How do I interpret an elevated serum C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) or vice-versa?

Discordance between serum CRP and ESR is not uncommon (1,2). This phenomenon may be due to a variety of factors including the fact that the kinetics of these two tests is quite different, as discussed under “Should I order C-reactive protein (CRP) or erythrocyte sedimentation (ESR) on patients suspected of having a new infection?” in this blog.

In a study of CRP/ESR discordance (defined as results differing by 2 or 3 quartiles) in adults, a high CRP/low ESR profile was more likely to be associated with  urinary, GI, blood stream, and pulmonary infections, myocardial infarction, and venous thromboembolism and less likely to be associated with bone and joint infections (1).

In the same study, a high ESR/low CRP was associated with connective tissue diseases, such as systemic lupus erythematosus and strokes (1).

1. Feldman M, Aziz B, Kang GN, et al. C-reactive protein and erythrocyte sedimentation rate discordance: frequency and causes in adults. Translational Research 2013;161:37-43. https://www.ncbi.nlm.nih.gov/pubmed/22921838

2. Colombet I, Pouchot J, Kronz V. Agreement between erythrocyte sedimentation rate and C-reactive protein in hospital practice. Am J Med 2010;123:864.e7-863.e13.https://www.ncbi.nlm.nih.gov/pubmed/20800157

How do I interpret an elevated serum C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) or vice-versa?

What is the mechanism of fluoroquinolone(FQ)-induced tendonopathy?

An uncommon but serious side effect of FQs (e.g. ciprofloxacin, levofloxacin, and moxifloxacin) is Achilles tendon rupture.   A putative mechanism for this adverse effect is inhibition of host mitochondrial components (1). Recall that mitochondria, the ATP-generating machine within our cells, are thought to be archaic bacterial ancestors that have co-evolved with us. Quinolones are inhibitors of bacterial gyrases and topoisomerases and also appear to be associated with DNA degradation of the mitochondria in some mammalian cells. In vitro, FQs appear to have a tropism for mitochondria in tenocytes, chondrocytes, and osteoblasts.   Thus, it is possible that at least in some patients (e.g. those ≥60 years of age, on higher doses of corticosteroids, or with several renal disease or other idiosyncratic factors) the mitochondrial damage is sufficient to cause serious injury to the Achilles tendon (2).

1. Barnhill AE, Brewer MT, Carlson SA. Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob Agents Chemother 2012;56:4046-4051.

2. Shakibaei M, Stahlmann R. Ultrastructure of Achilles tendon from rats after treatment with fleroxacin. Arch Toxicol 2001;75:97-102.

What is the mechanism of fluoroquinolone(FQ)-induced tendonopathy?

Does corticosteroid therapy impact the results of interferon-gamma (IG) release assays—IGRAs— in patients screened for latent tuberculosis?

There is relative dearth of data addressing this very important issue. A decreased IG response after mitogen stimulation during treatment with oral prednisolone has been reported (1). In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone (1). A meta-analysis of the performance of IGRAs (including T-SPOT.TB) concluded that these assays were negatively affected by immunosuppressive therapy (2). So, until more data becomes available, caution is advised in interpreting lack of positive test or indeterminate results of IGRAs in patients on corticosteroid therapy.

1. Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349.

2. Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042.

Does corticosteroid therapy impact the results of interferon-gamma (IG) release assays—IGRAs— in patients screened for latent tuberculosis?

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

Actually no!

In fact, a 2015 study of CAP from Netherlands, published in New England Journal of Medicine, demonstrated that empiric treatment with beta-lactam monotherapy was not inferior to strategies using a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality, or length of hospital stay (1). To help exclude Legionella pneumonia (often accounting for <5% of CAP[2]), urine Legionella antigen was routinely performed in this study.

So once Legionella has been reasonably excluded, unless suspicion for other atypical causes of CAP (i.e. Mycoplasma pneumoniae or Chlamydophila pneumoniae) remains high, empiric monotherapy with a beta-lactam (e.g. ceftriaxone) may be just as effective in many cases of CAP.

References

1. Postma DF1, van Werkhoven CH, van Elden LJ, et al. CAP-START Study Group Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372:1312-23.  https://www.ncbi.nlm.nih.gov/pubmed/25830421  

2. von Baum H, Ewig S, Marre R, et al. Competence Network for Community Acquired Pneumonia Study Group. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis 2008;46:1356. https://www.ncbi.nlm.nih.gov/pubmed/18419436

Contributed by Jessica A. Hennessey, MD, PhD, Mass General Hospital, Boston, MA

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

My patient with foot osteomyelitis due to methicillin-sensitive Staphylococcus aureus (MSSA) is ready to go home on IV antibiotic therapy. Is daily ceftriaxone therapy an appropriate option?

Yes, it appears to be!  Ceftriaxone is active against MSSA and may be an option for treatment of infections due to this organism at least in certain situations.  

In a retrospective study comparing ceftriaxone to oxacillin for osteoarticular infections due to MSSA, there was no difference in treatment success at 3-6 and > 6 months following completion of IV antibiotics; oxacillin had to be discontinued more often due to toxicity, however (1).    

In another retrospective study comparing cefazolin to ceftriaxone for treatment of MSSA infections ( ≥50% of patients with osteomyelitis),  favorable outcomes, adverse events and complications were similar between the 2 groups (2). 

Several other studies have reported no significant difference in treatment failure between cefazolin and ceftriaxone in MSSA infections (3).  A smaller retrospective study, however, reported higher rate of treatment failure (defined to include unplanned extension of parenteral therapy) with ceftriaxone in MSSA bacteremia without finding any difference in time to blood culture clearance, or rates of persistent bacteremia, relapse after treatment, achievement of source control, mortality or readmission (3).

References

1. Wieland BW, Marcantoni JR, Bommarito KM, et al. A retrospective comparison of ceftriaxone versus oxacillin for osteoarticular infections due to methicillin-susceptible Staphylococcus aureus. Clin Infect Dis 2012;54:585-590. https://www.ncbi.nlm.nih.gov/pubmed/22144536

2.  Winans SA, Luce Am, Hasbun R. Outpatient parenteral antimicrobial therapy for the treatment of methicillin-susceptible Staphylococcus aureus: a comparison of cefazolin and ceftriaxone. Infection 2013;41:769-774. https://www.ncbi.nlm.nih.gov/pubmed/23686435

3. Carr DR, Stiefel U, Bonomo RA, etal. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia in a tertiary care VA medical center. Open Forum Infectious Diseases, Volume 5, Issue 5, 1 may 2018, ofy089. https://academic.oup.com/ofid/article/5/5/ofy089/4999397

 

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My patient with foot osteomyelitis due to methicillin-sensitive Staphylococcus aureus (MSSA) is ready to go home on IV antibiotic therapy. Is daily ceftriaxone therapy an appropriate option?

Why does my patient with cirrhosis have a normal serum albumin?

The finding of normal serum albumin in cirrhotic patients is not at all uncommon. In fact, in a meta-analysis involving 8 published articles, the sensitivity of serum albumin (< 3.5 g/dL) in cirrhosis was only 45% (1).

It turns out that in many patients with cirrhosis, the synthetic ability of liver with respect to albumin appears well preserved until more advanced stages of liver dysfunction develop (2).

So don’t exclude cirrhosis just because serum albumin is normal.

 

References

1. Udell JA, Wang CS, Tinmouth J et al. Does this patient with liver disease have cirrhosis? JAMA 2012;307:832-842. https://www.ncbi.nlm.nih.gov/pubmed/22357834

2. Ballmer PE, Washe D. McNurlan M, et al. Albumin synthesis rates in cirrhosis: correlation with Child-Turcotte classification. Hepatology 1993;18:292-297. https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.1840180211

Why does my patient with cirrhosis have a normal serum albumin?

How good are arterial blood gases in ruling out pulmonary embolism (PE)?

Not as good as one would hope.  In an often quoted study involving 768 patients with suspected PE who underwent angiography, a combination of normal A-a gradient (<20 mm Hg ), normal PaO2 (>80 mm Hg), and normal PaCO2 (>35 mm Hg) was examined to help exclude PE (1).  Among patients with no known cardiopulmonary disease and normal values in all 3 parameters,  over 30% still had PE, while among those with cardiopulmonary disease and normal parameters 17% had PE.  In short, normal arterial blood gases may make PE less likely, they do not by any means exclude the possibility of PE.

1.Stein PD, Goldhaber SZ, Henry JW, et al. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism. CHEST 1996; 109:78-81.

How good are arterial blood gases in ruling out pulmonary embolism (PE)?

Is bridging anticoagulation necessary perioperatively in patients with non-valvular atrial fibrillation (AF)?

Until recently, there were no randomized-controlled trials (RCTs) available to help guide our decision.  A recent RCT, however, demonstrated that foregoing bridging anticoagulation was not inferior to bridging with low-molecular-weight heparin in patients with chronic or paroxysmal AF for the prevention of arterial thromboembolism and decreased the risk of major bleeding (1).  Ineligibility criteria included mechanical valve; stroke, systemic embolism, or transient ischemic attack within the previous 12 weeks; major bleeding within the previous 6 weeks; creatinine clearance < 30 ml/min; platelet count < 100K/ cubic ml; or planned cardiac, intracranial, or intraspinal surgery.  A caveat is that the study included relatively few patients (<5%) with CHADS2 score >4.

Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015 (published June 22 at NEJM.org).

Is bridging anticoagulation necessary perioperatively in patients with non-valvular atrial fibrillation (AF)?

Why is serum AST levels generally higher than ALT in alcohol-induced liver injury?

Alcohol is thought to cause injury to the mitochondria which contains AST but not ALT. In addition, in chronic alcoholics, pyridoxine (vitamin B6) deficiency may reduce the synthesis of ALT more than AST because the former is more B6-dependent (1).  

AST/ALT ratio >1 may be more common in advanced alcohol liver disease (e.g. cirrhosis) than in the setting of high alcohol consumption without severe liver disease (2). 

Also, remember that AST levels greater than 500 U/L and ALT levels greater than 300 U/L are uncommon in alcohol-related liver injury.  In this setting, other causes such as acetaminophen toxicity should be excluded (1).

Referemces

1. Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician1999;59:2223-30.  https://www.ncbi.nlm.nih.gov/pubmed/10221307  

2. Nyblom H, Berggren U, Balldin J, et al. High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol &Alcoholism 2004;39:336-39. https://www.ncbi.nlm.nih.gov/pubmed/15208167

Why is serum AST levels generally higher than ALT in alcohol-induced liver injury?

My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?

Absolutely! Besides HIV infection which should be excluded in all patients with recurrent bouts of bacterial pneumonia irrespective of age, “selective polysaccharide antibody deficiency” which may account for 8% of adults with recurrent CAP, should also be excluded (1). 

These patients (median age 48 years) often present with recurrent bouts of bacterial pneumonia  despite having normal serum total immunoglobulin (IgG, IgA, and IgM) levels (1,2).  They have a normal response to tetanus toxoid (a protein) but cannot mount adequate antibody response against polysaccharide antigens of pathogens such as pneumococcus.   IVIG may reduce the risk of future bouts of pneumonia in this condition (2). 

References

1. Cohn JA, Skorpinski E, Cohn JR. Prevention of pneumococcal infection in a patient with normal immunoglobulin levels but impaired polysaccharide antibody production. Ann Allergy Asthma Immunol 2006;97:603-5. https://www.ncbi.nlm.nih.gov/pubmed/17165266

2. Cheng YK, Kecker PA, O’Byrne MM, Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Alergy Asthma Immunol 2006;97:306-311. https://www.ncbi.nlm.nih.gov/pubmed/17042135

 

My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?