Primecuts – This Week in the Journals

September 3, 2020

By Jonathan Li, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial [1]

Septic shock remains a deadly complication of sepsis, with an estimated 40% mortality rate [2]. Currently early goal-directed therapy includes intravenous fluid resuscitation, empiric antibiotics, and infection source control. One investigational adjunctive therapy consists of ascorbic acid, corticosteroids, and thiamine for septic shock. Vitamin C is a potent antioxidant and improves microvascular barrier function and capillary blood flow [3]. Serum levels have been found to be very low in septic patients [4]. Hydrocortisone and vitamin C have several observed benefits, including increased vasopressor sensitivity and down-regulation of proinflammatory production through inhibition of nuclear factor-kB [5, 6, 7, 8]. There is potential synergy between vitamin C and hydrocortisone as well. Efficacy of glucocorticoids may be reduced by oxidation of glucocorticoid receptors, leading to ineffective ligand and DNA binding, and these changes can be reversed by the antioxidant properties of vitamin C [9]. Septic patients are often deficient in thiamine, which is associated with increased mortality [10].

Nonetheless, evidence is mixed. The original retrospective before-after study investigating this combination therapy found it was effective in decreasing mortality in patients with severe sepsis and septic shock while also decreasing progressive organ dysfunction [11]. However, the VITAMINS randomized clinical trial found no significant improvement in length of time alive and free of vasopressor treatment from this therapy compared to hydrocortisone alone [12].

The ACTS multicenter, randomized clinical trial enrolled 205 patients and assigned them to either receive the adjunctive combination therapy of parenteral ascorbic acid, hydrocortisone, and thiamine every 6 hours for four days or placebo. Additionally, every patient received standard sepsis management, including volume resuscitation and vasopressors to keep mean arterial pressure at least 65 mmHg, early antibiotics, and early infection source control. The primary outcome was difference in Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 is best) at 72 hours from enrollment. 30-day mortality and kidney failure were the major secondary outcomes.

There was no significant change in SOFA scores at 72 hours with treatment compared to placebo (mean difference, −0.8; 95% CI, −1.7 to 0.2; P = .12). With regards to kidney failure, there was also no significant difference with intervention vs placebo group (31.7% vs 27.3%; adjusted risk difference, 0.03; 95% CI, −0.10 to 0.17; P = .58). Similarly, no significant difference in 30-day mortality was observed between intervention vs placebo group (34.7% vs 29.3%; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26).

Consistent with the VITAMINS study, this trial unfortunately does not support the combination therapy of ascorbic acid, corticosteroids, and thiamine in patients with septic shock. However, the most common exclusion criterion was ongoing or planned corticosteroid use, which prevented enrollment of patients who may have had greater benefit from corticosteroids. Moreover, it is possible that certain subsets of patients in the study may respond better to the study treatment, but this study did not have sufficient statistical power for subgroup analyses. Lastly, it is possible that time from ICU admission to study treatment initiation may affect the therapy’s success. The original retrospective study that supported the effectiveness of this therapy described administration within 24 hours of ICU admission [11], and data regarding time of ICU admission was not described in the ACTS trial.

Diagnostic Accuracy of Symptoms, Physical Signs, and Laboratory Tests for Giant Cell Arteritis: A Systematic Review and Meta-analysis [13]

Without prompt treatment, giant cell arteritis (GCA) could lead to permanent vision loss; nonetheless, it is a difficult diagnosis to make without temporal artery biopsy (TAB) or vascular imaging, which are often not readily available and could delay appropriate treatment.  A high pretest probability based on clinical features and laboratory findings is thus paramount to timely diagnosis and treatment.

This systematic review and meta-analysis intended to elucidate the diagnostic value of symptoms, physical exam findings, and laboratory markers in suspected GCA. Classically, these include headache, vision loss, jaw claudication, temporal tenderness, enlarged temporal artery, elevated erythrocyte sedimentation rate (ESR), and elevated C-reactive protein (CRP). Clinical trials as well as retrospective or prospective observational studies were chosen from PubMed, EMBASE, and Cochrane from 1940 to 2020. The authors chose four study inclusion criteria: (1) participants consisted of consecutive patients with suspected GCA; (2) GCA reference standard was a TAB, imaging test, or clinical diagnosis (determined by at least 1 physician or using defined criteria); (3) a 2 x 2 contingency table was either directly available or could be calculated for at least 1 index test (symptom, physical sign, or laboratory test); and (4) at least 5 patients were confirmed to have GCA and at least 5 did not have GCA. Case-control studies and studies where GCA was diagnosed in all patients were excluded.

68 studies met the criteria out of 1436 screened, and 4277 (30.5%) of total 14,037 patients were diagnosed with GCA. The study characterized statistical significance as positive likelihood ratios (LR) of greater than 2.00 or negative LR less than 0.50. Limb claudication (LR 6.01; 95% CI, 1.38-26.16) and jaw claudication (LR 4.90; 95% CI, 3.74-6.41) proved the most reliable positive symptoms. With regards to physical exam findings, significant positive LR was seen with any temporal artery abnormality (2.29; 95% CI, 1.61-3.26) temporal tenderness (3.14; 95% CI, 1.14-8.65), temporal artery thickening (4.70; 95% CI, 2.65-8.33), temporal artery loss of pulse (3.25; 95% CI, 2.49-4.23), and anterior ischemic optic neuropathy (AION) (2.15; 95% CI, 1.53 -3.03). Significant lab findings include platelet count of greater than 400 × 103/μL (3.75; 95% CI, 2.12-6.64) and ESR of greater than 60 (2.40; 95% CI, 1.71-3.36), 80 (2.79; 95% CI, 1.78-4.37), and 100 mm/h (3.11; 95% CI, 1.43-6.78). Significant negative LR was seen in age greater than 70 years (0.48; 95% CI, 0.27-0.86) and elevated CRP (0.40; 95% CI, 0.29-0.56).

Headache, scalp tenderness, loss of vision, double vision, and elevated CRP each had positive LR with 95% CI above 1.00 but did not meet this study’s LR significance threshold of 2. History of polymyalgia rheumatica (PMR) had positive LR of 2.07, but the CI crossed 1.

Information from this study could be used to create a more accurate GCA risk stratification calculator. For instance, one GCA risk tool includes sex, which failed to show statistically significant predilection in this study [14]. Furthermore, while the study highlights certain significant clinical and lab findings, it is important to avoid using one single feature to make or break the diagnosis. Rather, this study encourages assessing the overall clinical picture to accurately inform pretest probability for further imaging or TAB. 

Prevalence of Infective Endocarditis in Streptococcal Bloodstream Infections Is Dependent on Streptococcal Species [15]

Classical teaching describes viridans streptococci and streptococcus bovis as two of the major culprits for streptococcal infective endocarditis (IE). In fact, the modified Duke criteria lists both, but does not stratify based on the specific groups and species. For example  viridans streptococci, which is a pseudo-taxonomic term, includes such species as strep anginosus, mitis, and sanguinis, each of which may carry high risk of IE .This study aims to distinguish the risk of infective endocarditis based upon specific streptococci at the species level.

This study included 6506 monospecies streptococcal blood stream infection (BSI) cases from 6224 distinct patients in Denmark from 2008-2017 from the Danish Population Registry. Cases without available streptococcal species identification and patients aged 18 years or less were excluded.

Streptococcal species with very high risk (>30% prevalence) included strep mutans (47.9%; 95% CI, 33.3–62.8), Strep gordonii (44.2%; 95% CI, 34.0–54.8), Strep sanguinis (34.6%; 95% CI, 26.6–43.3), and Strep gallolyticus (30.2%; 95% CI, 24.3–36.7) Notable high-risk (10-30%) species included Strep mitis/oralis (19.4%; 95% CI, 15.6–23.5) and Strep parasanguinis (10.3%; 95% CI, 5.2-17.7). Low risk (<3%) species included Strep pneumoniae (1.2%; 95% CI, 0.8-1.6) and Strep pyogenes (1.9%; 95% CI, 0.9-3.3). There was also intra-group variability when IE prevalence was analyzed at a group level.

Based upon this study, identification of individual strep species seems a useful tool in stratifying risk of IE.  In fact, there already exists diagnostic tools such as the HANDOC score, which aims to delineate risk of IE in patients with non-beta hemolytic streptococcal bacteremia in order to reduce unnecessary TEE in patients with low IE risk and redirect investigation to those with higher IE risk [16]. Thus, this study provides valuable speciation information that can help refine the accuracy of clinical decision tools.


Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden [17]

As the modern world increases its use of antibiotics, there is growing concern that altering the gut microbiome may lead to an increase in inflammatory bowel disease [18]. This Swedish prospective case-control study included Swedish citizens aged 16 years or older diagnosed with histologically proven IBD, matched with up to five controls from the general population as well as unaffected full siblings of index patients. Patients with antibiotic use had a multivariable-adjusted odds ratio (aOR) of 1.88 (95% CI 1.79-1.98) for development of IBD compared to controls who never used antibiotics, with higher aOR associated with greater cumulative antibiotic dispensation and use of broad-spectrum antibiotics; a similar, though attenuated, association persisted when unaffected siblings were used for comparison. This study highlights yet another unintended consequence of antibiotic use, suggesting that development of IBD is associated with increased cumulative and broad-spectrum antibiotic administration.

COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study [19]

Elevated inflammatory markers including LDH, ferritin, d-dimer, and CRP [20, 21] have been observed in COVID-19 patients, especially those with severe disease, but there exists no formal classification of a hyperinflammatory phenotype. This retrospective cohort study defined COVID-19 hyperinflammation (COV-HI) by CRP concentration greater than 150 mg/L, CRP concentration doubling within 24 hours from original concentration of at least 50 mg/L, or ferritin concentration greater than 1500 ug/L. 33% of patients in the study met this COV-HI criteria on admission, and they were found to have increased risk of next-day escalation of respiratory support or death (hazard ratio 2.24; 95% CI, 1.62-2.87). Having a defined hyperinflammatory phenotype could help stratify patients in future research and thus aid in developing specific treatment for those with severe inflammation.

Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists [22]

The PIONEER-HF trial validated the safety and effectiveness of in-hospital initiation of sacubitril/valsartan (S/V) compared to enalapril [23]. This study utilized data from the PIONEER-HF trial to analyze subgroups comprised of prior HF (de novo vs chronic) status and treatment with ACE inhibitor or ARB (yes or no) They determined that regardless of preceding HF diagnosis or existing treatment with ACE inhibitor or ARB, S/V still demonstrated significant reduction in NT-proBNP and similar safety compared to enalapril in all four subgroups (p < 0.001), thus providing further reassurance for the increasingly common prescription of S/V in hospitalized HFrEF patients, even in those naïve to ACE inhibitor or ARB therapy.

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates [24]

Fears regarding increased risk of atypical femur fracture (AFF), defined as fragility fracture in the femoral diaphysis or subtrochanteric region, has led to a decline in bisphosphonate usage [25]. However, their efficacy in decreasing risk of hip and vertebral fractures as well as increasing bone mineral density has been validated by several randomized, controlled trials [26, 27]. This study analyzed a large, prospective cohort of women aged 50 years or older treated with bisphosphonates with primary outcome of AFF. Longer duration of bisphosphonate therapy correlated with increased incidence of AFF, demonstrated by adjusted hazard ratio of 8.86 (95% CI, 2.79 – 28.20) for 3 years to 5 years of use and 43.51 (95% CI, 13.70 – 138.15) for 8 or more years of use.  However, reduced risk of hip and osteoporotic fractures significantly outweighed the minimal absolute risk of AFF, though less so in Asian women compared to white women. Therefore, this trial suggests the low absolute risk of AFF, though significant, should not warrant avoidance or discontinuation of bisphosphonates for fracture prevention.


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[9] Okamoto K, Tanaka H, Makino Y, et al. Restoration of the glucocorticoid receptor function by the phosphodiester compound of vitamins C and E, EPC-K1 (l-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt), via a redox-dependent mechanism. Biochem Pharmacol. 1993;56(1):79-86. Doi:10.1016/S0006-2952(98)00121-X

[10] M.W. Donnino, L.W. Andersen, M. Chase, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2)360-367. Doi:10.1097/CCM.0000000000001572

[11] Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036

[12] Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020;323(5):423–431. doi:10.1001/jama.2019.22176

[13] van der Geest KSM, Sandovici M, Brouwer E, Mackie SL. Diagnostic Accuracy of Symptoms, Physical Signs, and Laboratory Tests for Giant Cell Arteritis: A Systematic Review and Meta-analysis. JAMA Intern Med. Published online August 17, 2020. doi:10.1001/jamainternmed.2020.3050

[14] Ing EB, Lahaie Luna G, Toren A, et al. Multivariable prediction model for suspected giant cell arteritis: development and validation. Clin Ophthalmol. 2017;11:2031-2042. doi:10.2147/OPTH.S151385

[15] Chamat-Hedemand S, Dahl A, Ostergaard L, et al. Prevalence of Infective Endocarditis in Streptococcal Bloodstream Infections Is Dependent on Streptococcal Species. Circulation. 2020;142:720–730. doi:10.1161/CIRCULATIONAHA.120.046723

[16] Sunnerhagen T, Törnell A, Vikbrant M, Nilson B, Rasmussen M. HANDOC: A handy score to determine the need for echocardiography in non-β-hemolytic streptococcal bacteremia. Clin Infect Dis. 2018; 66:693–698. doi: 10.1093/cid/cix880

[17] Nguyen L, Ortqvist A, Cao Y, et al. Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden. Lancet Gastroenterology & Hepatology. Published online August 17,2020. doi:10.1016/S2468-1253(20)30267

[18] Ananthakrishnan, A. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12, 205–217. doi:10.1038/nrgastro.2015.34

[19] Manson J, Crooks C, Naja M, et al. COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. Lancet Rheumatology. Published online August 21, 2020. doi:10.1016/S2665-9913(20)30275-7

[20] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Published online March 11,2020. doi:10.1016/S0140-6736(20)30566-3

[21] Stawicki SP, Jeanmonod R, Miller AC, et al. The 2019-2020 Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Pandemic: A Joint American College of Academic International Medicine-World Academic Council of Emergency Medicine Multidisciplinary COVID-19 Working Group Consensus Paper. J Glob Infect Dis. 2020;12(2):47-93. doi:10.4103/jgid.jgid_86_20

[22] Ambrosy A, Braunwald E, Morrow D, et al. Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists. JACC. 2020; 76(9):1034-1048. doi:10.1016/j.jacc.2020.06.073

[23] Velazquez E, Morrow D, DeVore A, et al. Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019;380:539-548. doi:10.1056/NEJMoa1812851

[24] Black D, Geiger E, Eastell R, et al. Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates. N Engl J Med. 2020;383:743-753. doi:10.1056/NEJMoa1916525

[25] Jha S, Wang Z, Laucis N, Bhattacharyya T. Trends in Media Reports, Oral Bisphosphonate Prescriptions, and Hip Fractures 1996-2012: An Ecological Analysis. J Bone Miner Res. 2015;30(12):2179-2187. doi:10.1002/jbmr.2565

[26] Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):1535-1541. doi:10.1016/s0140-6736(96)07088-2

[27] Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622. doi:10.1210/jc.2019-00221