Acute cardiac injury, variably defined as increased circulating troponin levels and/or new abnormalities on ECG or echocardiography, were noted in 7-22% of hospitalized patients in early reports from Wuhan (Ruan et al; Wang et al; Chen et al; Shi et al; Guo et al, Zhou et al). When present, these findings were associated with increased risk of ICU admission and death.
- Direct SARS-CoV-2 infection of cardiac myocytes (myocarditis)
- Demand ischemia, with either large or small vessel thrombosis
- Stress (Takotsubo) cardiomyopathy
- Pathological myocardial response to inflammation or cytokine storm
Specific cardiac pathologies include myocarditis, arrhythmia, and precipitation of an acute coronary syndrome. Hypercoagulability in COVID-19, including its impact on the heart, are discussed in Hematology.
Fulminant SARS-CoV-2 myocarditis was clinically suspected in some early case reports (Ruan et al; Zeng et al; Hu et al; Inciardi et al), based on pre-existing clinical criteria and, in some cases, suggestive findings on cardiac MRI (Inciardi et al, Kim et al). Subsequent examination of myocardial tissue in autopsy series (Fox et al; Elsoukkary et al; Basso et al) found direct evidence for viral myocarditis (e.g., lymphocytic infiltrates) were relatively rare (0-14%).
The clinical significance of direct SARS-CoV-2 myocarditis remains unclear. If a patient has elevated troponins with no evidence of obstructive coronary artery disease, it may be on the differential diagnosis but is unlikely to alter management.
- Provide supportive care for heart failure (Zhang et al.) or Cardiogenic Shock
- Where possible, discuss with cardiology and/or infectious disease consultants to see if the patient might benefit from antivirals or steroids (benefit is unknown)
- Endomyocardial biopsy is unlikely to be informative.
- See Advanced CV Imaging below regarding uses of cardiac MRI.
Cardiac arrhythmias can occur in COVID-19. An early case series of 138 patients in Wuhan, China, (Wang et al) found evidence of some arrhythmias in 17% of hospitalized patients with COVID-19, rising to 44% in those transferred to the ICU. Another early study of 189 hospitalized patients noted nearly 6% of inpatients had an episode of ventricular fibrillation or sustained ventricular tachycardia (Guo et al).
- Atrial Fibrillation/Atrial Flutter
- Consider beta-blockers, if no evidence of heart failure or shock.
- If acute heart failure or concern for hypotension, use amiodarone if not otherwise contraindicated.
- If unstable (with a pulse), synchronized DC cardioversion with 200 joules (biphasic).
- Ventricular Tachycardia
- If unstable or without palpable pulses: initiate local advanced life support protocol (e.g., ACLS).
- If stable:
- Involve a cardiologist. If cardiologist is not available, involve a senior clinician.Consider a single IV dose of amiodarone 150mg or lidocaine 100mg
Myocardial infarction in COVID-19 may be triggered by a combination of hypercoagulability, cardiac expression of SARS-CoV-2 entry receptor ACE2, possible direct viral myocardial injury, increased myocardial demand, or toxicity from inflammation. Cardiac markers and ECG changes alone may not be able to determine whether an underlying obstructive lesion exists as evidenced by the fact that up to 45% of hospitalized COVID patients have elevated cardiac markers (Lombardi et al).
The diagnosis of an acute coronary syndrome depends on:
- Symptoms (if able to communicate): worsening shortness of breath, chest pain, or other anginal equivalents
- Regional changes in the ECG or wall motion abnormalities on echocardiography
- Rate of change of troponin changes (rapid rise or fall suggests an acute event)
Tool: Life in the Fast Lane Acute Coronary Syndromes
When the diagnosis is not clear, a cardiologist should be consulted.
If a patient is diagnosed with ACS, management should be coordinated with a cardiologist if at all possible. Medical management typically includes:
- Treatment with full dose aspirin, clopidogrel (if not bleeding), heparin, oxygen (if hypoxemic), high-dose statin, nitrates (if hypertensive), and opioids as needed for symptom control. Beta blockers should be used with caution, given the risk of concomitant myocarditis or decompensated heart failure
- If cardiac catheterization is available, there are no fundamental contraindications for patients with COVID-19 as long as strict infection control precautions are followed.
- If cardiac catheterization is not available or if constrained resources unacceptably prolong door-to-balloon time, thrombolytic medications may be considered in lieu of PCI.
Laboratory markers of cardiac injury (troponins, CK-MB, BNP) and electrocardiography are appropriate for most COVID-19 patients admitted to the hospital. Depending on availability and expertise, point-of-care ultrasound can also be considered, particularly in patients with concerning symptoms, lab values or ECG.
The indications for more advanced cardiac diagnostics are similar to patients without COVID-19, but with additional consideration for infection control. Testing should be limited to cases where the results will alter management to avoid unnecessary risk to providers and other patients.
- Transthoracic echocardiography
- Do not obtain routinely.
- When possible, a bedside provider should assess cardiac function with point-of-care ultrasound for the following indications:
- Marked elevation in troponin or NTproBNP, or decline in ScvO2/MvO2
- New heart failure
- New persistent arrhythmia
- Significant ECG changes
- If abnormalities are identified on point-of-care ultrasound (such as a new decrease in LV ejection fraction to below < 50%) and the patient is stable, a formal echocardiogram should be obtained if possible.
- Evaluate both left and right ventricular function.
- The differential diagnosis for right ventricular dysfunction includes myocarditis, hypoxic vasoconstriction, pulmonary embolus, and cytokine mediated dysfunction.
- The differential diagnosis for left ventricular dysfunction includes myocarditis, acute coronary syndrome, and stress-induced cardiomyopathy.
- Regional wall motion abnormalities with elevated troponins suggest an acute coronary syndrome, though direct myocardial injury by the virus can also result in focal wall motion abnormalities.
- Stress Testing:
- Should not be commonly required in patients with active COVID. If needed (and if available), consider pharmacologic nuclear stress testing or coronary CT angiography rather than exercise stress test.
- Transesophageal Echocardiogram (TEE)
- Only request if absolutely necessary. Although unclear whether this generates aerosolized virus, it likely does represent increased risk to the patient and provider.
- Consider alternative noninvasive imaging modalities (such as cardiac CT or PET/CT) if they are available and appropriate for the question being asked.
- Cardiac CT
- Can consider for selected patients with elevated cardiac biomarkers when there is a need to distinguish myocardial injury from acute coronary syndrome. The decision to use CT in this context should be discussed with a cardiologist.
- Consider in selected patients as a substitute for TEE to rule out left atrial appendage clot or to evaluate for endocarditis.
- In appropriate cases, multiphase data acquisition may be used to evaluate both left and right ventricular function while concurrently evaluating the lung parenchyma or pulmonary artery.
- Cardiac MRI
- Consider for selected patients with elevated cardiac biomarkers and concern for myocarditis, if this information will impact patient management.
- In the acute and subacute periods, T1 and T2 mapping as well as assessment of extracellular volume fraction (ECV) may improve sensitivity for myocarditis. However, the prognostic significance of such abnormalities (especially in the presence of normal ventricular function or when late enhancement abnormalities are absent) remains unclear.
- In selected patients who have recovered from COVID, cardiac MRI using late gadolinium enhancement may be useful for evaluating for residual scar tissue.
- Nuclear Imaging
- In COVID-19 patients who require stress testing, vasodilator stress testing is preferred over exercise testing.
- In selected patients who have recovered from COVID-19, PET MPI using a quantitative assessment of myocardial blood flow may be useful for evaluating microvascular dysfunction.
Preexisting cardiovascular disease and metabolic disorders (including diabetes and hyperlipidemia) worsen prognosis in acute COVID-19 (Izcovich et al).
See Anticoagulation in the Hematology section below.
Patients with pre-existing heart failure have a nearly two-fold increased mortality and over three-fold greater risk of mechanical ventilation when they develop COVID-19 (Alvarez-Garcia et al).
There are currently no specific medication changes recommended for patients with prior heart failure who develop COVID-19, though all medications should be titrated based on other clinical context (e.g., in a patient with fevers and decreased oral intake, home diuretic doses may need adjustment).
Patients with rheumatic heart disease or other conditions requiring surgical intervention should continue to be considered as a potential priority case during the COVID-19 pandemic.
Patients with pre-existing hypertension have a significantly increased risk of developing severe COVID-19 disease or dying (Izcovich et al).
Antihypertensive medications, such as RAAS inhibitors (e.g. ACE inhibitors) were initially suspected to be harmful in COVID-19, but these harms have not been supported by subsequent data (e.g., Baral et al). Other classes, such as calcium channel blockers, were thought to possibly be beneficial, but this also remains unsubstantiated.
Unless new data become available, patients with well-controlled hypertension should continue their current anti-hypertensive medications, unless those drugs need to be stopped for other reasons (e.g. renal issues).
The initial protocol used by Brigham and Women’s Hospital, USA, for patients with heart transplant who develop COVID-19 is available here.
COVID-19 can cause hyperglycemic crisis in patients with and without known insulin resistance (summarized in Rubino et al). A systematic review of 110 reported cases of diabetic ketoacidosis (DKA) or combined DKA/hyperglycemic hyperosmolar state (HHS), found that 10% of patients with these severe presentations did not have a prior diagnosis of diabetes (Pal et al).
All patients with moderate to severe COVID-19 should thus be evaluated for hyperglycemia. Patients who do have blood glucose levels over 10 mmol/L (180 mg/dl) are generally managed with insulin rather than oral agents. Targets are similar to the management in patients without COVID-19, while recognizing that insulin requirements may be labile.
Treatment of DKA and/or HHS also has the same goals as patients without COVID-19, while recognizing provider safety concerns and limited resources in a pandemic. An example protocol for mild-to-moderate DKA at Brigham and Women’s Hospital, USA, uses subcutaneous insulin with slightly less frequent monitoring than standard protocols, in an effort to minimize provider exposure and conserve PPE while maintaining patient safety.
Section in process
Section in process
People with diabetes who develop COVID-19 have ~2-3 fold increases in both mortality and risk of severe COVID-19 (summarized in Izcovich et al).
This risk in part reflects the chronic effects of diabetes, including increased susceptibility to several infections and an association with other chronic diseases, such as dyslipidemia, hypertension, and obesity.
As noted above, however, Pal et al. systematically reviewed several case reports where patients with diabetes and COVID-19 developed severe hyperglycemic crises, including diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS).
- Seventy-four the 110 cases who presented with DKA or combined DKA/HHS had a prior diagnosis of type 2 diabetes. Since these are case reports, however, they do not define how frequently DKA occurs in severe COVID-19 compared to other severe infections.
- Instruct them to continue their normal oral or insulin regimens and monitor their glucose more frequently than usual. Depending on their glucose, they may need to temporarily increase their regimen.
- This includes those patients with type 2 diabetes not on insulin who may not be accustomed to monitoring their glucose -- they should check twice daily if possible.
- Use caution with oral hypoglycemic agents such as sulfonylurea or SGLT2 inhibitors, which can lead to euglycemic DKA, in patients with decreased caloric intake.
For all patients,
- Frequent blood glucose and/or ketone (blood or urine) monitoring should be performed.
- Target blood glucose remains the same as without COVID-19; for hospitalized patients, the Joint British Diabetes Society recommends 6-10 mmol/L, while the American Diabetes Association targets 140-180 mg/dl (Corsino et al.). Blood ketones should be kept below 0.6 mmol/L
- Do not stop basal insulin even if febrile in those with type 1 diabetes or those with type 2 diabetes and require basal insulin for glycemic control. COVID-19 can significantly increase baseline insulin requirements.
- Monitor and maintain appropriate salt and water balance.
- For patients requiring systemic steroids, appropriate insulin adjustments are required.
- Manage DKA and HHS as discussed above.
A BMI over 25-30 (different cutoffs depending on the study) appears to increase the odds of mortality from COVID-19 by nearly 50% and the odds of severe disease by ~2-4 fold (Izcovich et al, Popkin et al). The latter of these two papers raises the concern that BMI may impact the response to vaccination for COVID-19, based on experience with influenza and other vaccines.
There are no specific recommendations for management of COVID-19 patients with elevated BMI, but providers should be cautious with drug dosing, remain aware of possibly altered respiratory mechanics, and stay vigilant for decompensation.
Coagulopathy is common in patients with COVID-19; early reports found 8-10% of hospitalized patients met criteria for disseminated intravascular coagulation (DIC; Tang et al) 16 of 183 hospitalized patients in Wuhan , most commonly in the critically ill or those with multi-organ dysfunction (Zhou et al). However, the coagulopathy in COVID-19 differs from DIC in bacterial sepsis and may require different management (Merrill et al; Asakura et al).
Median time to diagnosis of DIC in the series by Tang et al was 4 days into hospital admission, and this diagnosis was associated with worse survival in COVID-19 patients. Out of 183 COVID-19 patients in Wuhan, 71% of non-survivors had ISTH score ≥ 5 compared to 0.6% of survivors..
To diagnose DIC you can use the ISTH DIC score (MDcalc online calculator)
- If score < 5, no DIC; recalculate in 1-2 days
- If the patient develops DIC, measure PT/INR, PTT, D-dimer, fibrinogen every 3 days until discharge or death. Elevated PT/PTT and D-dimer correlate with worse prognosis
Management If Not Bleeding:
- See Blood Products. If fibrinogen < 150 mg/dl: use FFP, cryoprecipitate or fibrinogen concentrate if you are worried about infusion volume of other options and it is available (RiaSTAP or Fibryga)
- If platelets <30 k/mcl, transfuse (Consider holding anticoagulation if the patient requires blood products if benefits outweigh risks)
Management if Bleeding:
- See Blood Products. For elevated PT/PTT and bleeding, use FFP, cryoprecipitate or fibrinogen concentrate if you are worried about infusion volume of other options and it is available
- Hold anticoagulation for active bleeding in most cases. Start systemic anticoagulation only if critical thromboembolism or organ failure due to clot (i.e., purpura fulminans). There has been no mortality benefit of therapeutic anticoagulation in DIC (Levi et al).
Most patients with COVID-19 have either a normal white blood cell count (WBC). A small number may have elevated WBC or low WBC. Leukocytosis (>10,000/µL) in 13% and leukopenia (<4000/µL) in 15.5% (Goyal et al Lymphocytopenia, or lymphopenia, typically defined as an absolute lymphocyte count < 1000/µL, is the most common abnormality on the CBC in COVID-19 and is found in over 80% of hospitalized patients (Guan et al; Huang et al). Low lymphocytes are also associated with poor prognosis, with lymphocyte percentage <10% on the WBC differential is strongly associated with decreased survival. (Ruan et al; Tan et al; Yang).
Numerous possible explanations for lymphopenia in COVID-19 have been proposed including
- Invasion/ destruction of lymphocytes via ACE2 receptor
- Acidemia, nutrition, bone marrow suppression
- Cytokine Storm
- Lymphatic organ damage (thymus, spleen) This possibility still requires pathological evidence and remains speculative (Tan et al).
- Host Endothelial function. With age and chronic disease, there is more leukocyte adhesion and extravasation (Bermejo-Martin)
- Sequestration of lymphocytes. Cytokine release leads to movement of the lymphocytes to the site of infection, the lung tissue, which could contribute to peripheral lymphopenia (Rahimmanesh).
Any patient with low lymphocytes should be considered potentially infected with COVID unless there is an alternate explanation.
- Please note that concurrent infection and the use of steroids may skew these results. See Secondary Infections.
No current treatment regimen management changes based on lymphopenia.
- There is no evidence for giving pneumocystis jiroveci prophylaxis given the transient nature of lymphopenia with COVID-19
Thrombocytopenia affected ~12% of patients with COVID-19 in one large meta-analysis (Zong et al). Another early report found thrombocytopenia in 72.5% of hospitalized patients (Chang et al), and the degree of thrombocytopenia appears to correlate with worse prognosis (Yang et al). Multiple proposed mechanisms have been proposed (Xu et al; Amgalan et al). Click here for a flow chart summarizing possible mechanisms. Disseminated Intravascular Coagulation (DIC) may contribute as a related or independent process.
- Consider other potential contributing etiologies of thrombocytopenia. Medication, additional infection(s), liver disease, splenomegaly, heparin-induced thrombocytopenia (HIT), thrombotic microangiopathy (TTP, HUS, DIC), alcohol, malignancy, pregnancy, rheumatologic/autoimmune, bone marrow disorders
- Initial workup can include: Peripheral blood smear, PT, aPTT, fibrinogen, LDH, LFTs, B12, folate
- If concerned for Heparin Induced Thrombocytopenia, the pretest probability of HIT can be calculated by 4Ts score (MDCalc 4Ts Calculator)
- Laboratory testing for HIT should typically only be sent in patients with at least intermediate probability of HIT (4 or more points on 4Ts score), although need to consider clinical context.
- If sending PF4, use a non-heparin anticoagulant (e.g. bivalirudin or other direct thrombin inhibitor per institutional protocols) while awaiting PF4 results. Serotonin release assays may be necessary to confirm positive PF4 results.
- If concern for DIC, refer to DIC Protocol Section
- If not bleeding, transfuse platelets if < 10,000/µL
- If bleeding, transfuse platelets according to clinical situation
- In ICU patients, cumulative incidences range from 9% to 70% in patients on varying levels of prophylactic anticoagulation, and whether patients were screened with compression ultrasonography or imaged for change in clinical status (Klok et al; Middeldorp et al; Klok et al; Llitjos et al; Nahum et al; Moll et al). One study suggests COVID-19 patients at increased risk for thrombosis and bleeding (Xu et al).
- We found that in 102 COVID-19 positive ICU patients, there were 9 radiographically-confirmed DVT or PE, based on imaging obtained for a change in clinical status; all patients received standard dose prophylactic anticoagulation (enoxaparin 40 mg daily or unfractionated heparin 5000 IU three times daily). No events occured in 108 wards patients (Moll et al). Similar findings were reported in Indianapolis (Maatman et al).
- Higher D-dimer and FDP levels track with multi-organ dysfunction syndrome and poorer prognosis (Wang et al).
- The mechanism for VTE are unknown and likely multifactorial:
- Systemic inflammatory response as seen in sepsis
- Stasis/critical illness
- Possibly direct endothelial damage from viral injury/ACE2 binding
- An autopsy series of 10 patients from New Orleans reported thrombotic and microangiopathic pathology (and diffuse alveolar damage) (Fox et al). Our discussions with pathology colleagues indicate more cellular debris than microthrombi.
- There is a theory from the SARS epidemic that SARS-CoV1 Spike protein can be cleaved by FXa and FIIa. Cleavage of the Spike protein activates it which promotes infectivity (Du). By extension, it is hypothesized that anticoagulation might inhibit SARS-CoV-2 replication, however this remains unproven.
- There is a small case series suggesting dipyridamole may be useful, though anticoagulation and antiplatelet agents require further investigation prior to being used therapeutically (Liu et al; Lin et al).
- Management of known DVT/VTE is with standard anticoagulation regimens (typically this would qualify as a provoked DVT). See Therapeutic Anticoagulation.
- Prophylaxis for DVT/VTE is an evolving area and is addressed in Anticoagulation under Prophylaxis
In patients previously anticoagulated with vitamin K antagonists (e.g. warfarin), PT/INR should be monitored closely. Both fever and acute infection may result in increases in INR. Other medications that may be used in COVID-19, such as antibiotics for suspected coinfection, can also result in increased or decreased warfarin metabolism. If frequent INR measurement for dose-titration is not available, and switching to an alternative, parenteral anticoagulant is not feasible, the warfarin dose may be empirically reduced by approximately 10% (e.g. from 5mg daily to 4.5mg daily) when a patient develops fever.
Anticoagulation should not be stopped for patients with COVID-19 unless there is a different reason to do so. See prophylactic and therapeutic anticoagulation for full recommendations on the treatment of COVID patients with anticoagulation.
In sickle cell crisis, patients have to consider the risk of COVID-19 exposure when going to the hospital for management of sickle cell crisis. Based on the local risk of nosocomial infection, providers and patients should discuss in advance regarding the patient-specific criteria which would warrant hospital evaluation versus staying at home with oral pain medications, hydration, and rest.
Data on coinfection and secondary infections in COVID-19 are limited.
Rates: There is enormous variance in the rates of viral coinfection depending on location, season, and viral coinfection epidemiology. A study in San Francisco found ~20% of symptomatic COVID-19 patients were also PCR positive for another viral pathogen (Kim et al). A meta-analysis of 1014 hospitalized COVID-19 patients found a viral co-infection rate of 3% (95% CI 1-6%, I2=62.3%), with RSV and influenza being the most common coinfections (Lansbury et al). In contrast, two studies in San Francisco and Wuhan, China where hospitalized COVID-19 patients tested for influenza and RSV found that none of these patients had evidence of viral co-infection (Myers et al; Chen et al).
- The decision to test for concurrent viral panels should be based on availability and local epidemiology. Many COVID testing locations do not have the ability to also test for respiratory viruses
- All respiratory viral infections should be considered COVID until proven otherwise (see testing), even if they present with minimal symptoms.
- Empiric oseltamivir is reasonable in some circumstances where influenza rates are high and the patient has tested negative for COVID infection
Most patients who have COVID do not have concurrent bacterial infections. However, as with other viral infections, impaired mucociliary clearance can make these patients susceptible to secondary bacterial infections.
- Coinfection vs secondary infection: One meta-analysis of 3448 COVID-19 patients broke bacterial infections down into co-infection and secondary infection and found the risk of co-infection on presentation to be 3.5%, while the risk of secondary infection after presentation was 15.5%. In this same cohort, 71.3% of patients received antibiotics, despite only 7.1% of patients overall having a bacterial infection (Langford et al) Other studies of secondary bacterial infections show incidence of around 7-8% of hospitalized patients. One meta-analysis of 2183 hospitalized COVID-19 patients found 7% had a bacterial coinfection (95% CI 3-12%, I2=92.2%) (Lansbury et al) Another meta-analysis of 806 hospitalized COVID-19 patients found 8% developed bacterial and/or fungal infections during admission (Rawson et al).
- Most common infections: pneumonia (32%), bacteremia (24%), and urinary tract infections (22%) (He et al).
- Glucocorticoid treatment was also found to be positively associated with secondary infection (He et al). However, we do not recommend withholding steroids in patients who qualify, even if they have concurrent bacterial infection.
Tool: A group out of the University of Toronto created a Living Systematic Review of the Data
Clinical reports indicate that rates of bacterial superinfection with COVID-19 are low, but when present, increase mortality risk. That said, unnecessary antibiotics carry risks of fluid overload and drug-resistance, as well as the possibility that antibiotics may become a limited resource. (Zhou et al; Yang et al; Lippi et al; WHO, COVID-19 Interim guidance, May 2020). The choice about whether to give empiric antibiotics will rely on whether or not secondary bacterial infection can be safely ruled out and the acuity of the patient.
- If laboratory and imaging guidance is available, use this evidence to guide the choice about whether to use antibiotics. There is a disproportionate high use of antibiotics despite paucity of evidence for bacterial secondary infection (He et al; Zhou et al; Rawson et al).
- Workup can include any or all of WBC count, left shift and bandemia, procalcitonin, sputum culture, urine analysis and color, cholangitic picture on liver function tests or RUQ ultrasound, urine strep + legionella antigen, blood cultures, stool or other relevant cultures
- If laboratory and imaging is not available or cannot be used to rule out a concurrent bacterial infection, antibiotics should be considered depending on the clinician’s expectations about risks and benefits
- On the one hand, not treating a bacterial co-infection (depending on the type) could be fatal in some patients. There is a strong association between nosocomial infection and mortality (He et al; Wang et al). On the other hand, in one study 75% of patients who developed secondary infection were already receiving prophylactic antibiotics, suggesting prophylactic agents may not prevent hospital-acquired infections and risk selecting for more drug-resistant pathogens (He et al).
- If a patient has shock or multiorgan failure it is appropriate to give antibiotics for the first 24-48 hours until the source is identified
- If antibiotics are to be used, they should reflect guidelines based on presumed source and multi-drug resistant organism risk factors. Administer oral antibiotics (azithromycin, levofloxacin, ciprofloxacin, etc.) when possible to reduce volume load, unless concerns for poor oral absorption.
- Organisms reported for those with secondary bacterial infections included those commonly seen with hospital-acquired infections including Mycoplasma sp., Haemophilus influenzae, Pseudomonas aeruginosa, Klebsiella sp., Enterobacter sp., Staphylococcus aureus, Acinetobacter sp., and E.coli, and vancomycin-resistant Enterococcus sp. (Langford et al; Lansbury et al)
- For empiric coverage for a presumed pulmonary source of infection, we recommend using your institutions antibiogram if one is available. If not, some possibilities include:
- In patients without risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas (i.e., those living in community without a history of resistant organisms), initiate ceftriaxone and (azithromycin or doxycycline)
- In patients with risk factors for MRSA or Pseudomonas (i.e., chronic hospitalization, prior resistant infections), obtain a respiratory culture and a MRSA nares screen if available and initiate an antipseudomonal cephalosporin (e.g. cefepime) and vancomycin
Tool: IDSA Guidelines
Tool: Sanford Guide
- Unnecessary antibiotics should be discontinued as soon as possible (ideally, within 48 hours) upon culture maturation. Clinical judgement should prevail over any specific lab value, but we suggest discontinuing when the following criteria are met:
- Clinical status is not deteriorating
- Cultures do not reveal pathogens at 48 hours and/or procalcitonin and WBC are relatively stable from 0 to 48 hours
Malaria often presents with fever and could be confused with COVID in some patients. Where testing is possible (RDT, blood smear), it is important to test for these and to plan for increased demands on testing (Dittrich et al).
- Where incidence is high and testing is not available, empiric (presumptive) therapy with Artemisinin Combined Therapy or the locally-approved regimen is appropriate (even though in non-COVID times empiric treatment this is generally discouraged by the WHO). Chloroquine may be used, but only if it is part of the preferred regimen for Malaria, and not for COVID (see Hydroxychloroquine).
- Corticosteroids in concurrent malaria and COVID infection is not yet studied (Brotherton et al). Despite this we recommend using them for COVID infection as you would if the patient was not co-infected.
Dengue fever, like malaria, should be on the differential for COVID in places where it is prevalent. Treatment is largely supportive (oral rehydration or IV rehydration therapy, analgesics, antipyretics).
Parasitic infections should be treated as they would normally (with normal dose antihelminthic agents). We do not support the use of High-Dose Ivermectin for COVID outside of clinical trials.
Strongyloidiasis is a parasitic infection that is often asymptomatic. However, a life-threatening hyperinfection syndrome can occur with immunosuppression, including the use of corticosteroids. Because Corticosteroids are a recommended therapy for COVID with hypoxemia or critical illness, we recommend the following: (Stauffer et al).
Confirmed COVID with asymptomatic, minimally symptomatic, or mild disease (not a current candidate for corticosteroids)
Birth, residence, or long-term travel in Asia, Oceania, Sub-Saharan Africa, South America, Caribbean, Mediterranean countries, Middle East, North Africa*
Screen for Strongyloides infection and treat with ivermectin if positive
Confirmed COVID and likely candidate for corticosteroid treatment
Birth, residence, or long-term travel in Asia, Oceania, Sub-Saharan Africa, South America, Caribbean, Mediterranean countries, Middle East, North Africa*
Empiric treatment with ivermectin
*These groups are at moderate to high risk for disseminated strongyloides infection with administration of corticosteroids (A K Boggild et al).
Fungal pathogens such as Aspergillus sp., Candida albicans, and Pneumocystis jirovecii have been described in a subset of patients (Lansbury et al; Menon et al). Some case series have reported COVID-19 associated pulmonary aspergillosis rates of 20-35% (Arastehfar et al), while others are as low as 3.8% (Lamoth et al). Unsurprisingly, aspergillus infection appears to be associated with increased mortality (OR 3.53). In a prospective Italian cohort of 108 mechanically ventilated COVID-19 patients, probable pulmonary aspergillosis was diagnosed in 30 patients (27.7%) after a median of 4 days from ICU admission, and these patients had a much higher risk of 30-day mortality (OR 3.53 (95% CI 1.29-9.67, p=0.014). Of note, most patients received tocilizumab or steroids in this cohort (Bartoletti et al).
- At this time we do not recommend screening all patients with galactomannan and beta glucan, but patients who are already immunosuppressed, BMT, or oncologic patients should be screened with weekly
- Treatment, and choices around immunosuppression, in these cases is highly individualized and infectious disease consultation is suggested where available.
The interaction between HIV and SARS-CoV-2 remains poorly defined and is likely complex. It remains unclear if, and how, HIV infection affects risk or severity of COVID-19.
Risk of acquiring COVID infection and outcomes in those infected: Multiple studies from New York City (Richardson et al; Sigel et al; Karmen-Tuohy et al), Spain (Vizcarra et al), and China (Guo et al) have found that HIV-positive patients develop COVID-19 at a similar rate as the general population. However, the patients included in these studies were largely on antiretroviral therapy (ART) with well-controlled HIV. A large Spanish cohort study of people with well-controlled HIV found that the rate of COVID-19 diagnosis and hospitalization in HIV patients was decreased to 30.0 cases per 10,000, compared with 41.7 per 10,000 in the general population (Del Amo et al). There is very limited data on COVID-19 patients with poorly controlled HIV or AIDS. One study examined public healthcare data in South Africa, which has the highest rate of HIV in the world at about 20%, with about ⅔ of those on ART (UNAIDS). In this population, HIV infection conferred an adjusted hazard ratio of 2.75 for risk of death from COVID-19 (Davies M, presentation on behalf of Western Cape Department of Health). Detailed information, including the number of participants, CD4+ T cell counts, HIV viral loads, and ART treatment status, has not yet been made available.
Antiretrovirals : Some antiretroviral therapies used for HIV may be protective against COVID-19, but this is not yet fully supported by the data. For further information about antiretroviral agents under investigation for treatment of COVID-19, please see Lopinavir-Ritonavir in the therapeutics chapter (this so far has not been shown to benefit patients (Cao et al) or reduce viral shedding (Cheng et al)). Tenofovir has also been hypothesized to have a protective benefit, but data seems to be confounded by age and health of participants. A large Spanish cohort study of over 77,000 people with HIV, 236 of whom were diagnosed with COVID-19, found that patients taking tenofovir disproxil fumarate (TDF)/emtricitabine (FTC) had a significantly decreased risk of COVID-19 diagnosis and hospitalization compared with those taking tenofovir alafenamide (TAF)/FTC or abacavir (ABC)/lamivudine (3TC). This may be an effect of increased blood concentrations of tenofovir with TDF compared with TAF, though may also reflect that patients taking TDF are typically younger and healthier than those on TAF (Del Amo et al). Conversely, a smaller observational Spanish study of 2873 HIV-positive individuals, 51 of whom had COVID-19, found that tenofovir (either TDF or TAF) use was disproportionately enriched among COVID-19 cases (Vizcarra et al).
- Keep in mind that people with HIV may present differently. Fever may be less frequent.
- HIV should not change the role of either NAAT or antigen testing.
- The impact of prior HIV on immune response and development of antibodies is not yet known.
Studies to date suggest that well-controlled HIV does not substantially increase the risk or severity of COVID-19, but data on patients with low CD4+ counts remains sparse. Given the limitations of the existing evidence at this time, we recommend that HIV-positive patients be considered high risk and be counseled on precautions accordingly
- Per existing standard of care, all patients with HIV should remain on a daily ART regimen under the supervision of a trained provider
- There is speculation that lymphopenia and immune dysfunction in HIV-positive individuals may protect from the hyperinflammatory state thought to contribute to severe COVID-19 disease (Mascolo et al), but no evidence currently exists to support this theory. This is not a reason to stop HIV treatment.
- We do not recommend changing an existing ART regimen for the purposes of prophylaxis or treatment of COVID-19 in HIV-positive patients
- HIV-positive patients who develop COVID-19 do not require any change from standard protocol in management or treatment strategies
- Given the high prevalence of malnutrition among patients with TB/HIV, ensuring continued social support including food packages is important for disease control.
- Patients with HIV who present with respiratory symptoms should be evaluated for TB in addition to COVID-19 if clinically indicated.
The association of Chagas disease with socioeconomic vulnerability, its large disease burden in Latin America, and the possibility of often-undiagnosed chronic cardiac injury (PAHO) all raise concerns about co-infection of Trypanosoma cruzi and SARS-CoV-2, though data from 2020 are limited to a few case reports (e.g., Alberca et al; Kurizky et al). A recent consensus opinion (Zaidel et al) considering the pathophysiology of both diseases and the impact on the healthcare system recommends that a COVID-19 diagnosis should not delay urgent antiparasitic treatment in acute Chagas disease or in those with evidence of reactivation though they recognize that drug interactions and the clinical severity of COVID-19 must be taken into account. In individuals with known Indeterminate Chronic Chagas Disease, the benefits of antiparasitic therapy are more controversial and less urgent. When these patients are also diagnosed with COVID-19, the authors advise delaying treatment while closely monitoring for reactivation. They make an exception for patients who have already started antiparasitic therapy when testing positive for SARS-CoV-2 only if no COVID-19 symptoms are present.
Not enough is known about the incidence of COVID in patients with tuberculosis. One case-study of 49 patients with tuberculosis (eight with drug resistant TB) showed a high case fatality at 12.3% (Tadolini et al). Some have posited that the increased social distancing measures from COVID will decrease tuberculosis, however it is more likely that any benefit on TB deaths is likely to be outweighed by health service disruption (McQuaid et al).
Tool: This Multi-Institution Consensus Statement describes TB public health and treatment plans during the COVID epidemic in great detail. Core management issues described include medications, drug-drug interactions, novel therapies, and principles of infection control and workplace safety.
Patients who are newly diagnosed with viral hepatitis B should initiate hepatitis treatment if they qualify, regardless of COVID-19 status. However, patients who are newly diagnosed with viral hepatitis C should defer treatment until after the COVID-19 infection has cleared. For patients with viral hepatitis B or C who are already on treatment, they should continue treatment while being monitored for drug-drug interactions (Reddy).
Incidence of Acute Kidney Injury in COVID-19 varies widely, but estimates have ranged from 0.5% (Guan et al) to 27% (Diao et al). The wide range of estimates of AKI incidence may reflect different populations included in studies. The most likely etiology of AKI is acute tubular necrosis (ATN) based on autopsy series from China, but other findings including interstitial inflammation, thrombotic microangiopathy, complement-mediated injury and direct viral infection of tubular cells and podocytes has also been described (Su et al; Diao et al). Studies find variable onset of AKI, from 7 days (Cheng et al) to 15 days after illness onset (Zhou et al). Onset of AKI more rapid and severe in patients with underlying CKD (Cheng et al)
Role of the renin-angiotensin-aldosterone system and medications that target it on the severity of COVID-19 is a source of much speculation and research, since angiotensin-converting enzyme 2 (ACE2) is used by SARS-CoV-2 as a functional receptor to enter into cells (including type II pneumocytes and kidney tubular epithelial cells). There is no data to support issues with RAAS inhibitors during COVID at this time.
- Monitor serum creatinine and electrolytes at least daily where available
- In patients with AKI, order urine electrolytes (urine Na, urea and Cr) and urinalysis with sediment
- Patients may present with proteinuria (44%), hematuria (26.9%) (Cheng et al). For patients with proteinuria, quantify proteinuria with spot urine protein-to-creatinine and albumin-to-creatinine ratios
- Consider other common etiologies of AKI that can occur in patients who do not have COVID-19 (e.g. volume depletion, ATN from hypotension, contrast-associated nephropathy, acute interstitial nephritis and urinary tract obstruction)
- If laboratory testing for serum creatinine is unavailable, check urinalysis to identify proteinuria. Patients with proteinuria can be classified as possible AKI until proven otherwise.
- Discontinue all medications that can contribute to AKI (e.g. NSAIDs, ACE inhibitors, ARBs, and diuretics in volume depleted patients) and avoid using iodinated contrast with CT imaging as much as possible
- Consider a gentle fluid challenge (e.g. 1 liter of isotonic crystalloid fluid) to determine if there is a pre-renal component to AKI, especially in patients with clinical or laboratory signs suggestive of intravascular volume depletion (e.g. hypotension, tachycardia, dry mucous membranes, FENa<1% and/or FEurea<35%).
- Be cautious with fluid administration in patients with severe hypoxemia
- If available, consult nephrology for patients with any of the following:
- Creatinine clearance <30 ml/min/1.73m2
- Oliguria: urine output <500cc/day or <0.5cc/Kg/hour
- Volume overload not improving with diuretics
- Hyperkalemia (>5.5) not responsive to dietary K restriction and diuretics
Estimates for RRT range from 0.8 to 5% of hospitalized patients (Guan et al; Zhou et al) in studies including floor patients. Among critically ill patients in the ICU, need for CRRT has been reported as high as 39% (Chen et al). Few studies have reported outcomes of RRT. One case series reported that out of 191 patients, 10 received CRRT, and all 10 died (Zhou et al). The nephrology consult service will determine the need, timing, and modality of renal replacement on a case-by-case basis. Indications for RRT in COVID-19 patients are the same as the indications for all patients.
For patients in LMICs with COVID-19 without ARDS, consider peritoneal dialysis as first choice, where available and feasible. Locally produced peritoneal dialysis solutions can be used in situations where commercially produced solutions are unavailable or unaffordable. With ARDS, consider hemodialysis, where available and feasible, in order to optimize fluid removal.
Mild creatinine kinase elevation is relatively common with SARS-CoV-2 infection, with muscle pain and elevated CK occuring in 11-45% of hospitalized patients, depending on the study. It is more common in severe disease (23.9%, median CK 525 U/L) vs non-severe disease (5.0%, median CK 230 U/L) (Mao; Wang)
- Up to 10% of patients developed rhabdomyolysis complicated by acute renal failure (Chen). Other case reports of rhabdomyolysis in SARS have been published (Tsai; Huang; Wang)
The cause is likely to be some combination of direct viral myopathy, and critical illness/immobility myopathy (which can be made worse by corticosteroids, though do not discontinue them for this reason alone).
- Mild muscle injury: myalgias, proximal weakness, and/or mildly elevated CK (100s U/L)
- Rhabdomyolysis: myalgias, muscle weakness, myoglobinuria, moderate-marked elevation in CK (> 5x ULN, usually > 1500 U/L)
- Also check: CK, BMP, Phosphate, LFTs, TSH, UA, strength exam. Muscle biopsy is rarely likely to change management
- Mild muscle injury does not require specific intervention if renal function is normal
- Rhabdomyolysis carries risk of AKI, usually associated with CK >15-20k U/L. Increased risk of AKI in the setting of sepsis, dehydration, or acidosis (Bosch)
This section is in progress
Depending on the severity of the COVID outbreak, some surgical centers are reducing or stopping elective cases. The following is based on former BWH Pre-operative decision pathway during severe outbreak and included suggestions about managing operating room screening/ testing.
If the case is elective:
- Reschedule for a future date.
If the patient has no COVID-19 symptoms or high-risk features:
- Proceed with standard precautions
- Face shield, surgical mask
- Double glove
- Avoid contamination of work surfaces with secretions
- Concerning symptoms include:
- Cough, sore throat
- Shortness of breath, respiratory failure
- Muscle aches, fatigue
- High-risk features include:
- Difficulty differentiating symptoms from baseline in patients with thoracic or upper respiratory disease
- Contact with known cases
If the case can not be delayed until COVID-19 test results are positive:
- Proceed with increased precautions
- Head cover, face shield, N95
- Double glove
- Avoid contamination of work surfaces with secretions
- Experienced provider intubating
- Minimize providers entering and exiting the OR/theatre
- Perioperative droplet precautions (patient masked, in isolation room)
If COVID-19 test results are available prior to surgery:
- If the patient has a single negative test,
- Proceed with increased precautions, as above.
- If the patient has a positive test,
- Reconsider if the case needs to be done.
- Consider delay for 14 days or repeat testing 24 hours after symptoms resolve.
- Ok to proceed after 2 negative tests 24 hours apart
- If delay may cause significant morbidity or mortality,
- Proceed with COVID-19 precautions
- All “increased precautions as above”
- Patient should be on isolation precautions perioperatively
- All aerosol generating portions of the case should ideally be done in a negative pressure room
- Full PPE for all providers in the room
Tracheostomy for patients with COVID is a clinical challenge, as it can expose health care practitioners to significant aerosols.
The timing of tracheostomy in any patient is complex. Patients should have adequate time to recover and avoid patient/provider risk, and the course of COVID-19 is longer than many pneumonias. However, earlier tracheostomy can make it easier to wean sedation and mobilize patients. Different institutions require different timeframes for tracheostomy eligibility. Early in the pandemic many institutions were waiting a full 21 days, but now practice patterns are changing.
Tool: This Consensus Guidance covers timing and patient selection and management of tracheostomy
Tool: BWH’s Tracheostomy (Percutaneous and Open) Surgical Protocols
Both upper and lower endoscopy are considered aerosolizing procedures.
Tool: A comparison of guidance from endoscopic societies worldwide, including Wuhan, Hong Kong, Australia, Canada, US, UK, and European societies, can be found here.
Guidance from the US GI societies (AGA, ACG, ASGE, AASLD) can be found here:
- Joint GI Society, Clinical Insights for Gastroenterologists, March 2020.
- Joint GI Society, Guidance on Endoscopic Procedures, March 2020.
- Joint GI Society Statement, Statement on the Use of PPE in Endoscopy, April 2020.
Guidance from the European Society of Gastroenterology and Endoscopy Nurses and Associates can be found here:
Updated Date: December 11, 2020
In one large retrospective study, asthma appeared less prevalent in those with COVID than in those without it (6.75 vs 9.72%), and hospitalization rates did not appear very different between each group. As with all retrospective studies, these are somewhat limited by confounding (Green et al). One large study of about 44,000 people looking at risk factors for severity and mortality in China did not find asthma as a risk factor for disease severity (Li et al). Multiple smaller studies have shown similar results. It is not yet known if or why asthma may be protective against infection and/or not linked to worse outcomes.
This Green et al study also did not find any difference between those using ICS or LABA. ICS use in asthma has been dose-dependently associated with lower ACE2 and transmembrane protease serine 2 mRNA expression, but the impact of this on disease status is unknown. (Peters et al). It has also been posited that ICS may reduce airways inflammation and thus offer some protection (Carli et al). At this time we do not recommend treating patients with comorbid asthma and COVID any differently than you would normally, save for avoiding nebulizers (aerosol generating) and favoring MDIs where possible.
In one large metanalysis of 22 studies involving 11,000 patients, COPD was associated with three-fold higher mortality in COVID infected patients (OR 3.23, 1.59-6.57; P<0.05), but it was not more prevalent (5% of the patients(437/9337) than it is in the global population (9%) (Vankata et al). The severity difference in this study did not appear to be related to active smoking. Currently we do not recommend treating patients with comorbid COPD and COVID any differently than you would normally save for avoiding nebulizers (aerosol generating) and favoring MDIs where possible.
Nebulizers can increase risk of transmission of COVID-19. Patients should avoid use. If nebulizer use is required, it should be done in isolation from others. COVID-19 virus may persist in droplets in the air for several hours.
The relationship between COVID-19 infection and smoking remains unclear. Metanalysis has shown that in terms of testing positive for disease, there may be a slight risk reduction in current smokers compared with nonsmokers (RR=0.73; 95% CI: 0.73–0.99). However, the evidence is not high-quality and may be confounded by other factors (testing and social behaviors may be very different in these groups).Test positivity risk amongst former smokers and never-smokers was similar (Farsalinos et al; Grundy et al). In most studies smoking is associated with more severe disease (OR rates in many metanalyses around ~2 (Grundy et al). Smoking poses multiple health risks and cannot be considered as a protective habit.
Patients with febrile neutropenia (ANC < 500 cells/mm3 AND T ≥ 101F or T ≥ 100.5 for 1hr) should be worked up for COVID infection at the same time as they are evaluated for other infections. In patients with heme malignancy or SCT: findings are more subtle or absent in neutropenic and immune suppressed patients.
- Examine catheters (port, CVC, others) daily. Avoid rectal exams and any per-rectum therapies in neutropenic patients, but examine the perirectal area if symptoms or persistent fevers.
Tool: BWH guidance on Neutropenic Fever (workup, empiric antibiosis, line management, etc)
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). Prognosis for various cancers is highly variable, and the patient’s oncologist should be involved in goals of care conversations.
In additional labs to standard workup, if available we recommend also obtaining:
- Weekly glucan/galactomannan in neutropenic/transplant patients.
- Specific patient populations may require additional monitoring (such as CMV, EBV monitoring in transplant patients – ask primary oncologist).
Patients with solid tumors are at very high risk of thrombosis but at lower risk of infection than most heme malignancy patients. Prophylactic anticoagulation is particularly important in this setting.
- Hold pharmacologic prophylaxis if platelet count < 30K, use pneumoboots
Immune Checkpoint Inhibitors (ICIs) Most common ICIs are CTLA-4 inhibitor (ipilimumab) and PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, durvalumab, atezolizumab and avelumab). are not immunosuppressive when used alone, but the steroid dosages used to treat immune toxicities are often immunosuppressive. If patient develops organ dysfunction, it may be due to immune toxicity and not COVID. Please see BWH guidance for more information.
Tool: Please report cases at aad.org/covidregistry