Sharp HealthCare COVID-19 Treatment Guidelines (V7)

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Sharp HealthCare COVID-19 Treatment Guidelines (V7)

Intro
The intent of this guideline was to summarize existing clinical framework for clinical
management of adult hospitalized patients COVID-19 (Covid) at Sharp HealthCare facilities.
Now more than 18 months into the pandemic, and will the availability of excellent and
regularly updated guidelines, we refer providers to NIH COVID Treatment Guidelines as
our primary treatment guideline for care at Sharp hospitals and facilities.

For any provider regularly caring for patients with Covid or MIS, please sign up through the
NIH website to receive guideline updates via email.

Sharp HealthCare Emergency Use Authorization (EUA) Workgroup
To provide safe, effective, and high-value care to our patients with Covid, Sharp HealthCare
convened an emergency use authorization (EUA) pharmacy and therapeutics Covid
workgroup which reports to HID. This group is composed of physician leaders including all
site CMOs, pulmonology, hospitalists, emergency medicine, OB, infectious disease,
rheumatology, occupational health, as well as our system pharmacy and ASP experts. The
workgroup regularly reviews existing literature on treatments for Covid, with focus on
drugs that have received EUA approval, as well as the off-label use of some select agents.

This workgroup may occasionally supplement this document or provide SBAR updates to
the medical and pharmacy staff based on the evolving nature of the pandemic, available
therapies, drug shortages, and contingency planning needs—such as availability and
preference on the use of DMARDs that may not be covered within the scope of NIH
Guidelines.

If new and highly promising therapies become available, or existing ones have a serious
safety signal, the EUA workgroup may in some instances provide guidelines and workflow
support ahead of updated NIH practice recommendations.

We also emphasize NIH’s position that “whenever possible, the Panel recommends that
promising, unapproved, or unlicensed treatments for COVID-19 be studied in well-
designed, controlled clinical trials. This recommendation also applies to drugs that have
been approved or licensed for indications other than the treatment of COVID-19. The Panel
recognizes the critical importance of clinical research in generating evidence to address
unanswered questions regarding the safety and efficacy of potential treatments for COVID-
19.”

Select topics that are out of scope or not covered by NIH guidelines are also elaborated
upon below.

Diagnostic Testing
Please refer to NIH guidelines about viral-specific testing for SARS-CoV-2 infection

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Sharp HealthCare remains unique among healthcare organizations, reflexively sending
nearly 100% of positive PCR cases for viral whole genome sequencing from emergency
department and hospitalized patients. De-identified viral genomic profile of our patients
are included and regularly updated at Outbreak.info, SEARCH Alliance, and Nextstrain.org.

Covid Treatment Summary
As of August 2021 we refer providers to the NIH COVID-19 Treatment Guidelines for
additional guidance on care for patients with Covid. Information is available for the
following and additional topics on the NIH website:
        Non-hospitalized patients general management and therapeutic management
        Hospitalized adults: therapeutic management
        Critical care

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Multisystem Inflammatory Syndrome
Beyond the well-described COVID-19 syndrome, large case series from the US1,2 and
Europe3 also indicate SARS-CoV-2 infection triggers a Multisystem Inflammatory Syndrome
(MIS) reminiscent of Kawasaki and toxic shock syndromes in a small percent of infected
persons.

Early symptoms of this syndrome in pediatric patients (MIS-C) are notable for the absence
of significant respiratory symptoms; children instead may present with fever, abdominal
symptoms including diarrhea, rash, limb swelling1,4. In addition to elevated inflammatory
markers, myocarditis and other cardiovascular changes may be seen5. At present, three
tentative phenotypes appear to present in pediatric cohorts: fever and elevated
inflammatory markers without mucocutaneous inflammation or end-organ damage; shock
with myocarditis and left ventricular dysfunction; and typical + atypical Kawasaki
syndrome, occasionally progressing to a shock syndrome 2,6.

Since June 2020, several case reports have also described a similar syndrome in adults,
now called Multisystem Inflammatory Syndrome in Adults (MIS-A). In contrast to Covid,
the patients with MIS-A had minimal respiratory symptoms, hypoxemia, or radiographic
abnormalities at the time of presentation to care—though half of cases did report
respiratory symptoms before onset of MIS-A. Case series indicate a wide range of
susceptible ages – 20 to 50 years-old – though generally MIS-A appears to be more
common in younger to middle age adults. As with MIS-C, ethnic and racial minorities
appear to be at much higher risk for this condition.

Similar to the pediatric presentation, MIS-A cases predominantly reported non-respiratory
complaints at the time of initial assessment: constitutional (fever), cardiovascular
symptoms (chest pain, palpitations), gastrointestinal (diarrhea, abdominal pain), and
dermatologic (rash, mucositis) symptoms were all common features. As with COVID, these
MIS-A cases also had markedly elevated CRP, ferritin and d-dimer levels, and some
demonstrated lymphopenia. Cardiac abnormalities including elevated troponin, abnormal
ECG, and abnormal echocardiogram findings (LV and/or RV dysfunction) were common.
Testing for SARS-CoV-2 PCR has been negative in about half of these cases, and serology for
SARS-CoV-2 infection if sometimes but not always positive. Many of these patients
developed serious or critical illness, with treatment regimens akin to MIS-A (IVIG,
corticosteroids)6–8.

Summary of CDC case definitions of Multisystem Inflammatory Syndrome in Adults8
  1. Severe illness requiring hospitalization in a person aged ≥21 years; with
  2. Positive test result for current or previous SARS-CoV-2 infection (nucleic acid, antigen,
     or antibody) during admission or in the previous 12 weeks; and
  3. Severe dysfunction of one or more extrapulmonary organ systems (e.g., hypotension or
     shock, cardiac dysfunction, arterial or venous thrombosis or thromboembolism, or acute
     liver injury; and
  4. Laboratory evidence of severe inflammation (e.g., elevated CRP, ferritin, D-dimer, or
     interleukin-6); and

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   5. Absence of severe respiratory illness (to exclude patients in which inflammation and
      organ dysfunction might be attributable simply to tissue hypoxia).

   *Patients with mild respiratory symptoms who met these criteria were included.
   Patients were excluded if alternative diagnoses such as bacterial sepsis were identified.

NOTES:
Some individuals may fulfill full or partial criteria for Kawasaki disease but should be
reported if they meet the case definition for MIS.

PRACTICE ADVICE:
   1. Providers should consider MIS in adults with compatible signs or symptoms
   2. Both SARS-CoV-2 PCR and serology testing should be ordered on any person suspected
      of MIS
   3. Additional lab work for suspected cases of MIS should include: CBC with differential,
      BMP, LFT, ferritin, D-dimer, CRP, ESR, LDH, high-sensitivty troponin, BNP, along
      with additional labs as clinically indicated
   4. Provider should order and ECG and transthoracic echocardiogram in any patient suspect
      of MIS
   5. Providers should initial continuous cardiac telemetry in any patient suspect of MIS
   6. Providers should consider following additional diagnostic and treatment guidelines
      detailed in the American College of Rheumatology Clinical Guidance for Multisystem
      Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and
      Hyperinflammation in Pediatric COVID‐199, with dosing adjustments in consultation
      with pharmacy. Additional guidance is available at UpToDate: Multisystem
      inflammatory syndrome in children (MIS-C) management and outcome
   7. Providers should consider contacting the Rady Children’s Hospital Kawasaki group for
      research and clinical care recommendations. (Dr. Lichtenstein is available to faciltiate
      rapid contact with the RHCSD KD group if needed.)

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Endocrinologic Complications
Inpatient Glycemic Management in Diabetic Patients with COVID
The serious consequences of diabetes mellitus (DM) with COVID are now well recognized.
Over one third of Sharp hospitalized COVID patients have diabetes. Admission hyperglycemia
(with or without diabetes), known diabetes, in hospital blood glucose (BG) > 180 mg/dl and
hypoglycemia with COVID are all associated with increased complications and mortality10–13. In
addition, new onset diabetes associated with COVID often presents with severe metabolic
disturbances such as diabetic ketoacidosis and hyperosmolarity, frequently requiring very high
doses of insulin. COVID hyperglycemia is the result of the virus causing decreased insulin
production and increased insulin resistance14–17. Maintaining BG < 180 mg/dl during
hospitalization without hypoglycemia is associated with lower mortality and
complications14,15,18–21.

While reports show that controlling hyperglycemia is associated with benefit, the management is
very challenging. Not only is glycemia compounded by frequent treatment with corticosteroids
and alteration in nutrition, the logistics dictated by COVID isolation creates barriers to any
treatment requiring frequent monitoring such as insulin treatment.

The cornerstone of diabetes management with COVID is early recognition of hyperglycemia and
early treatment. POC (point of care) BG should be started immediately if admission or any
fasting BG > 140 mg/dl, with or without known diabetes. Treatment should be started if two
fasting BGs are > 140 mg/dl or any BG > 180 mg/dl. The current medication of choice is
insulin. The possible use of non-insulin hypoglycemia agents is under investigation especially
DPP4i (dipeptidyl peptidase-4 inhibitors, e.g., sitagliptin) and metformin22–26.

The key to insulin management is to adjust the TDD (total daily dose), use the "enhanced phase"
in the insulin power plans early, provide ≥ 60% of the TDD as basal and adjust meal doses for
steroids. At the same time, keep POC BGs to 4/day for eating and 4-6/day for NPO patients.
The POC BGs and insulin doses should be bundled with otherwise needed RN patient visits. In
the ICU insulin infusion (CII) should be used to stabilize hyperglycemia with 2-hour monitoring
and the COVID target of 140-180 mg/dl as delineated in the CII power plan.

Current subcutaneous power plans provide the framework to order insulin COVID patients just
as for any hospitalized patient with diabetes or hyperglycemia. The guidelines attached to the
subcutaneous power plans (accessed with the evidence-based link) are applicable to COVID
patients. A summary approach is outlined the practice advice table detailed below.

The enhanced NPO or eating phase should be used for most well-nourished patients, especially if
receiving corticosteroids. Insulin should be escalated daily if BGs are > 180 mg/dl and doses
revised if any BG is < 100 mg/dl. Major contributors to uncontrolled hyperglycemia should be
corrected such as excessive calories in diets, or enteral nutrition, or glucose in IV fluids and
piggybacks. If serum HCO3 ≤15 moll/L, acetone and/or β-hydroxybutyrate should be checked.

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PRACTICE ADVICE:

Table 1. Management recommendations for hyperglycemic or diabetic COVID patient.
 Start POC BG and Insulin
 POC BG at least 2- 3x /day        Admit BG > 140 mg/dl
                                   Any fasting BG > 140 mg/dl
 Start insulin                     All Type 1 DM patients
                                   All known Type 2 DM patients
                                   After any BG > 180 mg/dl, with or without DM
 Starting Insulin
 TDD – total daily dose            Simple estimate – 0.6 units /kg
     Obese                         0.6 to 2 units/kg
    Average patient                0.6 – 0.9 units/kg
    Frail, malnourished, elderly   0.4 – 0.6 units /kg
 Basal - Glargine                  60% of TDD (simple weight based estimate - 0.3 to 0.4 units /kg;
                                   single dose at 2200
 Correction                        Order for all patients receiving insulin; check the box for 2200
                                   coverage for patients on an insulin eating phase
 Meal                              Chose the Average or Resistant (high ) phases of the power plan
                                   Chose the Sensitive phase for frail, malnourished, elderly
                                   Steroids increase the meal dose insulin needs much more than basal
                                   needs
 Daily review and adjustment
 Escalate basal on “10/20/30 rule”
   Fasting BG 180- 200             ↑ basal by 10%
   Fasting BG 201-300              ↑ basal by 20%
   Fasting BG > 300                ↑ basal by 30%

 Adjust meal dose                         ↑ 1-3 units if BG following the meal is > 140
                                          ↓ 1-3 units if BG following the meal is < 100
 Deescalate                               Rapidly if corticosteroid are stopped or when decreased
                                          As patient’s condition improves
 ICU                                      For uncontrolled hyperglycemia, insulin infusion with the COVID
                                          modifications which are now part of the power plan
 DKA or HHS                               ICU with DM Crisis Power Plan
 Special Considerations
 HCO3 < 18 mmol/L                         Check acetone

DPP-4 inhibitors
Dipeptidyl peptidase 4 (DPP-4) inhibitors, e.g. sitagliptin, saxagliptin, linagliptin, are a class of
oral diabetes drugs that inhibit the DPP-4 enzyme. It is postulated that DPP-4 may interact with
the S1 domain of the viral spike glycoprotein of SARS-CoV-227. Current guidelines do not
endorse or reference the use of DPP-4 inhibitors for the treatment of patients with COVID.
Observational, retrospective studies reporting on the relationship between DPP-4 inhibitor

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therapy and patient outcomes among those with diabetes and COVID have provided
heterogeneous results, preventing definite conclusions of their impact 27.

A multicenter, case-control, retrospective, observational study was conducted in patients with
type 2 diabetes and COVID in Italy21. 169 patients received sitagliptin in addition to standard of
care (SC or IV insulin) and 169 patients received standard of care alone. Sitagliptin was
associated with lower mortality, clinical score reduction, hospital discharge, and decreased need
for intensive care and mechanical ventilation. However, these results are tempered by significant
limitations including selection bias, differences in patient characteristics, incomplete data
collection in 30%-40% of patients, and lack of reporting on concomitant therapies, including
corticosteroids (remdesivir not standard of care during trial period). Glycemic control, which has
been associated with improved outcomes in diabetic patients with COVID, was significantly
better in the sitagliptin group. Given the limitations of available literature, RCTs are needed to
confirm these results. Although hypoglycemia is not common with DPP-4 inhibitors, the risk is
significantly increased when administered concomitantly with insulin or insulin secretagogues 28.

At present, the use of DPP-4 inhibitors are not routinely used for glycemic control for
hospitalized patients and constitute a non-formulary class of medications at most entities.

PRACTICE ADVICE:
   The use of DPP-4 inhibitors specifically for treatment of patients with COVID is not
     recommended outside of a clinical trial
   DPP-4 inhibitors may be continued during admission for type 2 DM patients who were
     taking the drug at home prior to hospitalization
         o SMV: orderable as formulary medication
         o SGH, SCO, SCV, SMB: non-formulary; approved for patient’s own medication
         o SMH: non-formulary, available under restrictions

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Discontinuation of Isolation
Share HealthCare Infection Prevention affirms the updated CDC guidelines for
discontinuation of isolation precautions in COVID patients. Please refer to SHIP for
reference and further guidance on this important topic. Providers are encouraged to review
individual cases with SHIP for case-specific guidance.

Please note that entity-level IP are the ultimate arbiters of whether to continue or
discontinue transmission-based precautions in patients with COVID. A summary of their
assessment and determinations may be viewed in Cerner under “Interdisciplinary
Documentation”, “Infection Prevention Note”.

General Discharge Considerations
Prolonged hospitalizations, often complicated by critical illness and mechanical ventilation,
remain a major challenge for patients hospitalized with COVID. In anticipation of discharge,
providers should work closely with case managers to identify patient needs and barriers to
discharge.

PRACTICE ADVICE:
    Patients may be ready for discharge when clinically stabilized and recovering. This
     typically means that the patient is no longer febrile or hypoxemic, and any residual
     dyspnea or other symptoms do not preclude them from engaging in activities of daily
     living. Consistent with the clinical picture, other lab testing should also improve and/or
     normalize prior to discharge.
    All patients should be evaluated for resting and exertional hypoxemia prior to discharge.
    Consider PT and OT evaluation in all patients with COVID who required mechanical
     ventilation and/or prolonged hospitalization, are hemodynamically stable and able to
     follow commands.
    Transmission-based precautions may be discontinued at discharge using a time- or
     symptom-based strategy as outlined by CDC29 and SHIP30. Please refer to SHIP for
     additional details.
    For patients who do not meet symptom- or time-based criteria to discontinue
     transmission-precautions, isolation should be maintained at home or another suitable
     discharge venue identified until the patient can meet criteria to discontinue transmission-
     precautions29

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References
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      Syndrome Potentially Associated with COVID-19. Accessed May 13, 2020.
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2.    Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a
      Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-
      CoV-2. JAMA. Published online June 8, 2020. doi:10.1001/jama.2020.10369
3.    Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease
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4.    Cai X, Ma Y, Li S, Chen Y, Rong Z, Li W. Clinical Characteristics of 5 COVID-19 Cases
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5.    Center for Disease Control and Prevention (CDC). HAN Archive - 00432 | Health Alert
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      https://emergency.cdc.gov/han/2020/han00432.asp
6.    Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S.
      Children and Adolescents. N Engl J Med. Published online June 29,
      2020:NEJMoa2021680. doi:10.1056/NEJMoa2021680
7.    Godfred-Cato S, Bryant B, Leung J, et al. COVID-19–Associated Multisystem
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8.    Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory
      Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and
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      doi:10.15585/mmwr.mm6940e1
9.    Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology
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10.   Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and
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11.   Pazoki M, Keykhaei M, Kafan S, et al. Risk indicators associated with in-hospital
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12.   Gregory JM, Slaughter JC, Duffus SH, et al. COVID-19 Severity Is Tripled in the
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      Type 2 Diabetes. Diabetes Care. 2020;44(2):dc202260. doi:10.2337/dc20-2260
13.   Ge Y, Sun S, Shen Y. Estimation of case-fatality rate in COVID-19 patients with
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14.   O’Malley G, Ebekozien O, Desimone M, et al. COVID-19 Hospitalization in Adults with

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      Type 1 Diabetes: Results from the T1D Exchange Multicenter Surveillance Study. J
      Clin Endocrinol Metab. 2020;106(2). doi:10.1210/clinem/dgaa825
15.   Rubino F, Amiel SA, Zimmet P, et al. New-Onset Diabetes in Covid-19. N Engl J Med.
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17.   Chang DJ, Moin T. Coronavirus disease 2019 and type 1 diabetes mellitus. Curr Opin
      Endocrinol Diabetes Obes. 2021;28(1):35-42. doi:10.1097/MED.0000000000000598
18.   Bode B, Garrett V, Messler J, et al. Glycemic Characteristics and Clinical Outcomes of
      COVID-19 Patients Hospitalized in the United States. J Diabetes Sci Technol.
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19.   Zhu L, She ZG, Cheng X, et al. Association of Blood Glucose Control and Outcomes in
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      2020;31(6):1068-1077.e3. doi:10.1016/j.cmet.2020.04.021
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21.   Solerte SB, D’Addio F, Trevisan R, et al. Sitagliptin treatment at the time of
      hospitalization was associated with reduced mortality in patients with type 2
      diabetes and covid-19: A multicenter case-control retrospective observational study.
      Diabetes Care. 2020;43(12):2999-3006. doi:10.2337/dc20-1521
22.   Pasquel FJ, Umpierrez GE. Individualizing Inpatient Diabetes Management During the
      Coronavirus Disease 2019 Pandemic. J Diabetes Sci Technol. 2020;14(4):705-707.
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23.   Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the
      management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol.
      2020;8(6):546-550. doi:10.1016/S2213-8587(20)30152-2
24.   Rayman G, Lumb AN, Kennon B, et al. Dexamethasone therapy in COVID-19 patients:
      implications and guidance for the management of blood glucose in people with and
      without diabetes. Diabet Med. 2021;38(1). doi:10.1111/dme.14378
25.   Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: from
      pathophysiology to clinical management. Nat Rev Endocrinol. 2021;17(1):11-30.
      doi:10.1038/s41574-020-00435-4
26.   Korytkowski M, Antinori-Lent K, Drincic A, et al. A pragmatic approach to inpatient
      diabetes management during the COVID-19 pandemic. J Clin Endocrinol Metab.
      2020;105(9):1-12. doi:10.1210/clinem/dgaa342
27.   Scheen AJ. DPP-4 inhibition and COVID-19: From initial concerns to recent
      expectations. Diabetes Metab. Published online November 2020.
      doi:10.1016/j.diabet.2020.11.005
28.   Cao Y, Gao F, Zhang Q, et al. Efficacy and safety of coadministration of sitagliptin with
      insulin glargine in type 2 diabetes. J Diabetes. 2017;9(5):502-509. doi:10.1111/1753-
      0407.12436
29.   Center for Disease Control and Prevention (CDC). Discontinuation of Transmission-
      Based Precautions and Disposition of Patients with COVID-19 in Healthcare Settings
      (Interim Guidance) | CDC. Accessed May 14, 2020.
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      https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-
      patients.html
30.   Sharp HealthCare. Discontinuing COVID-19 Transmission-Based Precautions.
      Published online 2021.

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Supplemental References
NIH
https://www.covid19treatmentguidelines.nih.gov/overview/

IDSA
https://www.idsociety.org/practice-guideline/Covid-guideline-treatment-and-
management/

ACOG
https://www.acog.org/clinical/clinical-guidance/practice-
advisory/articles/2020/03/novel-coronavirus-2019

Authors
The authors of this document have no conflicts of interest or disclosures to report.

To reach the authors or to provide feedback on this document, please reach out to:
General Editor:
    Brian Lichtenstein, MD, Hospital Medicine (brian.lichtenstein@sharp.com)
Section Authors:
    Anticoagulation, Pulmonary Disease: Roland El Ghazal, MD, Pulmonology and Critical
       Care (roland.elghazal@sharp.com)
    Antimicrobials: Norihiro Yogo, MD, Infectious Disease (norhiro.yogo@sharp.com),
       Louis Lteif, PharmD (louis.lteif@sharp.com)
    Endocrinology: Kalman Holdy, MD, Endocrinology (keholdy@att.net), Brandon Bailey,
       PharmD (Brandon.Bailey@sharp.com)
    Immunomodulators: Louis Lteif, PharmD (louis.lteif@sharp.com)
    Lab Medicine: Omid Bakhtar, MD, Pathology (omid.bakhtar@sharp.com)
    Obstetrics/MFM: Joanna Adamczak, MD, Maternal-Fetal Medicine
       (Joanna.adamczak@sharp.com)

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