Male;

How common is hyponatremia in patients with Covid-19 and what’s its significance?  

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

Hyponatremia has been reported between 20% and 35% of patients hospitalized for Covid-19, 1-5 with low serum sodium levels on admission often associated with progression to severe illness, mechanical ventilation, increased length of stay and death.1,2,4,5

A 2023 retrospective multicenter study involving over 2,600 hospitalized Covid-19 patients (between February 2020 and August 2022) found hyponatremia in 34.2%: Mild (Na 131-134 mmol/L) 25.1%, moderate (Na 126-130 mmol/L) 7.5% and severe (<126 mmol/L) 1.8%.3 There was a significant association between male sex at birth, hypertension, chronic kidney disease, immunosuppressives, thiazide diuretics and hyponatremia.3

Similarly, another retrospective study of hospitalized Covid-19 patients found an association between hyponatremia and several common chronic diseases, such as diabetes, hypertension, ischemic heart disease, chronic liver disease and chronic kidney disease.4 It’s important to note that since older age has also been found to be a risk factor for hyponatremia in Covid-19, the independent contribution of these conditions to hyponatremia is unclear.3

As with many other infectious diseases, the mechanism of hyponatremia in patients with Covid-19 likely has multiple causes, including hypovolemia, syndrome of inappropriate anti-diuretic hormone secretion (SIADH), diuretic use and corticosteroid deficiency, particularly in the critically ill. 1-4  

Interestingly, a study performed early in the pandemic (March 2020) found that the majority (57%)  of hospitalized Covid-19 patients with hyponatremic were euvolemic and that the administration of isotonic saline to such patients was independently associated with increased hospital mortality (cause unclear).2 The authors suggested closer attention to the volume status of Covid-19 patients with hyponatremia (eg, through closer attention to the jugular venous pressure on physical exam) before considering treatment with isotonic saline.

Last, Covid-19 may be associated with hyponatremia during the post-discharge period as well.  An intriguing 2024 study found nearly 25% of patients with Covid-19 developed hyponatremia (<135 mmol/L) during the 1-year follow-up period after discharge with most not reported to have hyponatremia during their index hospitalization.5 In the same study, hyponatremia was associated with older age, male sex, diabetes, hypertension, heart failure, previous invasive ventilatory support and increased rate of readmission.5

Bonus Pearl: Did you know that there is an inverse relationship between interleukin-6, a key pro-inflammatory cytokine, and plasma sodium levels in Covid-19 and that this association may be stronger than that of other viral or bacterial respiratory infections?2  

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References

  1. Ayus JC, Klantar-Zadeh K, Tantisattamo E, et al. Is hyponatremia a novel marker of inflammation in patients with Covid-19? Nephrol Dial Transplant 2023;38:1921-24. Is hyponatremia a novel marker of inflammation in patients with COVID-19? – PubMed (nih.gov)
  2. Pazos-Guerra M, Ruiz-Sanchez JG, Perez-Candel X, et al. Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients. Front Endocrinol 2023; 14:1227058. Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients – PubMed (nih.gov)
  3. De Haan L, ten Wolde, Beudel M, et al. What is the aetiology of dynatreaemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, restrospective observational study in 11 Dutch hospitals. BMJ Open 2023;13:e075232. Original research: What is the aetiology of dysnatraemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, retrospective observational study in 11 Dutch hospitals – PMC (nih.gov)
  4. Rehman F, Rehan ST, Rind BJ, et al. Hyponatremia causing factors and its association with disease severity and length of stay in Covid-19 patients: A retrospective study from tertiary care hospital. Medicine 2023; 102:45(e35920) Hyponatremia causing factors and its association with disease severity and length of stay in COVID-19 patients: A retrospective study from tertiary care hospital – PubMed (nih.gov)
  5. Biagetti B, Sanchez-Montalva A, Puig-Perez A, et al. Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions. Scientific Reports 2024:14:595. Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions – PubMed (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!

How common is hyponatremia in patients with Covid-19 and what’s its significance?  

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?

Are women at higher risk of Covid-19 vaccine-related adverse events?

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

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

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References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

Disclosures: 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 or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

Are women at higher risk of Covid-19 vaccine-related adverse events?

Does Covid-19 affect males more than females?

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

Although there is no clear gender pattern in terms of susceptibility to Covid-19, once infected, men have consistently been shown to have higher fatality rates when compared to women.1

In an earlier study involving over 1000 Covid-19 patients, males accounted for 58% of cases.2  However, a review of over 72,000 patients reported by the Chinese CDC found nearly equivalent male to female ratio (~1:1).3 Among Covid-19 patients who have died, male to female ratio has frequently been found to be between 1.5-3.8:1, depending on the reporting country.1  

In a case series from New York City, males accounted for 55% of Covid-19 patients not on invasive mechanical ventilation but 71% of those who required invasive mechanical ventilation.4 Chinese CDC reported case fatality rates of 2.8% for males and 1.7% for females.3 Higher case-fatality rates among males with 2 other coronavirus-related diseases, SARS and MERS, have also been reported.5

Potential explanations for more fatal outcomes among males with Covid-19 include more robust innate and humoral immune responses to infections among females.6 Immune suppressive activity of testosterone and potential immune enhancing effects of estrogens, such as increased expression of the anti-viral cytokine interferon (IFN)-gamma, have long been recognized.6 Life style differences between men and women such as higher prevalence of smoking in men are often mentioned as well.7 Interestingly, circulating ACE2, a receptor for SARS-CoV-2, has also been reported to be higher in men.8

Bonus pearl: Did you know that testosterone is associated with decreased production of pro-inflammatory cytokines such as IFN-gamma, TNF-alpha and may suppress immunoglobulin production?6

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 References

  1. Global Health 5050. Towards gender equality in global health. http://globalhealth5050.org/covid19/ , accessed April 27, 2020.
  2. Guan WJ, Ni AY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;Feb 28, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  3. Chinese CDC. Vital surveillances: the epidemiological charcteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China, 2020; 2:113-22. http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
  4. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020, April 17. https://www.nejm.org/doi/full/10.1056/NEJMc2010419
  5. Channappanavar R, Fett C, Mack M, et al. Sex-based differences in susceptibility to SARS-CoV infection. J Immunol 2017;198:4046-4053. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450662/#!po=3.84615
  6. Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology 2018;156:9-22. https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13004
  7. Wenham C, Smith J, Morgan R. COVID-19: the gendered impacts of the outbreak. Lancet 2020:395:846-7. https://www.ncbi.nlm.nih.gov/pubmed/32151325
  8. Patel SK, Velkoska E, Burrell LM. Emerging markers in cardiovascular disease: Where does angiotensin-converting enzyme 2 fit in? Clin Exp Pharmacol Physiol 2013;40:551-9. https://www.ncbi.nlm.nih.gov/pubmed/23432153/

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!

 

Does Covid-19 affect males more than females?

My 70 year old male patient is admitted with 1 day of fever, dysuria, and urinary frequency and urgency, but has a negative urine dipstick test for nitrites and leukocyte esterase. Could he still have acute bacterial prostatitis?

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

Short answer: Yes! In fact, no routine clinical imaging test can adequately rule out prostatic involvement in men with urinary tract infection (UTI) symptoms (1)! 

Although the presence of nitrites and leukocyte esterase (LE) may have a high positive predictive value for acute bacterial prostatitis (ABP) (~95%), their combined absence has a negative predictive value of only ~70%; ie, we may miss about one-third of patients with UTI symptoms if we relied solely on the results of nitrite and LE urine dipstick (2,3). Negative nitrites alone has a negative predictive value of only ~ 45%, while a negative LE has a negative predictive value of ~60% (3).

To evaluate for ABP, our patient should undergo rectal exam for prostatic tenderness, as should all men with UTI symptoms. The finding of a tender prostate in this setting is supportive of ABP, although its absence will still not rule out this diagnosis because the reported sensitivity of rectal exam may vary from 9% to 100% in ABP (1).

 
Although there may not be a general agreement on the definition of ABP, 2 studies utilizing indium-labeled leukocyte scintigraphy or a combination of PSA levels and transrectal ultrasound have provided evidence for frequent prostatic involvement in men with UTI symptoms (4,5).  In these studies, an inflammatory reaction within the prostate was seen in the majority of cases, even when the digital rectal examination was not painful or when clinicians diagnosed pyelonephritis without prostatitis.

Bonus pearl: Did you know that the lifetime probability of a man receiving a diagnosis of prostatitis is >25% (1)? 

Also see a related P4P pearl: Acute prostatitis and u/a

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References
1. Etienne M, Chavanet P, Sibert L, et al. Acute bacterial prostatitis: heterogeneity in diagnostic criteria and management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis. BMC Infect Dis 2008, 8:12 doi:10.1186/1471-2334-8-12. https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-8-12
2. Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis 2010;50:1641-1652. https://academic.oup.com/cid/article/50/12/1641/305217
3. Etienne M, Pestel-Caron M, Chavanet P, et al. Performance of the urine leukocyte esterase and nitrite dipstick test for the diagnosis of acute prostatitis. Clin Infect Dis 2008; 46:951-53. https://academic.oup.com/cid/article/46/6/951/351423
4. Velasco M, Mateos JJ, Martinez JA, et al. Accurate topographical diagnosis of urinary tract infection in male patients with (111)indium-labelled leukocyte scintigraphy. Eur J Intern Med 2004;15:157-61. https://www.ncbi.nlm.nih.gov/pubmed/15245717
5. Ulleryd P, Zackrisson B, Aus G, et al. Prostatic involvement in men with febrie urinary tract infection as measured by serum prostate-specific antigen and transrectal ultrasonography. BJU Int 1999;84:470-74. https://onlinelibrary.wiley.com/doi/full/10.1046/j.1464-410x.1999.00164.x

 

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!

My 70 year old male patient is admitted with 1 day of fever, dysuria, and urinary frequency and urgency, but has a negative urine dipstick test for nitrites and leukocyte esterase. Could he still have acute bacterial prostatitis?