D-dimer;

My patient with Covid-19-related generalized weakness has rhabdomyolysis. How common is rhabdomyolysis in Covid-19?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , Leave a comment

Covid-19-associated rhabdomyolysis has been reported since the early years of the pandemic with an overall prevalence ranging from 4%-20% among hospitalized patients and nearly 50% in ICU patients.1-5

In a 2023 scoping review of Covid-19-associated rhabdomyolysis involving 117 cases (January 2020-July 2022),1 68.4% had at least one reported non-Covid-19 risk factor (excluding hypoxemia), including age 65 years or older, metabolic syndrome features, hypothyroidism, previous rhabdomyolysis, hemoglobinopathy, trauma/compression or selected rhabdomyolysis-associated medications.  Presenting symptoms did not always include myalgias or weakness with some patients only presenting with fever, back pain, respiratory symptoms, or fatigue. Mortality was high (32% and 21% in those with or without other risk factors, respectively).  Routine creatine kinase (CK) testing was suggested for hospitalized patients with a low threshold for testing outpatients with Covid-19.

A 2024 cross-sectional study involving hospitalized Covid-19-patients (March 2020-March 2021) reported the following independent factors for concurrent rhabdomyolysis: male gender, dyspnea, hyponatremia, myalgia, elevated D-dimer, aspartate transaminase-AST (3x higher than normal) and platelet count >450,000 (cells/L).2 In the same study, myalgia was reported in only 30% of patients with rhabdomyolysis.   

Potential mechanisms explaining the association between Covid-19 and rhabdomyolysis include hypoxemia, viral myositis (either directly or immune-mediated), viral-induced mitochondrial dysfunction, cytokine storm, hypovolemia and Covid-related coagulopathies.1,2,4

Bonus Pearl: Did you know that although the 3 most common symptoms of patients with rhabdomyolysis are myalgias, muscle weakness and dark urine, the triad is present in only 10% of patients? 6

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References

  1. Preger A, Wei R, Berg B, et al. Covid-19-associated rhabomyolysis: A scoping review. Intern J Infect Dis 2023:136:115-126. COVID-19-associated rhabdomyolysis: A scoping review – PubMed (nih.gov)
  2. Hashemi B, Farhangi N, Toloul A, et al. Prevalence and predictive factors of rhabydomyolysis in Covid-19 patients: A cross-sectional study. Indian J of Nephrol 2024;34:144-48. Prevalence and Predictive Factors of Rhabdomyolysis in COVID-19 Patients: A Cross-sectional Study – PubMed (nih.gov)
  3. Samardzic T, Muradashvill T, Guirguis S, et al. Relationship between rhabdomyolysis and SARS-CoV-2 disease severity. Cureus 16:e53029 (January 27, 2024). Relationship Between Rhabdomyolysis and SARS-CoV-2 Disease Severity – PubMed (nih.gov)
  4. Haroun MW, Dielev V, Kang J, et al. Rhabdomyolysis in Covid-19 patients: A retrospective observational study. Cureus 13:e12552. Rhabdomyolysis in COVID-19 Patients: A Retrospective Observational Study – PubMed (nih.gov)
  5. Albaba I, Chopra A, Al-Tarbsheh AH, et al. Incidence, risk factors, and outcomes of rhabdomyolysis in hospitalized patients with Covid-19 infection. Cureus 13:e19802. Incidence, Risk Factors, and Outcomes of Rhabdomyolysis in Hospitalized Patients With COVID-19 Infection – PubMed (nih.gov)
  6. Lu W, Li X, You W, et al. Rhabdomyolysis in a patient with end-stage renal disease and SARS-CoV-2 infection: A case report. Medicine 2023;102:48(e36360). Rhabdomyolysis in a patient with end-stage renal disease and SARS-CoV-2 infection: A case report – PMC (nih.gov)

 

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

My patient with Covid-19-related generalized weakness has rhabdomyolysis. How common is rhabdomyolysis in Covid-19?

How should I generally go about treating my non-ICU hospitalized patient with newly diagnosed Covid-19 and who doesn’t require more than conventional O2?

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

Much of the management of Covid-19 hospitalized patients who don’t require ICU care and need no more than conventional 02 (ie, high-flow or mechanical/non-mechanical ventilatory support) depends on the severity of their disease: “mild/moderate” (eg, SpO2≥94% on room air) vs “severe” (eg, Sp02<94% on room air) disease; respiration rate ≥30/min and lung infiltrates on chest radiograph>50% may also be considered, but I personally find these parameters less reliable.  Generally, patients hospitalized with Covid-19-related symptoms (respiratory or otherwise) require specific treatment to keep them from progressing or succumbing to their disease (see Figure below). 1-5

In patients with mild/moderate Covid-19, the first step is to determine whether they are at low risk (ie, NO risk factors) or high risk (ie, ≥1 risk factors) of progression to severe disease.  Recall that there are numerous risk factors for progression, including age (eg, ≥50 y) and many comorbidities, such as diabetes, chronic kidney disease, obesity, smoking (current or former), disability (eg, wheelchair dependence), and mental health disorders (eg, depression), just to name a few.1 If your patient with mild/moderate Covid-19 has ANY Covid-related symptoms and ANY risk factors for progression, you should strongly consider IV remdesivir. If your patient’s admission has nothing to do with Covid-19 but qualify for anti-Covid treatment, an oral anti-viral regimen (eg, nirmatrelvir-ritonavir [Paxlovid]) used for ambulatory patients may also be considered (see related pearl on P4P). If your patient has NO risk factors for progression to severe disease, symptomatic treatment is all that’s needed.

If your patient has severe disease but no need for 02 supplementation, IV remdesivir and prophylactic heparin (either fractionated [eg, enoxaparin] or unfractionated) should be considered; no need for dexamethasone or systemic steroids in this situation.

If your patient has severe Covid-19 and needs supplemental 02, you should consider initiation of remdesivir, dexamethasone and, at the minimum, prophylactic anticoagulation with either a fractionated or unfractionated heparin product as soon as possible.  Use of therapeutic anticoagulation in this setting (ie, outside of ICU) is controversial with NIH guidelines recommending therapeutic heparin for those with elevated D-dimer without increased bleeding risk (CIIa, “weak” with moderate supportive evidence).2,6,7  You may also be able to forgo systemic steroids in your patient with minimal 02 requirement (ie, 1-2 L) per NIH, particularly if immunocompromised, as hypoxia in such patients may be more related to viral infection itself and not significant inflammatory reaction.

If your patient with severe Covid-19 gets progressively worse requiring high-flow oxygen or non-invasive ventilation outside of ICU, you should consider adding baricitinib as a first line immunomodulator (tocilizumab or others in NIH guidelines as an alternative)2 in patients who are not already immunocompromised or do not already have and are not at high risk of secondary infections.

The duration of remdesivir treatment in hospitalized patients is usually 5 days (or until discharge) for severe Covid-19, and 3 days for those with mild/moderate disease. The ultimate duration should be individualized in patients at risk of ongoing viral replication.  One retrospective study in immunocompromised patients hospitalized for Covid-19 found remdesivir to be effective in reducing hospitalization and mortality when initiated within 2 days of hospitalization and given for a median of 5 days, even among those not requiring 02 supplementation or requiring only low flow 02.

Couple more things to keep in mind when managing severe Covid-19. When indicated, remdesivir should be given ideally as early as possible and no later than 10 days after onset of symptoms and dexamethasone should be given for up to 10 days or until discharge.  Anticoagulation, prophylactic or therapeutic, should only be prescribed in the absence of any contraindications for bleeding (see Figure footnote) and continued until discharge for no more than 14 days total.

As with all drugs, please make sure you are thoroughly familiar with the dosing, adverse effects and contraindications to above-referenced medications before prescribing them.

Figure. Management of SARS-CoV-2 positive hospitalized patients requiring no or only conventional 02 due to Covid-19

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References

  1. CDC. Interim Clinical Considerations for COVID-19 Treatment in Outpatients | CDC. Accessed Feb 1, 2024
  2. NIH. Clinical Spectrum | COVID-19 Treatment Guidelines (nih.gov). Accessed Feb 1, 2024
  3. Uptodate. Coived-19 management in hospitalized patients. https://www.uptodate.com/contents/covid-19-management-in-hospitalized-adults. Accessed Feb 5, 2024.
  4. Bash K, Sacha G, Latifi M. Covid-19: A management update. Clev Clin J Med 2023;90:677-683. https://www.ccjm.org/content/90/11/677
  5. Mozaffari E, Chandak A, Gottlieb RL, et al. Remdesivir reduced mortality in immunocompromised patients hospitalized for Covid-19 across variant waves: Findings from routine clinical practice. Clin Infect Dis 2023; 77;1626-34. https://pubmed.ncbi.nlm.nih.gov/37556727/
  6. Merz LE, Fogerty AE. The conundrum of anticoagulation for hospitalized patient with Covid-19. NEJM Evidence 2023;2 (2).  https://evidence.nejm.org/doi/full/10.1056/EVIDe2200329
  7. ATTACC, CTIV-4a, REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically patients with Covid-19. N Engl J Med 2021; 385:790-802. https://pubmed.ncbi.nlm.nih.gov/34351721/

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How should I generally go about treating my non-ICU hospitalized patient with newly diagnosed Covid-19 and who doesn’t require more than conventional O2?

How does older people’s immune system place them at high risk of sepsis and death?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Increased risk of sepsis and death from infectious causes among the elderly is a well-known phenomenon—particularly as witnessed in the Covid-19 era— and is in part due to 2 major age-related alterations of their immune system: 1. Defective T and B cell functions in response to acute infections; and 2. Once infection sets in, inadequate control of sepsis-induced pro-inflammatory response and its attendant procoagulant state. Interestingly, the essential elements of the innate immunity (eg, neutrophils, dendritic cells, complements) are generally spared from the effects of aging.1,2

Increased susceptibility of the elderly to acute infections is in part caused by poorer T helper cell function and suboptimal B cell humoral response to neoantigens. Despite this, serum levels of pro-inflammatory cytokines such as IL-1, IL-6,TNF-alpha, and IFN-gamma are intact.  In fact, production of IL-6 and its duration of response is actually increased in the elderly.1,2

Poor control of the inflammatory state due to sepsis in older patients may be related to the difficulty in clearing a pathogen or dysfunction in the signaling by counter-regulatory cytokines, such as IL-10.2 Either way, unchecked inflammatory response is deleterious to the patient and is associated with increased risk of thrombosis and thromboembolism, multiorgan system failure, septic shock and death. 

Bonus Pearl: Did you know that even in the absence of infection, older people are more prone to thrombosis and thromboembolism , in part related to elevated plasma levels of fibrinogen, as well as factor VII, VIII, and IX, among others?2,3  

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 References

  1. Ticinesi A, Lauretani F, Nouvenne A, et al. C-reactive protein (CRP) measurement in geriatric patients hospitalized for acute infection. Eur J Intern Med 2017;37:7-12. https://pubmed.ncbi.nlm.nih.gov/27594414/
  2. Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis 2005;41: (Suppl 7) S504-12. https://pubmed.ncbi.nlm.nih.gov/16237654/
  3. Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Experimental Gerontology 2008;43:66-73. https://www.sciencedirect.com/science/article/abs/pii/S0531556507001404?via%3Dihub

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

How does older people’s immune system place them at high risk of sepsis and death?

Should I order serum procalcitonin on my patient with suspected infection?

FA Manian MD, MPH, , , , , , , , , , , 2 Comments

Two things to ask before you order procalcitonin (PCT): 1. Will it impact patient management?; and 2. If so, will the result be available in a timely manner ie, within hours not days?

Whatever the result, PCT should always be interpreted in the context of the patient’s illness and other objective data. Not surprisingly then, as a “screening” test, PCT may be more useful in patients with low pre-test likelihood of having bacterial infection, not dissimilar to the use of D-dimer in patients with low pre-test probability of pulmonary embolism1.  

Several potential clinical uses of this biomarker have emerged in recent years,  including:1,2

  • Helping decide when to initiate antibiotics in patients with upper acute respiratory tract infections and bronchitis. A normal or low PCT supports viral infection.
  • Helping decide when to discontinue antibiotics (ie, when PCT normalizes) in community-acquired or ventilator-associated pneumonia.
  • Helping monitor patient progress with an expected drop in PCT of about 50% per day (half-life ~ 24 hrs) with effective therapy.

Few caveats…

  • PCT may be unremarkable in about a third of patients with bacteremia (especially due to less virulent bacteria, including many gram-positives)3.  
  • PCT levels are lowered by high-flux membrane hemodialysis, so check a baseline level before, not after, hemodialysis4.
  • Lastly, despite its higher specificity for bacterial infections compared to other biomarkers such as C-reactive protein, PCT may be elevated in a variety of non-infectious conditions, including pancreatitis, burns, pulmonary edema or aspiration, mesenteric infarction (ischemic bowel), cardiogenic shock, and hypotension during surgery2.

 

References:

  1. Schuetz P, Muller B, Chirst-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (review). Evid-Based Child Health (A Cochrane Review Journal) 2013;8:4;1297-137. http://onlinelibrary.wiley.com/doi/10.1002/ebch.1927/pdf
  2. Gilbert GN. Use of plasma procalcitonin levels as an adjunct to clinical microbiology. J Clin Microbiol 2010;48:2325-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897488/pdf/0655-10.pdf
  3. Yan ST, Sun LC, Jia HB. Procalcitonin levels in bloodstream infections caused by different sources and species of bacteria. Am J Emerg Med 2017;35:779-83. https://www.ncbi.nlm.nih.gov/m/pubmed/27979420/#fft
  4. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis 2014;59:1761-7. https://www.ncbi.nlm.nih.gov/pubmed/25228701
Should I order serum procalcitonin on my patient with suspected infection?

Should I routinely consider the possibility of pulmonary embolism (PE) in my patients hospitalized for syncope?

FA Manian MD, MPH, , , , , , Leave a comment

Syncope is a well-known initial manifestation of pulmonary embolism (PE)1.  However, given the varied causes of syncope, determining the prevalence of PE among patients hospitalized for syncope is important.   

A multicenter prospective study2 enrolled 560 patients not already on anticoagulation who were hospitalized for a first episode syncope.  Of patients who had either a high pretest probability for PE, positive D-dimer assay or both, PE was diagnosed in 17%, or nearly 1 of 6 of enrolled patients, based on CT or ventilation/perfusion scan. PE was found more frequently among patients with syncope of undetermined cause than those with an alternative explanation (25.4% vs 12.7%). 

Another multicenter prospective study (2019), however, found a much lower prevalence of PE (0.6%) among patients evaluated in the ED for syncope, including those who were not hospitalized.3 A related commentary on the article reported a prevalence of 4.1% in the total study population, assuming a “worst-case scenario calculation.” 4 

Given these divergent results, perhaps the best advice is to consider PE as cause of syncope in the proper context and minimize overtesting when suspicion remains low.

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References 

  1. Thames MD, Alpert JS, Dalen JE. Syncope in patients with pulmonary embolism. JAMA 1977;238:2509-2511. https://www.ncbi.nlm.nih.gov/pubmed/578884
  2. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016;375:1524-31. http://www.nejm.org/doi/full/10.1056/NEJMoa1602172
  3. Thiruganasambandamoorthy V, Sivilotti MLA, Rowe BH, et al. Prevalence of pulmonary embolism among emergency department patients with syncope: a multicenter prospective cohort study [published online January 25, 2019]. Ann Emerg Med. doi:10.106/j.annemergmed.2018. https://www.annemergmed.com/article/S0196-0644(18)31535-X/fulltext
  4. Anonymous. Pulmonary embolism uncommon in syncope hospitalizations. Pulmonology Advisor. February 6, 2019.  https://www.pulmonologyadvisor.com/pulmonary-embolism-uncommon-in-syncope-hospitalizations/printarticle/832069/

 

Contributed in part by Rebecca Berger  MD, Department of Medicine, Mass General Hospital, Boston, MA

 

Should I routinely consider the possibility of pulmonary embolism (PE) in my patients hospitalized for syncope?

My patient with significant dyspnea appears to have an acute exacerbation of his chronic obstructive pulmonary disease (AE-COPD). How often do AE-COPD and pulmonary embolism (PE) coexist?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

Simultaneous presence of PE in patients with AE-COPD is not rare, particularly in those with unexplained AE-COPD.

A recent systematic review and meta-analysis reported a pooled PE prevalence of 16.1% (95% C.I. 8.3%-25.8%) in unexplained AE-COPD, with 68% of emboli found in the main pulmonary arteries, lobar arteries or inter-lobar arteries (i.e. not subsegmental); the pooled prevalence of deep venous thrombosis (DVT) was 10.5% (95% C.I. 4.3%-19.0%) 1. Pleuritic chest pain and signs of cardiac failure were associated with AE-COPD, while symptoms suggestive of a respiratory tract infection argued against PE.

It remains unclear, however, if the threshold for evaluation of venous thromboembolism (VTE) should necessarily differ between patients with explained vs unexplained AE-COPD.

In one small study, the prevalence of VTE in “unexplained” AE-COPD was significantly higher (25%) than “explained” AE-COPD (including cases with  tracheobronchitis, pneumonia, cardiac disorders, exposure to irritant inhalants, and lack of compliance with treatment), but the VTE prevalence for the latter group was still 8.4%2.  Serum D-dimer level and Wells criteria may help exclude VTE in this patient population.

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References

  1. Aleva FE, Voets LWLM, Simons SO, et al. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: A systematic review and meta-analysis. CHEST (2016), doi: 10.1016/j.chest.2016.07.034.
  2. Gunen H, Gulbas G, In E, Yetkin O, Hacievliyagil SS. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;35:1243-1248.

 

Contributed by Jeff Greenwald, MD, Core Educator Faculty, Department of Medicine, Massachusetts General Hospital

My patient with significant dyspnea appears to have an acute exacerbation of his chronic obstructive pulmonary disease (AE-COPD). How often do AE-COPD and pulmonary embolism (PE) coexist?