At-Home Monitoring for Chemotherapy | Part 2 — Clinical Literature Review

Athelas One finger-stick automated differential blood analyzer, FDA & Health Canada-cleared. Ref. K181288

Thanks to Dr. David Dale from U. of Washington for his review of this work.

Table of Contents: Challenges Reviewed

1. Time-to-treatment delay, challenges with emergency management
2. Cost-to-patient and health system, availability of outpatient care
3. The thermometer as the best measure of inflammatory response — in 2020
4. Operational uncertainty and patient outcomes in chemotherapy

Authors Note: Severe complications and death may result from incidence of febrile neutropenia and sepsis. The information in this article should not be interpreted as medical advice. Complications are generally not discussed. Please contact your doctor for information specific to you.

1) Time-to-treatment delay, challenges with emergency management

18% increase in mortality for each hour delay in treatment [1]

International guidelines recommend the administration of antibiotic therapy within 60 minutes of emergency department presentation with neutropenic fever; various working groups go further, recommending treatment within 30 minutes and immediately after blood cultures are taken [1].

In practice, this has been a challenge to achieve. In a study conducted at Northwestern Memorial Hospital, in 91% of visits, i.v. antibiotics were administered in the emergency department within a 50th percentile range of 1.2–2.8 hours (median 1.7, n=57) [2]. In another study from a large, New York, academic health center, patients waited an average of 21 hours before seeking treatment and once at the hospital, the median time-to-treatment was 3.5 hours, including a 1.3 hour initial wait at triage (n=23) [3]. Time-to-treatment is critical, a 2014 study (n=307) showed that for each hour of delay in treatment there was an 18% increase in mortality for febrile neutropenia (FN) and in total up to 70% [1]

The reasons behind the time-to-treatment challenge are of particular interest. In the UK, where compliance with the 1 hour treatment target is low: achieved in 18–26% of cases, one the primary reasons included triage nurse awareness, with the remainder relating to administration issues [1]. Patients today are told by their oncologist to inform triage of recent chemotherapy (within 6-weeks) and the National Neutropenia Network goes further by advising members to carry wallet-cards to help triage prioritize, assess, and treat [4].

A lack of awareness of neutropenic fever and protocols not being available for quick reference, provide an interesting focal point because those variables are part of the patient information exchange and therefore partially in the control of the patient. The desired outcome is to achieve ESI-Level 2 priority on presentation to emergency [5].

Solution: A connected, at-home infection monitoring platform that activates hospital treatment pathways through planned direct admission. Where not possible, pathway-focused diagnostic reports are generated for emergency triage.

To activate an accelerated treatment pathway, the infection monitoring platform includes finger-stick WBC-differential, which will confirm the presence of neutropenia or neutrophilia (five-part differential result), and assess the required triage inflammation parameters for infection: temperature, pulse, respiratory rate, blood pressure, and oxygen saturation [1].

In the at-home setting, an adverse event is flagged by the combination of results and trend information, with notice provided to the patient’s clinician to request direct admission. A digital diagnostic report is subsequently generated for the patient to provide to triage in cases where direct admission is not possible and includes the patient’s condition history, process to confirm assessment, and recommended care pathway.

In the hospital-triage environment, this infection screening platform is similarly useful as a triage tool that acts as a stop-gap for delayed laboratory blood work. The finger-stick WBC-differential provides the five-part differential (neutropenia) in less than two minutes. The platform does not replace the need for bloodwork, but does provide the ability to prioritize and make an early assessment of risk when combined with the inflammation screening tools mentioned above.

As validation of approach, when the primary reasons for triage delay are addressed, including the distribution of febrile neutropenia-alert cards to patients, time-to-treatment has been shown to drop significantly. In one study, antibiotic therapy through emergency reduced from 3.9 hours to 1.4 hours (n=276) [6].

An additional advantage of planned hospital admissions from earlier-flagged cases is that from the increased time available for treatment, novel broad-spectrum antibiotics can be preserved for if and when the condition advances to a critical stage, assisting with policy goals of minimizing use.

2) Cost-to-patient & health system, availability of outpatient care

$22,086 per in-patient neutropenic fever episode (2001–2006 USA) [9]

Advances in outpatient management of febrile neutropenia have been made since the introduction of the Talcott risk factors in 1992 [7]. When antibiotic therapy is administered as a low-risk outpatient, the total cost of incidence reduces from an average of $22,086, over an average 9.6 day stay, to $985 (n=91,560) [8,9]. At this expense, funding in-patient febrile neutropenia therapy in the United States can present serious financial challenges for families: 42.6% of cases are funded by variable private insurance plans or self-funded sources [8]. This does not include the cost of related, ongoing treatments, such as the $86,243 average cost of chemotherapy [9]. Today, between 15–20% of patients qualify as low-risk and are managed on an outpatient basis (n=128–401) after screening by MASCC and CISNE criteria [10–13].

Solution: Integrate CISNE criteria for robust outpatient monitoring alternative with planned pathways for adverse events.

In place of daily laboratory venous blood draws and clinical follow-ups, at-home, finger-stick monitoring of the CISNE criteria: integrated WBC differential counts, body temperature, pulse rate, glycemic index, and symptom tracking provides the opportunity for higher resolution trend data that will improve confidence and flag non-responsive patients earlier. With active infection monitoring by CISNE, safe outpatient therapy could be extended to select intermediate-risk class patients (CISNE Score 1–2) in an effort to optimize both therapy for and the financial impact of the condition.

A manually scored version of this approach has validated to reduce complication occurrence, shifted unplanned emergencies into planned interventions, and achieved 90% patient satisfaction (n=41) [14].

3) The thermometer as the best measure of inflammatory response — in 2020.

38% of select immunotherapy patients are on therapies that mute fever [15]

Sepsis can generally be understood as a condition where an infection progresses to trigger dynamic changes in the body’s inflammatory response, beyond the presence of a fever. 55% of febrile neutropenia oncology patients present to emergency with a defined sepsis syndrome and with 45% of that population in the severe or shock category [16]. Sepsis outside of the febrile neutropenia condition has a similar time-dependent outcome correlation to FN. Each hour delayed in receiving antimicrobial therapy resulted in an 8% increase in mortality (n=2731) [17]. In-hospital mortality dropped from 33% to 20% when the time from triage to antimicrobial therapy was 1 hour or less [18].

As mentioned, neutropenic fever is currently assessed at triage, at minimum, by temperature (oral when possible) and absolute neutrophil count (ANC). The thermometer, although the simplest device to quantify illness, is not comprehensive for infection. Sepsis indicators describe a more extensive state of infection and are used to describe febrile neutropenia not only in advanced cases, but also when a patient may be on fever-suppressing medications to assist with treatment: glucocorticoids for immunotherapy [15].

The specific criteria used to define sepsis inflammation are generally-accepted as SIRS, criticized for being overly sensitive, and SOFA (including the home-version qSOFA). The benefit and limitation of Sequential Organ Failure Assessment (SOFA) is it’s utility to describe sepsis as a simple process, using straightforward tests, as opposed to predict outcomes with some additional complexity [19]. SOFA, as a useful measure of advanced infection, would not be as ideal for indicating early-stage infection of immune-compromised patients. Such a platform would have it’s utility based in predictive risk flagging to activate treatment pathways.

Solution: Integrate SIRS & SOFA criteria to complement thermometry in comprehensive assessment of inflammation. Because it’s 2020, leverage WBC-differential to define a predictive infection-index useful for early-stage infection monitoring, currently under-measured.

A finger-stick WBC-differential platform, complimented with inflammation monitoring by platelet count, pulse oximetry, blood pressure, thermometry, and symptom tracking not only satisfies the requirements for rapid triage screening, but also all SIRS & qSOFA parameters used today for home-screening sepsis inflammation. Further, this infection monitoring platform includes WBC-differential, useful to predict early-infection and progress.

WBC differential is of particular interest because in addition to the absolute count itself, higher-resolution trends and the relationship between neutrophils, lymphocytes, and monocytes explain the progression of infection. As an example, Lymphopenia (<=700/uL) at day 5 following chemotherapy has been shown useful in predicting febrile neutropenia with 94% specificity, 55% sensitivity (n=321–950) [20]. The same condition at day 1 is also a predictor of treatment toxicity and anemia and severe thrombocytopenia [20]. Monocytopenia is scored in the CISNE criteria based on its retrospective significance to complications from febrile neutropenia (CISNE) [21]. The Neutrophil-to-Lymphocyte ratio, NLR, is a useful indicator of inflammation and clinical outcomes for oncology patients [22]. Specifically, lymphocytopenia and neutrophilia are characteristic of sepsis inflammation and compound to drive this ratio, not entirely different from what is described in the SIRS WBC criteria [23].

These examples are meant to illustrate the practicality and benefit of at-home, predictive, risk monitoring for immuno-compromised patients toward the goal of activating planned treatment pathways. Inflammation markers for early-infection and sepsis are evolving around advances in ubiquitous, easy-to-use technology and the platform described herein creates the opportunity to define the next generation inflammation-index, useful not only for sepsis, but also early prediction.

4) Impact of febrile neutropenia on chemotherapy management

~10% of chemotherapy appointments are rescheduled due to variability

Chemotherapy-induced neutropenia presents a significant challenge for both patient outcomes and management of clinical operations. In one study reviewing increased mortality from receiving less than 85% of planned dose, chemotherapy-induced neutropenia was responsible for delays or dose reductions in 61% of breast cancer cases (n=1,111) [24]. Often these delays happen after the patient arrives to receive drug therapy at the clinical site and completes blood-work, only to be turned away. With sporadic data points at significant time delay, the patient baseline, nominal variability, and treatment-induced changes can be difficult to ascertain. Studies have shown the importance of completing baseline blood work more frequently than the 6-week guideline, with a revised target of within 7-days prior to starting therapy [25]. Warr reports that significant changes in blood counts occurred in 33% of cases and 17% provided indication for dose adjustment when the two data-points were compared (n=335) [25].

Solution: Blood-work trend flagging for oncologists with advance notice of intervention requirements and risk-adaptive scheduling changes.

As a compliment to baseline laboratory venous blood tests, at-home patient monitoring of trends in hematological variables (WBC-differential and platelet counts) with non-invasive cardiac and pulmonary monitoring (pulse oximetry, blood pressure, & ECG), can provide early-indication of treatment toxicity, allowing the patient to make lifestyle and receive outpatient growth factor adjustments (with physician approval) prior to receiving therapy, as opposed to being screened out of therapy onsite at significant cost. Advance notice of patient risk will assist healthcare professionals to provide intermediate care optimizations and administrators to optimize resource allocation.

Summary

A simple, predictive, at-home infection monitor featuring a white blood cell differential complemented with inflammation monitoring by platelet count, pulse oximetry, blood pressure, thermometry, and glucometry can redefine patient outcomes for infection in patients with uncertain immune health and has the following benefits:

1. Achieve time-to-treatment international guidelines of <1 hour by planned direct hospital admission based on early-infection risk identification.
2. Enable select intermediate risk FN patients (CISNE Score 1–2) to receive outpatient antibiotic therapy at reduced risk.
3. Reduce the use of broad-spectrum antibiotics through planned hospital admissions at early-infection stages.
4. Expand resource utilization of oncology services through efficiency improvements while simultaneously improving patient experience.
5. Create opportunity for a new, comprehensive infection-index that assesses early- risk for the immune-compromised and modern medicine.
6. Capture edge cases, such as drug-induced suppressed fever that confound home-screening tools.

References

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