Brigham and Women's Hospitals

Immunosuppressed Patients

Updated: June 19, 2020

Oncology

  1. Data:
  1. Based on early descriptive studies from China, patients with cancer - particularly those on active treatment for cancer - appear to have a worse prognosis. This includes higher prevalence, higher risk of severe disease, and higher risk of death from COVID-19 in patients with cancer compared to those without. (WHO-China Joint Mission on COVID-19, Yu et al, JAMA Oncology 2020, anecdotal reports)
  1. Oncology Consultation/Coverage:
  1. For established DFCI patients, oncology consultation and guidance is provided by each patient’s primary oncologist (or coverage).
  2. Contact primary oncologist via page, not the general pager or fellow on call, to establish the best means of ongoing communication.
  1. Prognosis:
  1. Many patients have a reasonable or even good oncologic prognosis with current therapies. Do not assume an oncologic prognosis, even with metastatic disease: involve the primary oncologist.
  1. Meds:
  1. Check in Epic medications tab and in “Research: Active” tab to include experimental medications. Contact the primary oncologist with questions.
  1. Workup:
  1. Additional labs to standard workup:
  1. Weekly glucan/galactomannan in neutropenic/transplant patients.
  2. Specific patient populations may require additional monitoring (such as CMV, EBV monitoring in transplant patients – ask primary oncologist).
  1. Exam:
  1. Examine catheters (port, CVC, others) daily.
  2. Avoid rectal exams and any per-rectum therapies in neutropenic patients, but examine the perirectal area if symptoms or persistent fevers.
  3. In patients with heme malignancy or SCT: findings are more subtle or absent in neutropenic and immune suppressed patients.
  1. Pain management:
  1. Patients with cancer-related pain may have high opiate needs at baseline. Opiates should not be stopped but type may need to be adjusted in the setting of respiratory failure, renal injury, or liver injury.
  1. Consider Pain / Palliative Care consult
  1. Goals of Care:
  1. Involve primary oncologist whenever possible (recognizing that in critical/emergent situations, this may not be possible).
  1. Anticoagulation:
  1. Patients with solid tumors are at very high risk of thrombosis but at lower risk of infection than most heme malignancy patients.
  2. Thrombosis prophylaxis for all unless contraindicated
  1. Hold pharmacologic prophylaxis if platelet count < 30K, use pneumoboots
  2. Both COVID-19 infection and malignancy increase thrombotic risk, particularly with solid tumors.
  3. See “Thrombotic Disease” section for guidelines on both prophylactic and therapeutic anticoagulation.
  1. Transfusions:
  1. The BWH blood bank reviews orders and releases appropriate products (i.e., irradiated, leukoreduced, etc).
  2. See Blood Products section for transfusion thresholds of all patients - of note, the recommended RBC transfusion threshold for all patients, including oncology patients, is Hgb 7, Hct 21.

Febrile Neutropenia

  1. Definition:
  1. ANC < 500 cells/mm3 AND T ≥ 101F or T ≥ 100.5 for 1hr
  1. Workup:
  1. Blood cultures from peripheral (ideally two sets), and each lumen of central line (label clearly); UA/sed with urine culture (UA may not be as informative with neutropenia); glucan and galactomannan (if not checked recently), sputum if able; CXR
  1. Continue DAILY blood cultures while febrile.
  2. Monitor serum galactomannan and 1-3-beta glucan once weekly.
  3. Any positive glucan or galactomannan prompts ID consult.
  1. Initial Empiric Antibiotics:
  1. Cover GNRs in all patients: Ceftazidime 2g Q8h or Cefepime 2g Q8h
  1. Alternatives: Piperacillin-tazobactam (2nd line, high dose 4.5g Q6h) or meropenem (3rd line, 1g Q8h).
  1. GPCs: add Vancomycin if hemodynamically unstable, or if MRSA pneumonia or catheter-associated infection is suspected. Check dosing with pharmacy if able.
  1. Removal of lines:
  1. Catheter removal should be discussed if associated infection is suspected - involve primary oncologist and/or ID team to weigh risks and benefits, given that not all lines require removal.
  1. Persistent Neutropenic Fever:
  1. If fever persists x3 days despite antibiotics
  1. Add Micafungin 100mg IV daily
  2. Consideration of further imaging even if the patient appears stable (discuss with oncology / ID).
  1. Anti-infective course:
  1. Anti-Infectives should be continued until the patient has met all of these criteria:
  1. clinically improved, and
  2. has been afebrile for 48h, and
  3. has been non-neutropenic for 48h.

Immune Checkpoint Inhibitors

  1. Overview
  1. Immune Checkpoint Inhibitors (ICIs) are not immunosuppressive when used alone, but the steroid dosages used to treat immune toxicities are often immunosuppressive.
  2. Most common ICIs are CTLA-4 inhibitor (ipilimumab) and PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, durvalumab, atezolizumab and avelumab).
  1. Immune toxicity
  1. If patient develops organ dysfunction, it may be due to immune toxicity
  1. Consult the service team of the involved organ system and inform primary oncologist.
  1. Common immune toxicities include pneumonitis / respiratory failure (may be difficult to distinguish between COVID19 disease or may be aggravated by COVID19 infection), colitis, endocrine dysfunction (thyroid, pituitary / hypothalamic, adrenal), nephritis. Less common hepatitis, meningitis, dermatitis.
  1. Check TSH, ACTH, cortisol if hypotension or concern for endocrine dysfunction.
  2. Check T-spot, HIV, HBV, HCV serologies if immune toxicity is suspected, in case additional immunosuppression (particularly TNF-alpha blockade) is required.
  1. Immune toxicities are usually treated with high dose steroids
  1. risks and benefits must be weighed immediately with primary oncologist and ID consult teams if immune toxicity is suspected concurrent with COVID19 infection.
  1. BWH/DFCI iTox guidelines can be found here (Partners login required)

Rheumatology

COVID-19 in Patients with Rheumatic Disease

  1. Please enroll patients with rheumatologic/autoimmune disease who are diagnosed with COVID-19 into the COVID-19 Global Rheumatology Alliance Registry and/or the EULAR – COVID-19 Database.
  2. Clinical Presentation:
  1. Patients with rheumatologic disease are not known to differ from other patients in terms of clinical presentation of COVID-19, though further information will be elucidated from the studies of the Global Rheumatology Alliance Registry.
  1. A report of 86 patients with immune-mediated inflammatory disease in New York reported high percentages of patients with fever (84%), cough (42%) and shortness of breath (41%), with lower rates of diarrhea, rhinorrhea and loss of taste and smell. Similar to reports from immunocompetent patients. (Haberman et al, NEJM, 2020) Similar findings were found in smaller studies of patients with rheumatic disease: 13 patients with chronic arthritis in Italy (Monti S et al. Ann Rheum Dis, 2020) and 52 rheumatic disease patients in Boston (D’Silva K et al. Ann Rheum Dis, 2020)
  1. Outcomes:
  1. Studies looking at outcomes for COVID patients with rheumatic disease are limited to date, and major conclusions cannot be drawn at this time.
  1. Incidence appears to be similar to the general population
  1. In one prospective case series of 86 patients in New York City with a variety of immune-mediated inflammatory diseases. (Haberman et al, NEJM, 2020)
  1. Hospitalization and mortality rates appear similar to the general population
  1. In one comparative cohort study of 52 patients with rheumatic disease (75% on immunosuppressive medications) hospitalization and mortality rates were similar. However, rheumatic patients were more likely to require mechanical ventilation than healthy comparators, though the number of patients was low (11 patients [48%] vs 7 patients [18%], multivariable OR with 95% CI 1.07 to 9.05).(D’Silva K et al. Ann Rheum Dis, 2020)
  2. In a case series from the Global Rheumatology Research Alliance of 600 patients with rheumatic disease and COVID-19 from 40 countries, glucocorticoid exposure >= 10mg daily was associated with modestly higher odds of hospitalization (OR 2.05, 95% CI 1.06-3.96) while use of anti-TNF agents was associated with lower odds of hospitalization (OR 0.40, 95% CI 0.19-0.81). Neither use of DMARDs nor NSAIDs changed odds of hospitalization. (Gianfrancesco M et al. Ann Rheum Dis 2020)
  1. Management:
  1. Data are evolving. We have included our recommendations below based upon guidelines as developed by the American College of Rheumatology. The authors also have outlined a helpful resource on UptoDate.
  2. General Management
  1. Patients should be counseled on general measures to prevent infection including physical distancing, hygiene, and wearing masks.
  2. For physician follow-up, telemedicine or video visits should be used when possible.
  3. Decrease frequency of routine laboratory testing or other in-person health care exposures where possible and safe.
  1. Pharmacologic treatment for patients without infection with or exposure to COVID-19
  1. Most anti-inflammatory and immunosuppressive medications including DMARDs and biologics may be continued or started.
  1. This recommendation applies to hydroxychloroquine, chloroquine, sulfasalazine, methotrexate, leflunomide, tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine, tocilizumab, anakinra, and NSAIDs.
  2. In patients with systemic inflammatory or organ-threatening disease, glucocorticoids and immunosuppressants in high doses can be started.
  3. Jak inhibitors block signaling through multiple cytokine receptors, including interferons, which are important for the body's antiviral immune response. In theory, these effects may considerably increase the risk of complications from COVID-19. Until more data are available, clinicians may want to choose other classes of medications for patients in need of a new immunosuppressive treatment. For patients already taking Jak inhibitors with good disease control, these medications can be continued.
  1. Doses of most anti-inflammatory and immunosuppressive medications should not generally be reduced
  1. This is especially in instances where the patient has a history of organ-threatening rheumatic disease
  2. Glucocorticoids should be reduced to the lowest safe dose as deemed by the treating physician, though should not be abruptly stopped.
  1. Pharmacologic treatment for stable patients after exposure to COVID-19 (without symptoms)
  1. Continue medications such as: hydroxychloroquine, sulfasalazine, and NSAIDs.
  2. If safe to do so, stop other immunosuppressive medications temporarily with the possibility to restart after a negative test result for COVID-19 or after 2 weeks of observation without symptoms.
  1. The panel noted that it is not clear whether to stop methotrexate or leflunomide.
  2. In certain cases, IL-6 inhibitors may be continued pending shared decision-making with the patient’s provider.
  1. Pharmacologic treatment in rheumatic patients with confirmed or suspected COVID-19 infection
  1. Continue medications such as: Hydroxychloroquine and chloroquine
  2. If safe to do so, stop: sulfasalazine, methotrexate, leflunomide, azathioprine, mycophenolate mofetil, non-IL-6 biologics, and JAK inhibitors.
  1. It was agreed that NSAIDs should be stopped in patients with severe respiratory symptoms, unclear if NSAIDs should be stopped in patients without severe symptoms.
  2. In certain cases, it’s possible IL-6 inhibitors can be continued as part of a shared-decision making process.

Rheumatic Manifestations of COVID-19

  1. COVID-19 can cause a number of symptoms that may overlap with those seen in rheumatologic diseases as outlined below. For patients with established rheumatologic disease who have confirmed or suspected COVID-19, careful evaluation will be required to determine if their symptoms are due to flare of the disease or are sequelae of viral infection. Other patients who have persistent or unexplained rheumatic symptoms may benefit from a rheumatology consult to determine if there are additional concerns for underlying rheumatologic disease.
  1. Arthralgias, Myalgias, Myositis
  1. Myalgia or arthralgia occur in approximately 15% of patients.
  1. 14.8% of patients (based on analysis as of 2/20/2020 on 55924 cases. (WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 2020)
  2. Myalgia or arthralgia in 14.9% of 1099 patients in mainland China (Guan et Al, NEJM, 2020)
  1. Occasionally arthralgia can be a presenting feature.
  1. Observation of one female patient in Thailand who presented with fever and low platelet count, initially misdiagnosed as Dengue. (Joob et al, Rheum Int, 2020)
  1. Rhabdomyolysis is also a potential late complication of Covid-19. (Tong et al, Emerg Infect Dis. 2020, Ronco et al, Nat Rev Nephrol, 2020)
  1. Please see Muscle Injury under Neuromuscular Disorders
  1. Parenchymal Lung Disease
  1. Please see Radiology and Acute Lung Injury
  1. Pericarditis and Myocarditis
  1. Please see Pericarditis and Myocarditis
  1. Cytokine Storm / Secondary HLH
  1. Please see Cytokine Storm
  1. Kawasaki-like Multisystem Inflammatory Syndrome in Children
  1. Please see section below
  1. Livedo Reticularis
  1. Please see Vasculopathies and Livido
  1. Pernio- or Chilblain-like lesions of hands and feets (“COVID toes”)
  1. Please see Perniosis
  1. Fever
  1. Please see Clinical Course
  1. Coagulopathy
  1. Please see Thrombotic Disease
  1. Elevated levels of inflammatory markers
  1. including CRP, ESR, and ferritin as well as elevated levels of cytokines including IL-1 and IL-6. Please see Diagnostics
  1. Lymphocytopenia and thrombocytopenia
  1. Can be present in active lupus, is also be seen in COVID-19 infection. Please see Lymphocytopenia and Thrombocytopenia

Multisystem Inflammatory Syndrome in Children (MIS-C): a Kawasaki disease-like syndrome associated with COVID-19

  1. Multisystem Inflammatory Syndrome in Children (MIS-C), also known as Pediatric Inflammatory Multi-System Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS or PIMS), is a relatively rare manifestation of COVID-19 that has been described now in children and some young adults in multiple case series. (Panupattanapong et al, Cleve Clin J Med, 2020, Riphagen et al, Lancet, 2020, Verdoni et al, Lancet, 2020, Toubiana et al, BMJ, 2020, Pouletty et al, Ann Rheum Dis. 2020, Jones et al, Hosp Pediatr, 2020)
  1. It appears to be a late (i.e. post-viral) manifestation that occurs as a reaction to COVID-19 rather than directly by the virus, as many of the patients presented 2-3 weeks after the peak of infection in the area and had negative COVID-19 PCR testing but positive serologies. (Panupattanapong et al, Cleve Clin J Med, 2020)
  2. MIS-C has manifestations that overlap with Kawasaki disease and toxic shock syndrome.
  3. MIS-C compared to Kawasaki disease
  1. Typical Kawasaki disease is a generally self-limited febrile illness affecting young children characterized by symptoms that, in addition to fever, can include a diffuse polymorphic rash, erythema and edema of the palms and soles, conjunctivitis, oral mucosal changes (classic “strawberry tongue”), and cervical lymphadenopathy. It can cause coronary artery aneurysm if left untreated.(Panupattanapong et al, Cleve Clin J Med, 2020)
  2. Kawasaki disease was suspected to be a post-viral phenomenon even before COVID-19
  1. MIS-C occurs in an older patient population than Kawasaki disease. Kawasaki disease tends to occur in very young children, mean age of 2 years, but essentially always < 5 years old, whereas the average age of MIS-C patients is 8 years old.Symptoms include:
  1. Fever, rash, conjunctivitis, distal extremity edema, and GI symptoms including abdominal pain, nausea, vomiting, and non-blood diarrhea. In some cases, the GI symptoms occurred 1-2 weeks prior to their presentation for clinical care and may represent the period of acute infection with COVID-19.
  2. Severe cases can cause cardiac dysfunction and shock. Unlike the case in adults, respiratory symptoms are rare.
  1. Laboratory abnormalities include:
  1. Lymphopenia, neutrophilia, thrombocytopenia, and marked elevation of inflammatory markers including CRP and ferritin. D-dimer and elevated triglycerides are also common. Many patients also have evidence of cardiac involvement with elevated NT-proBNP and/or troponin-T.
  1. Management
  1. Draft guidelines have been released by the American College of Rheumatology (https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf) (Kawasaki disease and many etiologies of pediatric macrophage activation syndrome are managed by rheumatology.)
  1. Current treatment recommendations include low-dose aspirin as well as corticosteroids IVIG. High-dose anakinra (IL-1 blockade) can also be considered depending on the severity. Anticoagulation is recommended for patients with very large coronary aneurysms, documented thrombosis, or reduced ejection fraction.
  2. Multidisciplinary management of the pediatrics/ICU team with infectious disease, cardiology, rheumatology, and hematology services is recommended.
  3. Formal treatment guidelines are expected later in summer 2020.

Patients on Immunosuppressants

Rheumatology

  1. See Rheumatology

Neurology

  1. Please see Neuromuscular disorders
  2. Please see Multiple Sclerosis and Neuromyelitis Optica

Gastroenterology

  1. See Inflammatory Bowel Disease

Dermatology

  1. See Outpatient Dermatology

HIV

  1. Please see HIV section of the Infectious Disease chapter

Transplant

  1. This section is under development
  2. See also Cardiac Transplant section