Cytokines

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?  

Can Covid-19 exacerbate seizures in patients with epilepsy?

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

There have been several reports of seizure exacerbation in epileptic patients after Covid-19 infection. Seizure exacerbations have been observed in epileptic patients with uncontrolled epilepsy, as well as patients who were previously controlled with antiepileptic drugs (AEDs).1,2

In a survey of 362 epileptic patients in Wuhan, China, the site of the initial outbreak, 31 (8.6%) patients reported an increased number of seizures in the month after the public lockdown began; 16 (51.6%) of the 31 patients with seizure exacerbation had prior exposure to Covid-19.1

In a study of 439 patients with Covid-19 infection in Egypt, 19 (4.3%) patients presented with acute seizures.2  Two of the 19 seizure patients had a previous diagnosis of epilepsy, which had been controlled for up to 2 years. Interestingly, the other 17 patients had new onset seizures without a previous epilepsy diagnosis.

Covid-19 has been proposed to induce seizures by eliciting inflammatory cytokines in the central nervous system, leading to neuronal necrosis and increased glutamate levels in the cerebral cortex and hippocampus.3

Covid-19 infection may have also indirectly caused seizure exacerbations in a number of epileptic patients. Interestingly, stress related to worrying about the effect of the outbreak on a patient’s seizure activity was associated with seizure exacerbations (odds ratio: 2.5, 95% CI: 1.1-6.1)2. It is also possible that some seizure exacerbations may have been due to fear of visiting the hospital and AED withdrawal, as was demonstrated during the 2003 SARS outbreak.4

Bonus Pearl: Did you know that Guillain–Barré Syndrome has also been observed in patients with Covid-19 infection?5

Contributed by Luke Vest, Medical Student, St. Louis University Medical School

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References:

  1. Huang, S., Wu, C., Jia, Y., et al. (2020). COVID-19 outbreak: The impact of stress on seizures in patients with epilepsy. Epilepsia, 61(9), 1884-1893. https://doi.org/10.1111/epi.16635  
  2. Khedr, E. M., Shoyb, A., Mohammaden, M., & Saber, M. (2021). Acute symptomatic seizures and COVID-19: Hospital-based study. Epilepsy Res, 174, 106650. https://doi.org/10.1016/j.eplepsyres.2021.106650
  1. Nikbakht, F., Mohammadkhanizadeh, A., & Mohammadi, E. (2020). How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders, 46, 102535. https://doi.org/10.1016/j.msard.2020.102535
  2. Lai, S. L., Hsu, M. T., & Chen, S. S. (2005). The impact of SARS on epilepsy: the experience of drug withdrawal in epileptic patients. Seizure, 14(8), 557–561. https://doi.org/10.1016/j.seizure.2005.08.010
  3.  Abu-Rumeileh, S., Abdelhak, A., Foschi, M., Tumani, H., & Otto, M. (2021). Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. Journal of neurology, 268(4), 1133–1170. https://doi.org/10.1007/s00415-020-10124-x   

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, or St. Louis University Medical School. 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!

Can Covid-19 exacerbate seizures in patients with epilepsy?

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?

Is there an association between infections and falls?

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

Although the list of factors that lead to falls is long and varied, increasing number of reports have identified falls as a manifestation of infections, including Covid-19.1-4

A retrospective study involving over 1400 patients (mean age 72 years) admitted to the hospital for a fall or its complications found coexisting systemic infections (CSIs) in 21% of patients; 26% in those ≥75 years. Urinary tract infection accounted for 55% of CSIs, followed by pneumonia (36%), skin and soft tissue infections (7%), influenza/influenza-like illness (5%), bacteremia (5%), gastrointestinal infections (2%), and others. 1

Risk factors for CSI include preexisting symptoms (eg, weakness, dizziness), inability to get up on own, confusion, age ≥ 50 years and meeting the systemic inflammatory response syndrome (SIRS) criteria on presentation.1 Of note, CSI may not initially be suspected by providers in about one-third or more of the cases, with 15% of patients presenting with “mechanical fall” having a CSI.1,2  Fever or SIRS criteria (≥2) are absent in the majority of patients with CSI.1,2

More recently, reports of falls as a presenting feature of Covid-19 have also appeared in the lay press as well as the literature, with 1 study finding 24% of patients with Covid-19 seek care primarily because of syncope, near syncope, or a nonmechanical fall.3,4

Several factors may explain the association of infections with falls, including impairment of skeletal muscle function (eg, through cytokines, hypophosphatemia), poor oral intake and dehydration. 1 Perhaps that’s why inability to get up by one’s self from a fall in the absence of an obvious reason (eg, fracture) may be a clue to a CSI in patient presenting with a fall.

Bonus Pearl: Did you know that falls are a leading cause of injury and death, afflicting one-third of adults aged greater than 65 years each year?1

Disclosure: The author of this blog also was a coinvestigator in 2 cited studies (ref. 1 and 2)

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References

  1. Manian FA, Hsu F, Huang D, et al. Coexisting systemic infections in patients hospitalized because of a fall: prevalence and risk factors. J Emerg Med 2020;58:733-40. https://www.sciencedirect.com/science/article/abs/pii/S0736467920300214
  2. Blair A, Manian FA. Coexisting systemic infections in patients who present with a fall. Am J Med Sci 2017;353:22-26. https://pubmed.ncbi.nlm.nih.gov/28104099/
  3. Chen T, Hanna J, Walsh EE, et al. Syncope, near syncope, or nonmechanical falls as a presenting feature of COVID-19. Ann Emerg Med 2020 July;76:115-117. https://pubmed.ncbi.nlm.nih.gov/32591120/
  4. Norman RE, Stall NM, Sinha SK. Typically atypical: COVID-19 presenting as a fall in an older adult. J Am Geriatr Soc 2020 July;68:E36-37. DOI:10.1111/gs.16526 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267373/pdf/JGS-9999-na.pdf

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!

Is there an association between infections and falls?

What role does obesity play in severe Covid-19?

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

Obesity has been shown to be a strong independent predictor of not only Covid-19-related hospitalization but also critical illness requiring invasive mechanical ventilation (IMV) or ICU support (1-3).

 
A large New York City study involving over 4,000 Covid-19 patients found obesity ( BMI≥30 kg/m2) to be an independent risk factor for hospitalization; BMI 30-40 kg/m2 was associated with ~4-fold and >40 kg/m2 with ~6-fold increased risk. Obesity was also strongly associated with increased risk of critical illness, stronger than other common preexisting conditions such as heart disease, hypertension or diabetes (1, preprint).

 
Another New York City study found that among Covid-19 patients younger than 60 years of age, obese patients were twice as likely to be hospitalized or have critical illness (2). Similarly, a French study found severe obesity (BMI >35 kg/m2) to be strongly associated with IMV compared to those with BMI <25 kg/m2 (O.R. 7.4, 1.7-33) (3).

 
Many factors likely play a role in making obese patients particularly susceptive to severe Covid-19. Obesity is a well-recognized inflammatory state and is associated with abnormal secretion of cytokines and adipokines which may have an effect on lung parenchyma and bronchi (1,3,4). Somewhat paradoxically, obese patients may also have an impaired adaptive immune response to certain infections, including influenza (4). Abdominal obesity is also associated with impaired ventilation of the base of the lungs resulting in reduced oxygenation (1).

 

 

Bonus Pearl: Did you know among pre-existing conditions commonly found in the population (eg, hypertension, diabetes, COPD), obesity has been found to be the only condition independently associated with pulmonary embolism in Covid-19 (O.R. 2.7, 1.3-5.5) (5).

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References
1. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospitalization and critical illness among 4, 103 patients with Covid-19 disease in New York City. MedRxiv preprint doi: https://doi.org/10.1101/2020.04.0820057794
2. Lighter J, Phillips M, Hochman S, et al. Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Clin Infect Dis 2020. https://pubmed.ncbi.nlm.nih.gov/32271368/
3. Simonnet A, Chetboun M, Poissy J, et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. https://pubmed.ncbi.nlm.nih.gov/32271993/
4. Sattar N, BcInnes IB, McMurray JJV. Obesity a risk factor for severe COVID-19 infection:multiple potential mechanisms. Circulation 2020. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047659
5. Poyiadji N, Cormier P, Patel PY, et al. Acute pulmonary embolism and COVID-19. Radiology 2020; https://pubmed.ncbi.nlm.nih.gov/32407256/

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!

What role does obesity play in severe Covid-19?

Do statins have a role in treating novel Coronavirus infection, COVID-19?

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

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

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References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

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!

Do statins have a role in treating novel Coronavirus infection, COVID-19?

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

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

Repurposing of older drugs such as chloroquine or hydroxychloroquine (HC) and more recently, azithromycin (AZ), has received much attention recently in the treatment of Covid-19. Both HC and AZ have immune modulating and antiviral activity that may potentially be effective in our fight against Covid-19.

 
Chloroquine/HC: Chloroquine is an old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. It is active in mice against a variety of viruses, including some enteroviruses, Zika virus, and influenza A H5N1 (1). Both chloroquine and HC are active in vitro against Covid-19, though HC appears to be more active (2).

 
Azithromycin: A macrolide often used for treatment of bacterial respiratory tract infections but also with anti-inflammatory and antiviral activity. Azithromycin has been shown to augment interferon response in rhinovirus-infected bronchial epithelial cells as well as in an experimental mouse model of asthma exacerbation (3,4). It also has activity against Zika virus (5). As recently as 2016, some authors opined that macrolides may be useful in pandemic influenza characterized by excessive inflammatory cytokine production because of their anti-inflammatory and interferon-boosting potential (6).

 
March 2020 French clinical trial: A small non-randomized clinical trial involving 36 confirmed Covid-19 patients (mean age 45 y) reported that HC (200 mg 3x/day x 10 days) was associated with rapid viral clearance from nasopharynx, often within 3-6 days (7). The effect was even more pronounced when AZ (500 mg 1st day, followed by 250 mg daily x 4 days) was added in 6 patients.

It’s worth emphasizing that most subjects in this study were either asymptomatic (17%) or had mild disease with upper respiratory tract infection symptoms only (61%). Pneumonia was diagnosed in only 6 patients.  A significant number of patients in the treatment arm also dropped out of the study, some due to ICU transfer.

 
Although such preliminary reports appear promising, the proof of the efficacy and safety of HC and/or AZ in the treatment of Covid-19 awaits larger properly designed clinical studies. Stay tuned!

 

 

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References
1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.ncbi.nlm.nih.gov/pubmed/32147496
2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respirartory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020, March 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618
3. Menzel M, Akbarshai H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Scientific Reports 2016;6:28698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923851/
4. Menzel M, Akbarshai H, Uller L. Azithromycin exhibits interferon-inducing properties in an experimental mouse model of asthma exacerbation. Eur Resp J 2015;46:PA5095. https://erj.ersjournas.com/content/46/suppl_59/PA5095
5. Retallack H, Di Lullo E, Knopp AC, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Nat Acad Sci USA 2016;113:14408-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167169/
6. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III-IFN-augmenting activity in airway epithelium. J Antimicrob Chemother 2016;71:2767-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031920/
7. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19:results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents—In Press 17 March 2020-DOI: 10.1016/j.ijantimicag.2020.105949 . https://www.sciencedirect.com/science/article/pii/S0924857920300996

 

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!

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

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

Although we may expect patients with DKA to present with hypotension due to hypovolemia, many patients with DKA may actually be hypertensive. This finding is particularly intriguing because hyperinsulinemia, not insulinopenia as found in DKA, has been associated with hypertension. 1,2

Though not proven, potential explanations for hypertension in DKA include elevated serum levels of catecholamines, pro-inflammatory cytokines, renin, angiotension II and aldosterone.3-5 Hyperosmolality may also lead to the release of antidiuretic hormone (ADH) which increases blood pressure via V2 receptors.  Another possibility is that the high insulin levels associated with the treatment of DKA suppress the catecholamine-stimulated production of vasodilative eicosanoids (eg, prostaglandins) by adipose tissue. 1 It’s possible that in any given patient, 1 or more of these mechanisms may be enough to override the potential hypotensive effect of insulin deficiency in DKA.

We should note that reports of frequent hypertension in DKA have primarily involved pediatric patients. A 2011 study found that 82% of pediatric patients with DKA had hypertension during the first 6 hours of admission with no patient having hypotension.3  

On the other extreme, refractory hypotension without obvious cause (eg, sepsis, acute adrenal insufficiency, cardiogenic causes) has also been reported in DKA.5Because insulin inhibits the production of vasodilative prostaglandins (eg, PGI2 and PGE2), severe insulin deficiency in DKA can also contribute to hypotension along with volume depletion. 

Potential genetic polymorphism in the synthesis and metabolism of prostaglandins may at least partially explain the varied blood pressure response and whether a patient with DKA presents with hypertension or hypotension. 5  

The author would like to acknowledge the valuable contribution of Lloyd Axelrod MD, Massachusetts General Hospital, to this post.

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References

  1. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991;40:1223-1227. https://diabetes.diabetesjournals.org/content/40/10/1223&nbsp;
  2. Chatzipantelli K, Head C, Megerman J, et al. The relationship between plasma insulin level, prostaglandin productin by adipose tissue and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis. Metabolism 1996;45:691-98. https://www.sciencedirect.com/science/article/abs/pii/S002604959690133X&nbsp;
  3. Deeter KH, Roberts JS, Bradford H, et al. Hypertension despite dehydration during severe pediatric diabetic ketoacidosis. Pediatr Diabetes 2011;12:295-301. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-5448.2010.00695.x&nbsp;
  4. Ferris JB, O’Hare JA, Kelleher CM, et al. Diabetic control and the renin-angiotensin system, catecholamines and blood pressure. Hypertension 1985 7(Suppl II):II-58-II-63. https://www.ahajournals.org/doi/abs/10.1161/01.HYP.7.6_Pt_2.II58  
  5. Singh D, Cantu M, Marx MHM, et al. Diabetic ketoacidosis and fluid refractory hypotension. Clin Pediatrics 2016;55:182-84. https://journals.sagepub.com/doi/abs/10.1177/0009922815584549?journalCode=cpja&nbsp;

 

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

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

 Absolutely! Although trauma, toxins, exertion, and medications are often listed as common causes of rhabdomyolysis, infectious etiologies should not be overlooked as they may account for 5% to 30% or more of rhabdomyolysis cases (1,2).

Rhabdomyolysis tends to be associated with a variety of infections, often severe, involving the respiratory tract, as well as urinary tract, heart and meninges, and may be caused by a long list of pathogens (1).  Among bacterial causes, Legionella sp. (“classic” pathogen associated with rhabdomyolysis), Streptococcus sp. (including S. pneumoniae), Salmonella sp, Staphylococcus aureus, Francisella tularensis have been cited frequently (3).  Some series have reported a preponderance of aerobic gram-negatives such as Klebsiella sp., Pseudomonas sp. and E. coli  (1,2).   Among viral etiologies, influenza virus, human immunodeficiency virus, and coxsackievirus are commonly cited (2,3).  Fungal and protozoal infections (eg, malaria) may also be associated with rhabdomyolysis (5).

So how might sepsis cause rhabdomyolysis? Several potential mechanisms have been implicated, including tissue hypoxemia due to sepsis, direct muscle invasion by pathogens (eg, S. aureus, streptococci, Salmonella sp.), toxin generation (eg, Legionella), cytokine-mediated muscle cell toxicity (eg, aerobic gram-negatives) as well as muscle ischemia due to shock (1,5).

Bonus Pearl: Did you know that among patients with HIV infection, infections are the most common cause (39%) of rhabdomyolysis (6)? 

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References

1. Kumar AA, Bhaskar E, Shantha GPS, et al. Rhabdomyolysis in community acquired bacterial sepsis—A retrospective cohort study. PLoS ONE 2009;e7182. Doi:10.1371/journa.pone.0007182. https://www.ncbi.nlm.nih.gov/pubmed/19787056.

2. Blanco JR, Zabaza M, Sacedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J 2002;95:542-44. https://www.ncbi.nlm.nih.gov/pubmed/12005014

3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis:three case reports and review. Clin Infect Dis 1996;22:642-9. https://www.ncbi.nlm.nih.gov/pubmed/8729203

4. Shih CC, Hii HP, Tsao CM, et al. Therapeutic effects of procainamide on endotoxin-induced rhabdomyolysis in rats. PLOS ONE 2016. Doi:10.1371/journal.pone.0150319. https://www.ncbi.nlm.nih.gov/pubmed/26918767

5. Khan FY. Rhabdomyolysis: a review of the literature. NJM 2009;67:272-83. http://www.njmonline.nl/getpdf.php?id=842

6. Koubar SH, Estrella MM, Warrier R, et al. Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrology 2017;18:242. DOI 10.1186/s12882-017-0656-9. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-017-0656-9

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

Why was the myocardial infarction in my postop patient silent?

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

Myocardial infarction (MI) in postop patients is in fact usually silent (1,2) but what is less clear is how myocardial ischemia can occur without any symptoms.

Although use of analgesics and narcotics postop may dampen or mask chest pain or other symptoms associated with MI, other factors are also likely to play an important role, such as decreased sensitivity to painful stimuli, autonomic neuropathy (eg, in diabetes mellitus), and higher pain threshold among some patients (3).

Additional factors associated with silent MIs include cerebral cortical dysfunction since frontal cortical activation appears to be necessary to experience cardiac pain. Mental stress is also a frequent trigger for asymptomatic myocardial ischemia, infarction and sudden cardiac death (4).  High levels of beta-endorphin, an endogenous opiate, may also play a role (5).

 
Perhaps the most intriguing explanation for lack of symptoms is the observation that the levels of anti-inflammatory cytokines (interleukin-4 and -10)—which block pain transmission pathways and increase the threshold for nerve activation—seem to be increased in patients with silent myocardial ischemia (6).  Even more relevant to our postop patient is the finding that interleukin-10 production increases during and after major abdominal surgery and correlates with the amount of intraoperative blood loss (7). 

No wonder MIs in postop patients are often silent!

References
1. Devereaux PJ, Xavier D, Pogue J, et al. Characteristics nd short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med 2011;154:523-8. https://annals.org/aim/article-abstract/746934/characteristics-short-term-prognosis-perioperative-myocardial-infarction-patients-undergoing-noncardiac 
2. Badner NH, Knill RL, Brown JE, et al. Myocardial infarction after noncardiac surgery. Anesthesiology 1998;88:572-78. http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1948483
3. Ahmed AH, Shankar KJ, Eftekhari H, et al. Silent myocardial ischemia:current perspectives and future directions. Exp Clin Cardiol 2007;12:189-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359606/ 
4. Gullette EC, Blumenthal JA, Babyak M, et al. Effects of mental stress on myocardial ischemia during daily life. JAMA 1997;277:1521-6. https://jama.jamanetwork.com/journals/jama/articlepdf/416233/jama_277_19_029.pdf
5. Hikita H, Kurita A, Takase B, et al. Re-examination of the roles of beta-endorphin and cardiac autonomic function in exercise-induced silent myocardial ischemia. Ann Noninvasive Electrocardiol 1997;2:319-25. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1542-474X.1997.tb00195.x
6. Mazzone A, Cusa C, Mazzucchelli I, et al. Increased production of inflammatory cytokines in patients with silent myocardial ischemia. J Am Coll Cardiol 2001;38:1895-901. https://www.ncbi.nlm.nih.gov/pubmed/11738291
7. Kato M, Honda I, Suzuki H, et al. Interleukin-10 production during and after upper abdominal surgery. J Clin Anesth 1998;10:184-8. https://www.ncbi.nlm.nih.gov/pubmed/9603586 

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Why was the myocardial infarction in my postop patient silent?