David Barnes, MD

From the Department of Medicine (Drs. Meisenberg, Muganlinskaya, Sharma, Amjadi, Arnold, Barnes, Clance, Khalil, Miller, Mooradian, O’Connell, Patel, Press, Samaras, Shanmugam, Tavadze, and Thompson), Department of Pharmacy (Drs. Jiang, Jarawan, Sheth, and Trinh), Department of Nursing (Dr. Ohnmacht), and Department of Women and Children’s Services (Dr. Raji), Luminis Health, Annapolis, MD, and Lanham, MD.

Objective: The COVID-19 pandemic has been a challenge for hospital medical staffs worldwide due to high volumes of patients acutely ill with novel syndromes and prevailing uncertainty regarding optimum supportive and therapeutic interventions. Additionally, the response to this crisis was driven by a plethora of nontraditional information sources, such as email chains, websites, non–peer-reviewed preprints, and press releases. Care patterns became idiosyncratic and often incorporated unproven interventions driven by these nontraditional information sources. This report evaluates the efforts of a health system to create and empower a multidisciplinary committee to develop, implement, and monitor evidence-based, standardized protocols for patients with COVID-19.

Methods: This report describes the composition of the committee, its scope, and its important interactions with the health system pharmacy and therapeutics committee, research teams, and other work groups planning other aspects of COVID-19 management. It illustrates how the committee was used to demonstrate for trainees the process and value of critically examining evidence, even in a chaotic environment.

Results: Data show successful interventions in reducing excessive ordering of certain laboratory tests, reduction of nonrecommended therapies, and rapid uptake of evidence-based or guidelines-supported interventions.

Conclusions: A multidisciplinary committee dedicated solely to planning, implementing, and monitoring standard approaches that eventually became evidence-based decision-making led to an improved focus on treatment options and outcomes for COVID-19 patients. Data presented illustrate the attainable success that is both adaptable and suitable for similar emergencies in the future.

Keywords: COVID-19; clinical management; pharmacy and therapeutics; treatment; therapy.

The COVID-19 pandemic has spread to nearly all countries, carrying with it high morbidity, mortality, and severe impacts on both well-developed and less-well-developed health systems. Media reports of chaos within overwhelmed hospitals have been prominent.^1,2 As of January 5, 2022, SARS-CoV-2 has infected more than 295 million people globally and directly caused the death of more than 5.4 million,³ though this number is likely an undercount even in countries with well-developed mortality tracking.⁴

Throughout the COVID-19 pandemic, hospital-based medical teams have been confronted with a flood of severely ill patients with novel syndromes. Initially, there were no standards for therapy or supportive care except for treatments borrowed from similar syndromes. In the setting of high volumes, high acuity, and public dismay, it is unsurprising that the usual deliberative methods for weighing evidence and initiating interventions were often pushed aside in favor of the solace of active intervention.⁵ In this milieu of limited evidence, there was a lamentable, if understandable, tendency to seek guidance from “nontraditional” sources,⁶ including email chains from colleagues, hospital websites, non–peer-reviewed manuscripts, advanced publication by medical journals,⁷ and nonscientific media presentations. In many localities, practitioners responded in idiosyncratic ways. For example, findings of high cytokine levels in COVID-19,⁸ along with reports of in-vitro antiviral activity with drugs like hydroxychloroquine against both SARS⁹ and SARS-CoV-2,¹⁰ drove laboratory test ordering and therapeutic interventions, respectively, carving shortcuts into the traditional clinical trial–dependent standards. Clinical trial results eventually emerged.¹¹COVID-19 created a clinical dilemma for hospital medical staffs in terms of how to organize, standardize, and rapidly adapt to a flood of new information. In this report, we describe how 1 health system responded to these challenges by forming a COVID-19 Clinical Management Committee (CCMC) and empowering this interdisciplinary team to review evidence, create and adjust order sets, educate practitioners, oversee care, and collaborate across teams addressing other aspects of the COVID-19 response.

Program Overview

Health System Description

Luminis Health is a health system with 2 acute care hospitals that was formed in 2019 just before the start of the pandemic. Anne Arundel Medical Center (hospital A) is a 385-bed teaching hospital in Annapolis, MD. It has more than 23 000 discharges annually. Patients with COVID-19 were cared for by either an internal medicine teaching service or nonteaching hospitalist services on cohorted nursing units. Doctor’s Community Medical Center, in Lanham, MD (hospital B), is a 206-bed acute care hospital with more than 10 350 annual discharges. COVID-19 patients were cared for by hospitalist groups, initially in noncohorted units with transition to cohorted nursing units after a few months. The medical staffs are generally distinct, with different leadership structures, though the Luminis Health Department of Medicine has oversight responsibilities at both hospitals. More than 47 physicians attended COVID-19 patients at hospital A (with medical residents) and 30 individual physicians at hospital B, respectively, including intensivists. The nursing and pharmacy staffs are distinct, but there is a shared oversight Pharmacy and Therapeutics (P&T) Committee.

The 2 hospitals had distinct electronic medical records (EMR) until January 2021, when hospital B adopted the same EMR as hospital A (Epic).

Mission and Formation of CCMC

In order to coordinate the therapeutic approach across the health system, it was important for the CCMC to be designated by the health system P&T committee as an official subcommittee so that decisions on restrictions of medications and/or new or revised order sets could be rapidly initiated across the system without waiting for the subsequent P&T meetings. The full committee retained oversight of the CCMC. Some P&T members were also on the CCMC.

The committee reviewed new reports in medical journals and prepublication servers and consulted recommendations of professional societies, such as the National Institutes of Health (NIH) COVID-19 guidelines, Infectious Diseases Society of America, Society of Critical Care Medicine, and US Food and Drug Administration (FDA) Emergency Use Authorizations (EUA), among other sources.

Composition of the CCMC

Physician leaders from both hospitals in the following specialties were solicited for participation: critical care, epidemiology, hospital medicine (internal medicine), emergency medicine, infectious diseases, nephrology, women and children’s services, and medical informatics. Specialists in other areas, such as hematology, were invited for topic-specific discussions. Hospital pharmacists with different specialties and nursing leadership were essential contributors. The committee members were expected to use various communication channels to inform frontline clinicians of new care standards and the existence of new order sets, which were embedded in the EMR.

Clinical Research

An important connection for the CCMC was with theCOVID-19 clinical research team. Three members of the research team were also members of the CCMC. All new study proposals for therapeutics were discussed with the CCMC as they were being considered by the research team. In this way, feedback on the feasibility and acceptance of new study opportunities could be discussed with the CCMC. Occasionally, CCMC decisions impacted clinical research accrual strategies. For example, new data from randomized trials about tocilizumab^1,2 demonstrated benefits in some subsets of patients and resulted in a recommendation for use by the NIH guideline committee in these populations.¹ The CCMC quickly adopted this recommendation, which required a reprioritization of clinical research enrollment for studies testing other immune-modulating agents. This important dialogue was mediated within the CCMC.

Guideline Distribution, Reinforcement, and Platform for Feedback

New guidelines were disseminated to clinicians via daily brief patient huddles held on COVID units, with participation by nursing and pharmacy, and by weekly meetings with hospitalist leaders and frontline hospital physicians. Order sets and guidelines were maintained on the intranet. Adherence was reinforced by unit-based and central pharmacists. Order sets, including admission order sets, could be created only by designated informatics personnel, thus enforcing standardization. Feedback on the utility of the order sets was obtained during the weekly meetings or huddles, as described above. To ensure a sense of transparency, physicians who had interest in commenting on a particular therapy, or who wished to discuss a particular manuscript, news article, or website, were invited to attend CCMC meetings.

Scope of CCMC

In order to be effective and timely, we limited the scope of our work to the report to the inpatient therapeutic environment, allowing other committees to work on other aspects of the pandemic response. In addition to issuing guidance and creating order sets to direct clinical practice, the CCMC also monitored COVID-19 therapeutic shortages^15,16 and advised on prioritization of such treatments as convalescent plasma, remdesivir (prioritization and duration of therapy, 5 vs 10 days), baricitinib, and tocilizumab, depending upon the location of the patient (critical care or not). The CCMC was not involved in the management of non–COVID-19 shortages brought about by supply chain deficiencies.

Table 1 shows some aspects of the health system pandemic-response planning and the committee workforce that undertook that work. Though many items were out of scope for the CCMC, members of the CCMC did participate in the planning work of these other committees and therefore stayed connected to this complementary work.

A Teaching Opportunity About Making Thoughtful Choices

Another important feature of the CCMC was the contributions of residents from both pharmacy and internal medicine. The purpose and operations of the committee were recognized as an opportunity to involve learners in a curriculum based on Kern’s 6-step approach.¹⁷ Though the problem identification and general needs assessment were easily defined, the targeted needs assessment, extracted from individual and group interviews with learners and the committee members, pointed at the need to learn how to assess and analyze a rapidly growing body of literature on several relevant clinical aspects of SARS-CoV-2 and COVID-19. To achieve goals and objectives, residents were assigned to present current literature on a particular intervention during a committee meeting, specifically commenting on the merit or deficiencies of the study design, the strength of the data, and applicability to the local context with a recommendation. Prior to the presentations, the residents worked with faculty to identify the best studies or systematic analyses with potential to alter current practices. We thus used the CCMC process as a teaching tool about evidence-based medicine and the dilemma of clinical equipoise. This was imperative, since trainees thrust into the COVID-19 response have often keenly observed a movement away from deliberative decision-making.¹⁸ Indeed, including residents in the process of deliberative responses to COVID-19 addresses a recent call to adjust medical education during COVID-19 to “adapt curriculum to current issues in real time.”¹⁹

Interventions and Therapies Considered

Table 2 shows the topics reviewed by the CCMC. By the time of the first meeting, nonstandardization of care was already a source of concern for clinicians. Dialogue often continued outside of the formal meetings. Many topics were considered more than once as new guidance developed, changes to EUAs occurred, and new data or new publicity arose.

Methods

The Human Protections Administrator determined that this work constituted “quality improvement, and not research” and was therefore exempt from institutional review board review.

Quantitative Analysis

All admitted patients from March 10, 2020, through April 20, 2021, were considered in the quantitative aspects of this report except as noted. Patients diagnosed with COVID-19 were identified by searching our internal data base using diagnostic codes. Patient admissions with the following diagnostic codes were included (prior to April 1, 2020): J12.89, J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29. After April 1, 2020, the guideline for coding COVID-19 was U07.1.

Descriptive statistics were used to measure utilization rates of certain medications and laboratory tests of interest over time. These data were adjusted for number of unique admissions. In a few cases, not all data elements were available from both hospitals due to differences in the EMR.

Case fatality rate was calculated based upon whether the patient died or was admitted to inpatient hospice as a result of COVID-19. Four patients transferred out of hospital A and 18 transferred out of hospital B were censored from case-fatality-rate determination.

Figure 1 shows the number of admissions for each acute care hospital in the health system and the combined COVID-19 case-fatality rate over time.

Results

A total of 5955 consecutive COVID-19 patients admitted from March 10, 2020, through April 30, 2021, were analyzed. Patients with International Statistical Classification of Diseases, Tenth Revision codes J12.89. J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29 (or the code UO7.1 after April 1, 2020), were included in the analysis. The median age of admitted patients was 65 years (range 19-91 years). Using the NIH classification system for severity,²⁰ the distribution of severity during the first 24 hours after the time of hospital admission was as follows: asymptomatic/presymptomatic, 0.5%; mild illness, 5.3%; moderate illness, 37.1%; severe illness, 55.5%; and critical illness, 1.1%.

The impact of the CCMC can be estimated by looking at care patterns over time. Since the work of the CCMC was aimed at influencing and standardizing physician ordering and therapy choices through order set creation and other forms of oversight, we measured the use of the CCMC-approved order sets at both hospitals and the use of certain laboratory tests and therapies that the CCMC sought either to limit or increase. These counts were adjusted for number of unique COVID-19 admissions. But the limits of the case collection tool meant it also collected cases that were not eligible for some of the interventions. For example, COVID-19 admissions without hypoxemia would not have been eligible for remdesivir or glucocorticoids. When admitted, some patients were already on steroids for other medical indications and did not receive the prescribed dexamethasone dose that we measured in pharmacy databases. Similarly, a few patients were hospitalized for indications unrelated to COVID-19, such as surgery or childbirth, and were found to be SARS-CoV-2-positive on routine screening.

Figure 2 shows the utilization of CCMC-approved standard COVID-19 admission order sets as a proportion of all COVID-19 admissions over time. The trend reveals a modest increase in usage (R² = 0.34), but these data do not reflect the progressive build of content into order sets over time. One of the goals of the order sets was to standardize and reduce the ordering of certain biomarkers: C-reactive protein, serum ferritin, and D-dimer, which were ordered frequently in many early patients. Orders for these 3 laboratory tests are combined and expressed as an average number of labs per COVID-19 admission in Figure 2. A downward trend, with an R² value of 0.65, is suggestive of impact from the order sets, though other explanations are possible.

Medication guidance was also a goal of the CCMC, simultaneously discouraging poorly supported interventions and driving uptake of the recommended evidence-based interventions in appropriate patients. Figure 3 shows the utilization pattern for some drugs of interest over the course of the pandemic, specifically the proportion of patients receiving at least 1 dose of medication among all COVID-19 admissions by month. (Data for hospital B was excluded from this analysis because it did not include all admitted patients.)

Hydroxychloroquine, which enjoyed a wave of popularity early on during the pandemic, was a target of successful order stewardship through the CCMC. Use of hydroxychloroquine as a COVID-19 therapeutic option after the first 2 months of the pandemic stopped, and subsequent use at low levels likely represented continuation therapy for outpatients who took hydroxychloroquine for rheumatologic indications.

Dexamethasone, as used in the RECOVERY trial,²¹ had a swift uptake among physicians after it was incorporated into order sets and its use encouraged. Similarly, uptake was immediate for remdesivir when, in May 2020, preliminary reports showed at least some benefits, confirmed by later analysis,²² and it received an FDA EUA.

Our data also show successful stewardship of the interleukin-6 antagonist toclilizumab, which was discouraged early on by the CCMC due to lack of data or negative results. But in March 2021, with new studies releasing data^12,13 and new recommendations¹⁴ for its use in some subsets of patients with COVID-19, this drug was encouraged in appropriate subsets. A new order set with qualifying indications was prepared by the CCMC and new educational efforts made to encourage its use in appropriate patients.

Ivermectin was nonformulary at the start of the pandemic. This drug enjoyed much publicity from media sources and was promoted by certain physicians and on websites,²³ based on in-vitro activity against coronaviruses. Eventually, the World Health Organization²⁴ and the FDA²⁵ found it necessary to issue advisory statements to the public against its use outside of clinical trials. The CCMC had requests from physicians to incorporate ivermectin but declined to add it to the formulary and recommended not approving nonformulary requests due to lack of data. As a result, ivermectin was not used at either hospital.

Discussion

COVID-19 represents many challenges to health systems all over the world. For Luminis Health, the high volume of acutely ill patients with novel syndromes was a particular challenge for the hospital-based care teams. A flood of information from preprints, press releases, preliminary reports, and many other nontraditional sources made deliberative management decisions difficult for individual physicians. Much commentary has appeared around the phenomenon but with less practical advice about how to make day-to-day care decisions at a time of scientific uncertainty and intense pressure to intervene.^26,27 The CCMC was designed to overcome the information management dilemma. The need to coordinate, standardize, and oversee care was necessary given the large number of physicians who cared for COVID-19 patients on inpatient services.

It should be noted that creating order sets and issuing guidance is necessary, but not sufficient, to achieve our goals of being updated and consistent. This is especially true with large cadres of health care workers attending COVID-19 patients. Guidelines and recommendations were reinforced by unit-based oversight and stewardship from pharmacy and other leaders who constituted the CCMC.

The reduction in COVID-19 mortality over time experienced in this health care system was not unique and cannot necessarily be attributed to standardization of care. Similar improvements in mortality have been reported at many US hospitals in aggregate.²⁸ Many other factors, including changes in patient characteristics, may be responsible for reduction in mortality over time.

Throughout this report we have relied upon an implicit assumption that standardization of medical therapeutics is desirable and leads to better outcomes as compared with allowing unlimited empiricism by individual physicians, either consultants or hospitalists. Our program represents a single health system with 2 acute care hospitals located 25 miles apart and which thus were similarly impacted by the different phases of the pandemic. Generalizability to health systems either smaller or larger, or in different geographical areas, has not been established. Data limitations have already been discussed.

We did not measure user satisfaction with the program either from physicians or nurses. However, the high rate of compliance suggests general agreement with the content and process.

We cannot definitively ascribe reduction in utilization of some nonrecommended treatments and increased utilization of the recommended therapies to the work of the CCMC. Individual physicians may have made these adjustments on their own or under the influence of other sources.

Finally, it should be noted that the mission to rapidly respond to data from well-conducted trials might be thwarted by too rigid a process or a committee’s lack of a sense of urgency. Organizing a committee and then empowering it to act is no guarantee of success; commitment to the mission is.

Conclusion

COVID-19 represented a challenge to medical staffs everywhere, inundating them with high volumes of acutely ill patients presenting with unfamiliar syndromes. Initial responses were characterized by idiosyncratic management approaches based on nontraditional sources of opinion and influences.

This report describes how a complex medical system brought order and standardization through a deliberative, but urgent, multidisciplinary committee with responsibility for planning, implementing, and monitoring standard approaches that eventually became evidence based. The composition of the committee and its scope of influence, limited to inpatient management, were important elements of success, allowing for better focus on the many treatment decisions. The important connection between the management committee and the system P&T committee, the clinical research effort, and teaching programs in both medicine and pharmacy are offered as exemplars of coordination. The data presented show success in achieving standardized, guideline-directed care. The approach is adoptable and suitable for similar emergencies in the future.

Acknowledgments: The authors thank Gary Scabis, Kip Waite, John Moxley, Angela Clubb, and David Woodley for their assistance in gathering data. We express appreciation and admiration for all our colleagues at the bedside.

Corresponding author: Barry R. Meisenberg, MD, Department of Medicine, Luminis Health, 2001 Medical Pkwy, Annapolis, MD 21401; [email protected].

Financial disclosures: None.

From the Department of Medicine (Drs. Meisenberg, Muganlinskaya, Sharma, Amjadi, Arnold, Barnes, Clance, Khalil, Miller, Mooradian, O’Connell, Patel, Press, Samaras, Shanmugam, Tavadze, and Thompson), Department of Pharmacy (Drs. Jiang, Jarawan, Sheth, and Trinh), Department of Nursing (Dr. Ohnmacht), and Department of Women and Children’s Services (Dr. Raji), Luminis Health, Annapolis, MD, and Lanham, MD.

Objective: The COVID-19 pandemic has been a challenge for hospital medical staffs worldwide due to high volumes of patients acutely ill with novel syndromes and prevailing uncertainty regarding optimum supportive and therapeutic interventions. Additionally, the response to this crisis was driven by a plethora of nontraditional information sources, such as email chains, websites, non–peer-reviewed preprints, and press releases. Care patterns became idiosyncratic and often incorporated unproven interventions driven by these nontraditional information sources. This report evaluates the efforts of a health system to create and empower a multidisciplinary committee to develop, implement, and monitor evidence-based, standardized protocols for patients with COVID-19.

Methods: This report describes the composition of the committee, its scope, and its important interactions with the health system pharmacy and therapeutics committee, research teams, and other work groups planning other aspects of COVID-19 management. It illustrates how the committee was used to demonstrate for trainees the process and value of critically examining evidence, even in a chaotic environment.

Results: Data show successful interventions in reducing excessive ordering of certain laboratory tests, reduction of nonrecommended therapies, and rapid uptake of evidence-based or guidelines-supported interventions.

Conclusions: A multidisciplinary committee dedicated solely to planning, implementing, and monitoring standard approaches that eventually became evidence-based decision-making led to an improved focus on treatment options and outcomes for COVID-19 patients. Data presented illustrate the attainable success that is both adaptable and suitable for similar emergencies in the future.

Keywords: COVID-19; clinical management; pharmacy and therapeutics; treatment; therapy.

The COVID-19 pandemic has spread to nearly all countries, carrying with it high morbidity, mortality, and severe impacts on both well-developed and less-well-developed health systems. Media reports of chaos within overwhelmed hospitals have been prominent.^1,2 As of January 5, 2022, SARS-CoV-2 has infected more than 295 million people globally and directly caused the death of more than 5.4 million,³ though this number is likely an undercount even in countries with well-developed mortality tracking.⁴

Throughout the COVID-19 pandemic, hospital-based medical teams have been confronted with a flood of severely ill patients with novel syndromes. Initially, there were no standards for therapy or supportive care except for treatments borrowed from similar syndromes. In the setting of high volumes, high acuity, and public dismay, it is unsurprising that the usual deliberative methods for weighing evidence and initiating interventions were often pushed aside in favor of the solace of active intervention.⁵ In this milieu of limited evidence, there was a lamentable, if understandable, tendency to seek guidance from “nontraditional” sources,⁶ including email chains from colleagues, hospital websites, non–peer-reviewed manuscripts, advanced publication by medical journals,⁷ and nonscientific media presentations. In many localities, practitioners responded in idiosyncratic ways. For example, findings of high cytokine levels in COVID-19,⁸ along with reports of in-vitro antiviral activity with drugs like hydroxychloroquine against both SARS⁹ and SARS-CoV-2,¹⁰ drove laboratory test ordering and therapeutic interventions, respectively, carving shortcuts into the traditional clinical trial–dependent standards. Clinical trial results eventually emerged.¹¹COVID-19 created a clinical dilemma for hospital medical staffs in terms of how to organize, standardize, and rapidly adapt to a flood of new information. In this report, we describe how 1 health system responded to these challenges by forming a COVID-19 Clinical Management Committee (CCMC) and empowering this interdisciplinary team to review evidence, create and adjust order sets, educate practitioners, oversee care, and collaborate across teams addressing other aspects of the COVID-19 response.

Program Overview

Health System Description

Luminis Health is a health system with 2 acute care hospitals that was formed in 2019 just before the start of the pandemic. Anne Arundel Medical Center (hospital A) is a 385-bed teaching hospital in Annapolis, MD. It has more than 23 000 discharges annually. Patients with COVID-19 were cared for by either an internal medicine teaching service or nonteaching hospitalist services on cohorted nursing units. Doctor’s Community Medical Center, in Lanham, MD (hospital B), is a 206-bed acute care hospital with more than 10 350 annual discharges. COVID-19 patients were cared for by hospitalist groups, initially in noncohorted units with transition to cohorted nursing units after a few months. The medical staffs are generally distinct, with different leadership structures, though the Luminis Health Department of Medicine has oversight responsibilities at both hospitals. More than 47 physicians attended COVID-19 patients at hospital A (with medical residents) and 30 individual physicians at hospital B, respectively, including intensivists. The nursing and pharmacy staffs are distinct, but there is a shared oversight Pharmacy and Therapeutics (P&T) Committee.

The 2 hospitals had distinct electronic medical records (EMR) until January 2021, when hospital B adopted the same EMR as hospital A (Epic).

Mission and Formation of CCMC

In order to coordinate the therapeutic approach across the health system, it was important for the CCMC to be designated by the health system P&T committee as an official subcommittee so that decisions on restrictions of medications and/or new or revised order sets could be rapidly initiated across the system without waiting for the subsequent P&T meetings. The full committee retained oversight of the CCMC. Some P&T members were also on the CCMC.

The committee reviewed new reports in medical journals and prepublication servers and consulted recommendations of professional societies, such as the National Institutes of Health (NIH) COVID-19 guidelines, Infectious Diseases Society of America, Society of Critical Care Medicine, and US Food and Drug Administration (FDA) Emergency Use Authorizations (EUA), among other sources.

Composition of the CCMC

Physician leaders from both hospitals in the following specialties were solicited for participation: critical care, epidemiology, hospital medicine (internal medicine), emergency medicine, infectious diseases, nephrology, women and children’s services, and medical informatics. Specialists in other areas, such as hematology, were invited for topic-specific discussions. Hospital pharmacists with different specialties and nursing leadership were essential contributors. The committee members were expected to use various communication channels to inform frontline clinicians of new care standards and the existence of new order sets, which were embedded in the EMR.

Clinical Research

An important connection for the CCMC was with theCOVID-19 clinical research team. Three members of the research team were also members of the CCMC. All new study proposals for therapeutics were discussed with the CCMC as they were being considered by the research team. In this way, feedback on the feasibility and acceptance of new study opportunities could be discussed with the CCMC. Occasionally, CCMC decisions impacted clinical research accrual strategies. For example, new data from randomized trials about tocilizumab^1,2 demonstrated benefits in some subsets of patients and resulted in a recommendation for use by the NIH guideline committee in these populations.¹ The CCMC quickly adopted this recommendation, which required a reprioritization of clinical research enrollment for studies testing other immune-modulating agents. This important dialogue was mediated within the CCMC.

Guideline Distribution, Reinforcement, and Platform for Feedback

New guidelines were disseminated to clinicians via daily brief patient huddles held on COVID units, with participation by nursing and pharmacy, and by weekly meetings with hospitalist leaders and frontline hospital physicians. Order sets and guidelines were maintained on the intranet. Adherence was reinforced by unit-based and central pharmacists. Order sets, including admission order sets, could be created only by designated informatics personnel, thus enforcing standardization. Feedback on the utility of the order sets was obtained during the weekly meetings or huddles, as described above. To ensure a sense of transparency, physicians who had interest in commenting on a particular therapy, or who wished to discuss a particular manuscript, news article, or website, were invited to attend CCMC meetings.

Scope of CCMC

In order to be effective and timely, we limited the scope of our work to the report to the inpatient therapeutic environment, allowing other committees to work on other aspects of the pandemic response. In addition to issuing guidance and creating order sets to direct clinical practice, the CCMC also monitored COVID-19 therapeutic shortages^15,16 and advised on prioritization of such treatments as convalescent plasma, remdesivir (prioritization and duration of therapy, 5 vs 10 days), baricitinib, and tocilizumab, depending upon the location of the patient (critical care or not). The CCMC was not involved in the management of non–COVID-19 shortages brought about by supply chain deficiencies.

Table 1 shows some aspects of the health system pandemic-response planning and the committee workforce that undertook that work. Though many items were out of scope for the CCMC, members of the CCMC did participate in the planning work of these other committees and therefore stayed connected to this complementary work.

A Teaching Opportunity About Making Thoughtful Choices

Another important feature of the CCMC was the contributions of residents from both pharmacy and internal medicine. The purpose and operations of the committee were recognized as an opportunity to involve learners in a curriculum based on Kern’s 6-step approach.¹⁷ Though the problem identification and general needs assessment were easily defined, the targeted needs assessment, extracted from individual and group interviews with learners and the committee members, pointed at the need to learn how to assess and analyze a rapidly growing body of literature on several relevant clinical aspects of SARS-CoV-2 and COVID-19. To achieve goals and objectives, residents were assigned to present current literature on a particular intervention during a committee meeting, specifically commenting on the merit or deficiencies of the study design, the strength of the data, and applicability to the local context with a recommendation. Prior to the presentations, the residents worked with faculty to identify the best studies or systematic analyses with potential to alter current practices. We thus used the CCMC process as a teaching tool about evidence-based medicine and the dilemma of clinical equipoise. This was imperative, since trainees thrust into the COVID-19 response have often keenly observed a movement away from deliberative decision-making.¹⁸ Indeed, including residents in the process of deliberative responses to COVID-19 addresses a recent call to adjust medical education during COVID-19 to “adapt curriculum to current issues in real time.”¹⁹

Interventions and Therapies Considered

Table 2 shows the topics reviewed by the CCMC. By the time of the first meeting, nonstandardization of care was already a source of concern for clinicians. Dialogue often continued outside of the formal meetings. Many topics were considered more than once as new guidance developed, changes to EUAs occurred, and new data or new publicity arose.

Methods

The Human Protections Administrator determined that this work constituted “quality improvement, and not research” and was therefore exempt from institutional review board review.

Quantitative Analysis

All admitted patients from March 10, 2020, through April 20, 2021, were considered in the quantitative aspects of this report except as noted. Patients diagnosed with COVID-19 were identified by searching our internal data base using diagnostic codes. Patient admissions with the following diagnostic codes were included (prior to April 1, 2020): J12.89, J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29. After April 1, 2020, the guideline for coding COVID-19 was U07.1.

Descriptive statistics were used to measure utilization rates of certain medications and laboratory tests of interest over time. These data were adjusted for number of unique admissions. In a few cases, not all data elements were available from both hospitals due to differences in the EMR.

Case fatality rate was calculated based upon whether the patient died or was admitted to inpatient hospice as a result of COVID-19. Four patients transferred out of hospital A and 18 transferred out of hospital B were censored from case-fatality-rate determination.

Figure 1 shows the number of admissions for each acute care hospital in the health system and the combined COVID-19 case-fatality rate over time.

Results

A total of 5955 consecutive COVID-19 patients admitted from March 10, 2020, through April 30, 2021, were analyzed. Patients with International Statistical Classification of Diseases, Tenth Revision codes J12.89. J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29 (or the code UO7.1 after April 1, 2020), were included in the analysis. The median age of admitted patients was 65 years (range 19-91 years). Using the NIH classification system for severity,²⁰ the distribution of severity during the first 24 hours after the time of hospital admission was as follows: asymptomatic/presymptomatic, 0.5%; mild illness, 5.3%; moderate illness, 37.1%; severe illness, 55.5%; and critical illness, 1.1%.

The impact of the CCMC can be estimated by looking at care patterns over time. Since the work of the CCMC was aimed at influencing and standardizing physician ordering and therapy choices through order set creation and other forms of oversight, we measured the use of the CCMC-approved order sets at both hospitals and the use of certain laboratory tests and therapies that the CCMC sought either to limit or increase. These counts were adjusted for number of unique COVID-19 admissions. But the limits of the case collection tool meant it also collected cases that were not eligible for some of the interventions. For example, COVID-19 admissions without hypoxemia would not have been eligible for remdesivir or glucocorticoids. When admitted, some patients were already on steroids for other medical indications and did not receive the prescribed dexamethasone dose that we measured in pharmacy databases. Similarly, a few patients were hospitalized for indications unrelated to COVID-19, such as surgery or childbirth, and were found to be SARS-CoV-2-positive on routine screening.

Figure 2 shows the utilization of CCMC-approved standard COVID-19 admission order sets as a proportion of all COVID-19 admissions over time. The trend reveals a modest increase in usage (R² = 0.34), but these data do not reflect the progressive build of content into order sets over time. One of the goals of the order sets was to standardize and reduce the ordering of certain biomarkers: C-reactive protein, serum ferritin, and D-dimer, which were ordered frequently in many early patients. Orders for these 3 laboratory tests are combined and expressed as an average number of labs per COVID-19 admission in Figure 2. A downward trend, with an R² value of 0.65, is suggestive of impact from the order sets, though other explanations are possible.

Medication guidance was also a goal of the CCMC, simultaneously discouraging poorly supported interventions and driving uptake of the recommended evidence-based interventions in appropriate patients. Figure 3 shows the utilization pattern for some drugs of interest over the course of the pandemic, specifically the proportion of patients receiving at least 1 dose of medication among all COVID-19 admissions by month. (Data for hospital B was excluded from this analysis because it did not include all admitted patients.)

Hydroxychloroquine, which enjoyed a wave of popularity early on during the pandemic, was a target of successful order stewardship through the CCMC. Use of hydroxychloroquine as a COVID-19 therapeutic option after the first 2 months of the pandemic stopped, and subsequent use at low levels likely represented continuation therapy for outpatients who took hydroxychloroquine for rheumatologic indications.

Dexamethasone, as used in the RECOVERY trial,²¹ had a swift uptake among physicians after it was incorporated into order sets and its use encouraged. Similarly, uptake was immediate for remdesivir when, in May 2020, preliminary reports showed at least some benefits, confirmed by later analysis,²² and it received an FDA EUA.

Our data also show successful stewardship of the interleukin-6 antagonist toclilizumab, which was discouraged early on by the CCMC due to lack of data or negative results. But in March 2021, with new studies releasing data^12,13 and new recommendations¹⁴ for its use in some subsets of patients with COVID-19, this drug was encouraged in appropriate subsets. A new order set with qualifying indications was prepared by the CCMC and new educational efforts made to encourage its use in appropriate patients.

Ivermectin was nonformulary at the start of the pandemic. This drug enjoyed much publicity from media sources and was promoted by certain physicians and on websites,²³ based on in-vitro activity against coronaviruses. Eventually, the World Health Organization²⁴ and the FDA²⁵ found it necessary to issue advisory statements to the public against its use outside of clinical trials. The CCMC had requests from physicians to incorporate ivermectin but declined to add it to the formulary and recommended not approving nonformulary requests due to lack of data. As a result, ivermectin was not used at either hospital.

Discussion

COVID-19 represents many challenges to health systems all over the world. For Luminis Health, the high volume of acutely ill patients with novel syndromes was a particular challenge for the hospital-based care teams. A flood of information from preprints, press releases, preliminary reports, and many other nontraditional sources made deliberative management decisions difficult for individual physicians. Much commentary has appeared around the phenomenon but with less practical advice about how to make day-to-day care decisions at a time of scientific uncertainty and intense pressure to intervene.^26,27 The CCMC was designed to overcome the information management dilemma. The need to coordinate, standardize, and oversee care was necessary given the large number of physicians who cared for COVID-19 patients on inpatient services.

It should be noted that creating order sets and issuing guidance is necessary, but not sufficient, to achieve our goals of being updated and consistent. This is especially true with large cadres of health care workers attending COVID-19 patients. Guidelines and recommendations were reinforced by unit-based oversight and stewardship from pharmacy and other leaders who constituted the CCMC.

The reduction in COVID-19 mortality over time experienced in this health care system was not unique and cannot necessarily be attributed to standardization of care. Similar improvements in mortality have been reported at many US hospitals in aggregate.²⁸ Many other factors, including changes in patient characteristics, may be responsible for reduction in mortality over time.

Throughout this report we have relied upon an implicit assumption that standardization of medical therapeutics is desirable and leads to better outcomes as compared with allowing unlimited empiricism by individual physicians, either consultants or hospitalists. Our program represents a single health system with 2 acute care hospitals located 25 miles apart and which thus were similarly impacted by the different phases of the pandemic. Generalizability to health systems either smaller or larger, or in different geographical areas, has not been established. Data limitations have already been discussed.

We did not measure user satisfaction with the program either from physicians or nurses. However, the high rate of compliance suggests general agreement with the content and process.

We cannot definitively ascribe reduction in utilization of some nonrecommended treatments and increased utilization of the recommended therapies to the work of the CCMC. Individual physicians may have made these adjustments on their own or under the influence of other sources.

Finally, it should be noted that the mission to rapidly respond to data from well-conducted trials might be thwarted by too rigid a process or a committee’s lack of a sense of urgency. Organizing a committee and then empowering it to act is no guarantee of success; commitment to the mission is.

Conclusion

COVID-19 represented a challenge to medical staffs everywhere, inundating them with high volumes of acutely ill patients presenting with unfamiliar syndromes. Initial responses were characterized by idiosyncratic management approaches based on nontraditional sources of opinion and influences.

This report describes how a complex medical system brought order and standardization through a deliberative, but urgent, multidisciplinary committee with responsibility for planning, implementing, and monitoring standard approaches that eventually became evidence based. The composition of the committee and its scope of influence, limited to inpatient management, were important elements of success, allowing for better focus on the many treatment decisions. The important connection between the management committee and the system P&T committee, the clinical research effort, and teaching programs in both medicine and pharmacy are offered as exemplars of coordination. The data presented show success in achieving standardized, guideline-directed care. The approach is adoptable and suitable for similar emergencies in the future.

Acknowledgments: The authors thank Gary Scabis, Kip Waite, John Moxley, Angela Clubb, and David Woodley for their assistance in gathering data. We express appreciation and admiration for all our colleagues at the bedside.

Corresponding author: Barry R. Meisenberg, MD, Department of Medicine, Luminis Health, 2001 Medical Pkwy, Annapolis, MD 21401; [email protected].

Financial disclosures: None.

From the Department of Medicine (Drs. Meisenberg, Muganlinskaya, Sharma, Amjadi, Arnold, Barnes, Clance, Khalil, Miller, Mooradian, O’Connell, Patel, Press, Samaras, Shanmugam, Tavadze, and Thompson), Department of Pharmacy (Drs. Jiang, Jarawan, Sheth, and Trinh), Department of Nursing (Dr. Ohnmacht), and Department of Women and Children’s Services (Dr. Raji), Luminis Health, Annapolis, MD, and Lanham, MD.

Objective: The COVID-19 pandemic has been a challenge for hospital medical staffs worldwide due to high volumes of patients acutely ill with novel syndromes and prevailing uncertainty regarding optimum supportive and therapeutic interventions. Additionally, the response to this crisis was driven by a plethora of nontraditional information sources, such as email chains, websites, non–peer-reviewed preprints, and press releases. Care patterns became idiosyncratic and often incorporated unproven interventions driven by these nontraditional information sources. This report evaluates the efforts of a health system to create and empower a multidisciplinary committee to develop, implement, and monitor evidence-based, standardized protocols for patients with COVID-19.

Methods: This report describes the composition of the committee, its scope, and its important interactions with the health system pharmacy and therapeutics committee, research teams, and other work groups planning other aspects of COVID-19 management. It illustrates how the committee was used to demonstrate for trainees the process and value of critically examining evidence, even in a chaotic environment.

Results: Data show successful interventions in reducing excessive ordering of certain laboratory tests, reduction of nonrecommended therapies, and rapid uptake of evidence-based or guidelines-supported interventions.

Conclusions: A multidisciplinary committee dedicated solely to planning, implementing, and monitoring standard approaches that eventually became evidence-based decision-making led to an improved focus on treatment options and outcomes for COVID-19 patients. Data presented illustrate the attainable success that is both adaptable and suitable for similar emergencies in the future.

Keywords: COVID-19; clinical management; pharmacy and therapeutics; treatment; therapy.

The COVID-19 pandemic has spread to nearly all countries, carrying with it high morbidity, mortality, and severe impacts on both well-developed and less-well-developed health systems. Media reports of chaos within overwhelmed hospitals have been prominent.^1,2 As of January 5, 2022, SARS-CoV-2 has infected more than 295 million people globally and directly caused the death of more than 5.4 million,³ though this number is likely an undercount even in countries with well-developed mortality tracking.⁴

Throughout the COVID-19 pandemic, hospital-based medical teams have been confronted with a flood of severely ill patients with novel syndromes. Initially, there were no standards for therapy or supportive care except for treatments borrowed from similar syndromes. In the setting of high volumes, high acuity, and public dismay, it is unsurprising that the usual deliberative methods for weighing evidence and initiating interventions were often pushed aside in favor of the solace of active intervention.⁵ In this milieu of limited evidence, there was a lamentable, if understandable, tendency to seek guidance from “nontraditional” sources,⁶ including email chains from colleagues, hospital websites, non–peer-reviewed manuscripts, advanced publication by medical journals,⁷ and nonscientific media presentations. In many localities, practitioners responded in idiosyncratic ways. For example, findings of high cytokine levels in COVID-19,⁸ along with reports of in-vitro antiviral activity with drugs like hydroxychloroquine against both SARS⁹ and SARS-CoV-2,¹⁰ drove laboratory test ordering and therapeutic interventions, respectively, carving shortcuts into the traditional clinical trial–dependent standards. Clinical trial results eventually emerged.¹¹COVID-19 created a clinical dilemma for hospital medical staffs in terms of how to organize, standardize, and rapidly adapt to a flood of new information. In this report, we describe how 1 health system responded to these challenges by forming a COVID-19 Clinical Management Committee (CCMC) and empowering this interdisciplinary team to review evidence, create and adjust order sets, educate practitioners, oversee care, and collaborate across teams addressing other aspects of the COVID-19 response.

Program Overview

Health System Description

Luminis Health is a health system with 2 acute care hospitals that was formed in 2019 just before the start of the pandemic. Anne Arundel Medical Center (hospital A) is a 385-bed teaching hospital in Annapolis, MD. It has more than 23 000 discharges annually. Patients with COVID-19 were cared for by either an internal medicine teaching service or nonteaching hospitalist services on cohorted nursing units. Doctor’s Community Medical Center, in Lanham, MD (hospital B), is a 206-bed acute care hospital with more than 10 350 annual discharges. COVID-19 patients were cared for by hospitalist groups, initially in noncohorted units with transition to cohorted nursing units after a few months. The medical staffs are generally distinct, with different leadership structures, though the Luminis Health Department of Medicine has oversight responsibilities at both hospitals. More than 47 physicians attended COVID-19 patients at hospital A (with medical residents) and 30 individual physicians at hospital B, respectively, including intensivists. The nursing and pharmacy staffs are distinct, but there is a shared oversight Pharmacy and Therapeutics (P&T) Committee.

The 2 hospitals had distinct electronic medical records (EMR) until January 2021, when hospital B adopted the same EMR as hospital A (Epic).

Mission and Formation of CCMC

In order to coordinate the therapeutic approach across the health system, it was important for the CCMC to be designated by the health system P&T committee as an official subcommittee so that decisions on restrictions of medications and/or new or revised order sets could be rapidly initiated across the system without waiting for the subsequent P&T meetings. The full committee retained oversight of the CCMC. Some P&T members were also on the CCMC.

The committee reviewed new reports in medical journals and prepublication servers and consulted recommendations of professional societies, such as the National Institutes of Health (NIH) COVID-19 guidelines, Infectious Diseases Society of America, Society of Critical Care Medicine, and US Food and Drug Administration (FDA) Emergency Use Authorizations (EUA), among other sources.

Composition of the CCMC

Physician leaders from both hospitals in the following specialties were solicited for participation: critical care, epidemiology, hospital medicine (internal medicine), emergency medicine, infectious diseases, nephrology, women and children’s services, and medical informatics. Specialists in other areas, such as hematology, were invited for topic-specific discussions. Hospital pharmacists with different specialties and nursing leadership were essential contributors. The committee members were expected to use various communication channels to inform frontline clinicians of new care standards and the existence of new order sets, which were embedded in the EMR.

Clinical Research

An important connection for the CCMC was with theCOVID-19 clinical research team. Three members of the research team were also members of the CCMC. All new study proposals for therapeutics were discussed with the CCMC as they were being considered by the research team. In this way, feedback on the feasibility and acceptance of new study opportunities could be discussed with the CCMC. Occasionally, CCMC decisions impacted clinical research accrual strategies. For example, new data from randomized trials about tocilizumab^1,2 demonstrated benefits in some subsets of patients and resulted in a recommendation for use by the NIH guideline committee in these populations.¹ The CCMC quickly adopted this recommendation, which required a reprioritization of clinical research enrollment for studies testing other immune-modulating agents. This important dialogue was mediated within the CCMC.

Guideline Distribution, Reinforcement, and Platform for Feedback

New guidelines were disseminated to clinicians via daily brief patient huddles held on COVID units, with participation by nursing and pharmacy, and by weekly meetings with hospitalist leaders and frontline hospital physicians. Order sets and guidelines were maintained on the intranet. Adherence was reinforced by unit-based and central pharmacists. Order sets, including admission order sets, could be created only by designated informatics personnel, thus enforcing standardization. Feedback on the utility of the order sets was obtained during the weekly meetings or huddles, as described above. To ensure a sense of transparency, physicians who had interest in commenting on a particular therapy, or who wished to discuss a particular manuscript, news article, or website, were invited to attend CCMC meetings.

Scope of CCMC

In order to be effective and timely, we limited the scope of our work to the report to the inpatient therapeutic environment, allowing other committees to work on other aspects of the pandemic response. In addition to issuing guidance and creating order sets to direct clinical practice, the CCMC also monitored COVID-19 therapeutic shortages^15,16 and advised on prioritization of such treatments as convalescent plasma, remdesivir (prioritization and duration of therapy, 5 vs 10 days), baricitinib, and tocilizumab, depending upon the location of the patient (critical care or not). The CCMC was not involved in the management of non–COVID-19 shortages brought about by supply chain deficiencies.

Table 1 shows some aspects of the health system pandemic-response planning and the committee workforce that undertook that work. Though many items were out of scope for the CCMC, members of the CCMC did participate in the planning work of these other committees and therefore stayed connected to this complementary work.

A Teaching Opportunity About Making Thoughtful Choices

Another important feature of the CCMC was the contributions of residents from both pharmacy and internal medicine. The purpose and operations of the committee were recognized as an opportunity to involve learners in a curriculum based on Kern’s 6-step approach.¹⁷ Though the problem identification and general needs assessment were easily defined, the targeted needs assessment, extracted from individual and group interviews with learners and the committee members, pointed at the need to learn how to assess and analyze a rapidly growing body of literature on several relevant clinical aspects of SARS-CoV-2 and COVID-19. To achieve goals and objectives, residents were assigned to present current literature on a particular intervention during a committee meeting, specifically commenting on the merit or deficiencies of the study design, the strength of the data, and applicability to the local context with a recommendation. Prior to the presentations, the residents worked with faculty to identify the best studies or systematic analyses with potential to alter current practices. We thus used the CCMC process as a teaching tool about evidence-based medicine and the dilemma of clinical equipoise. This was imperative, since trainees thrust into the COVID-19 response have often keenly observed a movement away from deliberative decision-making.¹⁸ Indeed, including residents in the process of deliberative responses to COVID-19 addresses a recent call to adjust medical education during COVID-19 to “adapt curriculum to current issues in real time.”¹⁹

Interventions and Therapies Considered

Table 2 shows the topics reviewed by the CCMC. By the time of the first meeting, nonstandardization of care was already a source of concern for clinicians. Dialogue often continued outside of the formal meetings. Many topics were considered more than once as new guidance developed, changes to EUAs occurred, and new data or new publicity arose.

Methods

The Human Protections Administrator determined that this work constituted “quality improvement, and not research” and was therefore exempt from institutional review board review.

Quantitative Analysis

All admitted patients from March 10, 2020, through April 20, 2021, were considered in the quantitative aspects of this report except as noted. Patients diagnosed with COVID-19 were identified by searching our internal data base using diagnostic codes. Patient admissions with the following diagnostic codes were included (prior to April 1, 2020): J12.89, J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29. After April 1, 2020, the guideline for coding COVID-19 was U07.1.

Descriptive statistics were used to measure utilization rates of certain medications and laboratory tests of interest over time. These data were adjusted for number of unique admissions. In a few cases, not all data elements were available from both hospitals due to differences in the EMR.

Case fatality rate was calculated based upon whether the patient died or was admitted to inpatient hospice as a result of COVID-19. Four patients transferred out of hospital A and 18 transferred out of hospital B were censored from case-fatality-rate determination.

Figure 1 shows the number of admissions for each acute care hospital in the health system and the combined COVID-19 case-fatality rate over time.

Results

A total of 5955 consecutive COVID-19 patients admitted from March 10, 2020, through April 30, 2021, were analyzed. Patients with International Statistical Classification of Diseases, Tenth Revision codes J12.89. J20.8, J40, J22, J98.8, J80, each with the additional code of B97.29 (or the code UO7.1 after April 1, 2020), were included in the analysis. The median age of admitted patients was 65 years (range 19-91 years). Using the NIH classification system for severity,²⁰ the distribution of severity during the first 24 hours after the time of hospital admission was as follows: asymptomatic/presymptomatic, 0.5%; mild illness, 5.3%; moderate illness, 37.1%; severe illness, 55.5%; and critical illness, 1.1%.

The impact of the CCMC can be estimated by looking at care patterns over time. Since the work of the CCMC was aimed at influencing and standardizing physician ordering and therapy choices through order set creation and other forms of oversight, we measured the use of the CCMC-approved order sets at both hospitals and the use of certain laboratory tests and therapies that the CCMC sought either to limit or increase. These counts were adjusted for number of unique COVID-19 admissions. But the limits of the case collection tool meant it also collected cases that were not eligible for some of the interventions. For example, COVID-19 admissions without hypoxemia would not have been eligible for remdesivir or glucocorticoids. When admitted, some patients were already on steroids for other medical indications and did not receive the prescribed dexamethasone dose that we measured in pharmacy databases. Similarly, a few patients were hospitalized for indications unrelated to COVID-19, such as surgery or childbirth, and were found to be SARS-CoV-2-positive on routine screening.

Figure 2 shows the utilization of CCMC-approved standard COVID-19 admission order sets as a proportion of all COVID-19 admissions over time. The trend reveals a modest increase in usage (R² = 0.34), but these data do not reflect the progressive build of content into order sets over time. One of the goals of the order sets was to standardize and reduce the ordering of certain biomarkers: C-reactive protein, serum ferritin, and D-dimer, which were ordered frequently in many early patients. Orders for these 3 laboratory tests are combined and expressed as an average number of labs per COVID-19 admission in Figure 2. A downward trend, with an R² value of 0.65, is suggestive of impact from the order sets, though other explanations are possible.

Medication guidance was also a goal of the CCMC, simultaneously discouraging poorly supported interventions and driving uptake of the recommended evidence-based interventions in appropriate patients. Figure 3 shows the utilization pattern for some drugs of interest over the course of the pandemic, specifically the proportion of patients receiving at least 1 dose of medication among all COVID-19 admissions by month. (Data for hospital B was excluded from this analysis because it did not include all admitted patients.)

Hydroxychloroquine, which enjoyed a wave of popularity early on during the pandemic, was a target of successful order stewardship through the CCMC. Use of hydroxychloroquine as a COVID-19 therapeutic option after the first 2 months of the pandemic stopped, and subsequent use at low levels likely represented continuation therapy for outpatients who took hydroxychloroquine for rheumatologic indications.

Dexamethasone, as used in the RECOVERY trial,²¹ had a swift uptake among physicians after it was incorporated into order sets and its use encouraged. Similarly, uptake was immediate for remdesivir when, in May 2020, preliminary reports showed at least some benefits, confirmed by later analysis,²² and it received an FDA EUA.

Our data also show successful stewardship of the interleukin-6 antagonist toclilizumab, which was discouraged early on by the CCMC due to lack of data or negative results. But in March 2021, with new studies releasing data^12,13 and new recommendations¹⁴ for its use in some subsets of patients with COVID-19, this drug was encouraged in appropriate subsets. A new order set with qualifying indications was prepared by the CCMC and new educational efforts made to encourage its use in appropriate patients.

Ivermectin was nonformulary at the start of the pandemic. This drug enjoyed much publicity from media sources and was promoted by certain physicians and on websites,²³ based on in-vitro activity against coronaviruses. Eventually, the World Health Organization²⁴ and the FDA²⁵ found it necessary to issue advisory statements to the public against its use outside of clinical trials. The CCMC had requests from physicians to incorporate ivermectin but declined to add it to the formulary and recommended not approving nonformulary requests due to lack of data. As a result, ivermectin was not used at either hospital.

Discussion

COVID-19 represents many challenges to health systems all over the world. For Luminis Health, the high volume of acutely ill patients with novel syndromes was a particular challenge for the hospital-based care teams. A flood of information from preprints, press releases, preliminary reports, and many other nontraditional sources made deliberative management decisions difficult for individual physicians. Much commentary has appeared around the phenomenon but with less practical advice about how to make day-to-day care decisions at a time of scientific uncertainty and intense pressure to intervene.^26,27 The CCMC was designed to overcome the information management dilemma. The need to coordinate, standardize, and oversee care was necessary given the large number of physicians who cared for COVID-19 patients on inpatient services.

It should be noted that creating order sets and issuing guidance is necessary, but not sufficient, to achieve our goals of being updated and consistent. This is especially true with large cadres of health care workers attending COVID-19 patients. Guidelines and recommendations were reinforced by unit-based oversight and stewardship from pharmacy and other leaders who constituted the CCMC.

The reduction in COVID-19 mortality over time experienced in this health care system was not unique and cannot necessarily be attributed to standardization of care. Similar improvements in mortality have been reported at many US hospitals in aggregate.²⁸ Many other factors, including changes in patient characteristics, may be responsible for reduction in mortality over time.

Throughout this report we have relied upon an implicit assumption that standardization of medical therapeutics is desirable and leads to better outcomes as compared with allowing unlimited empiricism by individual physicians, either consultants or hospitalists. Our program represents a single health system with 2 acute care hospitals located 25 miles apart and which thus were similarly impacted by the different phases of the pandemic. Generalizability to health systems either smaller or larger, or in different geographical areas, has not been established. Data limitations have already been discussed.

We did not measure user satisfaction with the program either from physicians or nurses. However, the high rate of compliance suggests general agreement with the content and process.

We cannot definitively ascribe reduction in utilization of some nonrecommended treatments and increased utilization of the recommended therapies to the work of the CCMC. Individual physicians may have made these adjustments on their own or under the influence of other sources.

Finally, it should be noted that the mission to rapidly respond to data from well-conducted trials might be thwarted by too rigid a process or a committee’s lack of a sense of urgency. Organizing a committee and then empowering it to act is no guarantee of success; commitment to the mission is.

Conclusion

COVID-19 represented a challenge to medical staffs everywhere, inundating them with high volumes of acutely ill patients presenting with unfamiliar syndromes. Initial responses were characterized by idiosyncratic management approaches based on nontraditional sources of opinion and influences.

This report describes how a complex medical system brought order and standardization through a deliberative, but urgent, multidisciplinary committee with responsibility for planning, implementing, and monitoring standard approaches that eventually became evidence based. The composition of the committee and its scope of influence, limited to inpatient management, were important elements of success, allowing for better focus on the many treatment decisions. The important connection between the management committee and the system P&T committee, the clinical research effort, and teaching programs in both medicine and pharmacy are offered as exemplars of coordination. The data presented show success in achieving standardized, guideline-directed care. The approach is adoptable and suitable for similar emergencies in the future.

Acknowledgments: The authors thank Gary Scabis, Kip Waite, John Moxley, Angela Clubb, and David Woodley for their assistance in gathering data. We express appreciation and admiration for all our colleagues at the bedside.

Corresponding author: Barry R. Meisenberg, MD, Department of Medicine, Luminis Health, 2001 Medical Pkwy, Annapolis, MD 21401; [email protected].

Financial disclosures: None.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.