].

Following the completion of ET patients HR, BP and their total VO2peak are recorded and analysed [20]. As a component of functional capacity, the VO2peak decides exercise prescription and is cited as an independent predictor of all-cause mortality in patients with cardiac conditions [11, 20]. After they have been discharged from CR, studies show patient’s functional capacity gets better [20]. The VO2peak test appears to be a valuable clinical assessment in the planning of patients’ management. If the test is not available to measure patients’ fitness capacity, the one metabolic equivalent (MET) formula is applied [11, 20]. The one METs is a very simple procedure to express the energy cost of physical activities as multiples of resting metabolic rate [11]. It is a measurement of the exertion intensity of physical activity, and it is defined by the amount of oxygen consumed while sitting quietly at rest and is equal to 3.5 ml O2 per kg body weight x min (i.e. 3.5 ml O2/kg/min) [11, 20]. For example, a physical activity requiring an 8-MET resting metabolic rate represents a VO2 of 28 ml • kg-1 • min-1. In calculating the absolute oxygen requirement of the activity with 8 MET the individual’s body weight is multiplied by the VO2 (kg-1 • min-1) (i.e. VO2 (kg-1 • min-1 =28 kg-1 • min-1 x 70 kg = 1.960 ml • min-1). A noted feature of the metabolic equivalent is that men and women do not produce the same values (i.e. METs= 14.7 – 0.11 x age for males and respectively 14.7 – 0.13 x age for females.) [20]. This gender difference in computation accounts for women’s having lower level of work capacity [11].

As mentioned earlier, patients’ exertion level in CR is estimated from the RPE scale. The scale ranges from 6 to 20, but the American Association of Cardiovascular and Pulmonary Rehabilitation (AACPR) suggest a RPE of 11 to 15 as a safe zone for patients [11]. An important characteristic of the RPE is that it works linearly with HR and with exercise intensity [11,21]. As such you can estimate the HR value of various levels of work intensity by adding a zero to each point on the PRE [21]. For instance, RPE of 6 becomes 60 and represents HR at rest, and 20 becomes 200, which may represent patients maximal HR [21]. Subsequently, you can use the RPP to know patients’ maximal HR and training workload. Case in point, if a patient develops some discomfort in the chest (i.e. angina pectoris) at a given level of exercise intensity, for safety the CR health professional should advise the patient to workout at a lower intensity. In this way, it would help to keep his training HR below the threshold where he may experience physical symptoms. The RPP is complementary to the RPE while having the ability to support safe CR exercise prescription for cardiac patients who might experience mild chest pain while they are exercising.

Rate Pressure Product (RPP)

To determine the energy requirement and establish the amount of stress put on the heart during exercise, cardiac specialist or exercise physiologists use the RPP. It is an observation of myocardial oxygen consumption (MVO2) [22-26] representing the internal myocardial workload when the heart beats while the external myocardial work is a reflection of different stages of exercise. [27]. Expressed as the product of systolic blood pressure (SBP) and resting heart rate, you can calculate the RPP by multiplying the SBP by the RHR and dividing by 100 (i.e. RPP = SBP x HR/100) [21-27]. PNs and SNs mediate both HR and SBP with SBP only affected by SN [25]. What’s more, depending on the individual physical or health condition RPP score may vary. Fornitano and de Godoy suggested RPP above 30,000 mmHg bpm are good values to predict the absence of obstructive coronary artery disease in patients with positive ET [27].

Heart Rate and Blood Pressure on Exercise Training

The heart needs sufficient amount of oxygen to work properly, and if there is not enough supply, it will cause the heart to weaken (e.g. heart failure) [22]. In this case, the RRP is important in providing information on patients’ myocardial oxygen consumption [20]. Blood pressure and HR is a determinant of physical fitness since they both increase during exercise, but not at the same pace [20, 24, 25]. In subjects with BP between 110 to 120 systolic and 60-80 diastolic whereas resting heart rate (RHR) is 65 to 70 beats per minute (bpm) is considered normal [26]. Under these conditions, the heart does not need to work as hard because the oxygen demand is less [26]. Conversely, in patients with BP over 140/90 mm Hg and an RHR of 85 bpm or higher the heart works harder as it requires more oxygen [26].

Typically, an increase in HR during exercise is a sign that more blood and oxygen is travelling to the working muscles, while elevated BP indicates more blood gets pumped to the heart [24, 26]. As noted, increased BP and HR do not occur at the same time. Thus, a rise in HR triggers blood vessels to widen which in turn helps to keep BP under control [24]. This situation is why healthy people can recover much faster from exercise as compared to someone with a medical condition [20, 22]. The quick recovery is also a sign that there is more parasympathetic vagal tone and less sympathetic activity, which also accounts for the reduction in HR [22].

Extensive clinical and rehabilitation studies on the impact of RPP noted its efficacy as a reliable index to assess patients’ with cardiovascular conditions or related complications on myocardial oxygen consumption during their exercise. Coelho and colleague identified positive changes in MVO2 values following training in patients with ischemic heart disease [28]. Keyhani and co-authors investigated the effects of an eight-week CR aerobic exercise programme on BP, HR, and RPP in patients with congestive heart failure (CHF) found their cardiac functional capacity improved as well as their autonomic function [29]. Still, Adams et al. compared peak RPP values with various modes of aerobic exercise after CR training discovered treadmill walking to associate with a higher score while resistance training produced a much lower number [21].

Looking at the RPP and autonomic responses of Tai Chi practitioners and non-practitioners at rest and using two different stressors: hand gripping and standing Figueroa and colleagues saw improved autonomic function (i.e. parasympathetic tone) with the Tai Chi group [27]. The Tai Chi practitioners’ sympathetic outflow and RPP were also significantly lower at rest suggesting they were better efficient in myocardial oxygen use during resting and pathological stress [27]. The positive outcomes are a testament that the RPP is a reliable tool and an acceptable approach in observing patient’s cardiac autonomic exercise responses that favour greater parasympathetic tone.
The magnitude and the time BP and HR changes after the cessation of exercise are not without discrepancies [28]. When compared to pre-exercise during the first hour of recovery, Somers et al. [30] found lower BP levels, whilst Pescatello et al. [30] saw a significant fall that was up to 12 hours following exercise. Equally, post-exercise HR was reported to enhance, cause no change or decrease [30]. These observations give us a hint that different exercise intensity, duration, and mode significantly influence BP and HR responses following training. Forjaz et al. [31] study recognised that exercise training at a lower intensity, does not only generate a small increase in RPP during exercise, but it also decreases post-exercise rate at rest. By doing so, this reduces myocardial oxygen consumption and lower cardiovascular risks after exercise. In regards to exercise at moderate or high intensity, RPP appears to be greater during training but it decreases below baseline following the recovery period [31]. As cited RPP varies with exercise and there is evident it has clinical implications in providing exercise prescription with those experiencing medical conditions [30].

Conclusion

In addition to standardised CR exercise tests, the RPP supplements with other ET. This autonomic measurement is efficient as gives clues and evaluates patient’s physical or cardiac functional capacity, exercise tolerance and oxygen demand during CR exercise testing and training. Importantly, its utilisation offers support to CR health professionals in selecting the right exercise intensity or training method for those patients whom may show cardiac risk.

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