My patient with cirrhosis and suspected infection has a normal serum C-reactive protein (CRP). Does cirrhosis affect CRP response to infection?

 

CRP is primarily synthesized by the liver mainly as a response to IL-6 production in inflammatory states1.  Lower CRP production may then be expected in cirrhotic patients with significant infections and several studies support this view2

In a particularly convincing study involving E. coli-infected patients with bacteremia, the median CRP level in cirrhotic patients was about 40% that of non-cirrhotic patients (62 mg/L vs 146 mg/L)3.  In another study involving bacteremic patients with or without liver dysfunction, median CRP level was about 60% that of  patients with preserved liver function (81 mg/L vs 139 mg/L)4.  Some investigators have reported a cut-off CRP value of 9.2 mg/L as a possible screening test for bacterial infections in patients with cirrhosis with a sensitivity and specificity of 88% (AUROC 0.93)5.

Collectively, these data suggest that although CRP response may be diminished in patients with advanced liver disease and acute infection, its synthesis is still maintained.

References

  1. Pieri G, Agarwal B, Burroughs AK. C-reactive protein and bacterial infection in cirrhosis. Ann Gastroenterol 2014;27:113-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982625/pdf/AnnGastroenterol-27-113.pdf
  2. Ha YE, Kang C-I, Joo E-J, et al. Usefulness of C-reactive protein for evaluating clinical outcomes in cirrhotic patients with bacteremia. Korean J Intern Med 2011;26:195-200. http://pubmedcentralcanada.ca/pmcc/articles/PMC3110852/pdf/kjim-26-195.pdf
  3. Park WB1, Lee KD, Lee CS et al. Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis. 2005 Apr;51(4):227-30. https://www.ncbi.nlm.nih.gov/pubmed/15808312
  4. Mackenzie I, Woodhouse J. C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction. Intensive Care Med 2006;32:1344-51. https://www.ncbi.nlm.nih.gov/pubmed/16799774
  5. Papp M, Vitalis Z, Altorjay I, et al. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infection. Liver Int 2011;603-11. https://www.ncbi.nlm.nih.gov/pubmed/22145664

 

My patient with cirrhosis and suspected infection has a normal serum C-reactive protein (CRP). Does cirrhosis affect CRP response to infection?

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

The popular urine pneumococcal antigen (UPA) (based on the C-polysaccharide of Streptococcus pneumoniae cell wall) has been a valuable diagnostic tool in diagnosing invasive pneumococcal infections, but may be associated with up to nearly 10% rate of false-positivity in hospitalized patients1.  Three factors have often been cited as the  cause of false-positive UPA results: a. Nasopharyngeal carriage; b.Prior invasive pneumococcal infection and;  c. Pneumococcal vaccination.

Among adults with nasopharyngeal carriage of S. pneumoniae, particularly those with HIV infection, 12-17% of positive UPA tests may be false-positive1. In patients with recent invasive pneumococcal disease, UAP may remain positive in over 50% of patient at 1 month and about 5% at 6 months1,2.

Among persons receiving the 23-valent polysaccharide pneumococcal vaccine (PPV), over 20% may have a positive UPA up to 30 hours following immunization, some potentially longer1.  In fact, the manufacturer of UPA assay recommends that UPA not be obtained within 5 days of receiving PPV. There is reason to believe that conjugated pneumococcal vaccine may be associated with the same phenomenon3.

So in a hospitalized patient with low suspicion for pneumococcal disease but a positive UAP, it would be wise to first exclude the possibility of PPV administration earlier during hospitalization before the sample was obtained1,4.

 

References

  1. Ryscavage PA, Noskin GA, Bobb A, et al. Incidence and impact of false-positive urine pneumococcal antigen testing in hospitalized patients. S Med J 2011;104:293-97.
  2. Andre F, Prat C, Ruiz-Manzano J, et al. Persistence of Streptococcus pneumoniae urinary antigen excretion after pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 2009;28:197-201.
  3. Navarro D, Garcia-Maset Leonor, Gimeno C, et al. Performance of the Binax NOW Streptococcus pneumoniae urinary assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection. J Clin Microbiol 2004; 42: 4853-55.
  4. Song JY, Eun BW, Nahm MH. Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward. Infect Chemother 2013;45:351-66.

 

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

How should I interpret a positive result for serum cryoglobulins?

Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1.  The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.

Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS).  A commonly cited classification scheme for CG is shown (Table)3.   It should be emphasized that some CGs may not fit neatly into this scheme.

In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.

 

Table. Classification of cryoglobulinemia

Category Description Examples
Type I Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C

References

  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.

 

Contributed by Kirstin Scott, Medical Student, Harvard Medical School

How should I interpret a positive result for serum cryoglobulins?

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

Polyuria is considered a classic symptom of hypercalcemia and was one of the symptoms described in the first published case of hyperparathyroidism (1). Several potential mechanisms may explain this phenomenon.

The calcium sensing receptors (CaSRs) found in the kidney play a major role in volume status due to their expression in the thick ascending loop (TAL) of Henle and the collecting duct. Interestingly, hypercalcemia activates the CaSR in the medullary portion of TAL, causing inhibition of the same cotransporter (Na-K-2Cl) inhibited by furosemide and other loop diuretics (2-4)! Hypercalcemia also inhibits vasopressin action ( therefore urine concentration) by activating CaSR in the collecting duct (5).  Lastly, inhibition of Na+-K+ ATPase in the proximal convoluted tubule may further contribute to natriuresis and subsequent polyuria.

Thus, hypercalcemia may lead to polyuria by interfering with the absorption of sodium as well as inhibiting the action of vasopressin.  One can’t help but compare its effect to that of a patient with diabetes insipidus taking a loop diuretic!  No wonder these patient may suffer from polyuria!

 

REFERENCES

  1. Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76.
  2. Quamme GA. Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol. 1982;60:1275-80.
  3. Peterson LN. Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo. Am J Physiol. 1990;259:122-9.
  4. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:485-99.
  5. Toka HR, Pollak MR, Houillier P. Calcium sensing in the renal tubule. Physiology (Bethesda). 2015;30:317-26.

 

Contributed by Michael Hughes, Medical Student, Harvard Medical School

 

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

When should I suspect spinal epidural abscess in my 55 year old patient with severe back pain?

Up to 75% of patients with spinal epidural abscess (SEA) are misdiagnosed on their initial healthcare encounter1 , in large part related to the non-specific nature of back pain.  Potential “red flags” for infectious causes of low back pain include age >50 y, night pain, unremitting pain even when supine, duration > 6 weeks, fever, chills, night sweats, weight loss, conditions associated with Staphylococcus aureus bacteremia (eg intravenous drug use), incontinence, saddle anesthesia, and severe or rapidly progressive neurologic deficits1,2.   It cannot be overemphasized that up 50% of patients with SEA have no known risk factors,  one-half may have no fever and 20-40% lack leukocytosis1.

ESR and C-reactive protein (CRP) are almost uniformly elevated in SEA1 and can serve as a good starting point in excluding this condition.   In patients ≥50 y of age with low back pain, obtaining ESR routinely was suggested in 2002 for detection of systemic disease (eg cancer, infection)3.  Similarly, in a recent algorithm of severe back pain, routine measurements of ESR and CRP even in the absence of any neurological findings, has been recommended1.  Elevation of either ESR or CRP should raise suspicion for SEA and  lead to the consideration of MRI as clinically indicated.

References:

  1. Bond, A, Manian FA. Spinal epidural abscess: a review with special emphasis on earlier diagnosis. BioMed Res International 2016; http://dx.doi.org/10.1155/2016/1614328
  2. Della-Giustina. Acute low back pain: recognizing the “red flags” in the workup. Consultant 2013;53:436-440.
  3. Jarvik JG, Deyo RA. Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 2002;137:586-597.

 

Disclosure: The author of this post (FAM) also coauthored reference 1.

When should I suspect spinal epidural abscess in my 55 year old patient with severe back pain?

When is the best time to obtain blood cultures (BCs) from my patient admitted with recent fevers?

A common medical myth is that the yield of BCs is highest when obtained around the time of a fever spike. In 1989, an abstract reported a non-significant trend toward higher frequency of positive BCs in the period immediately before a fever spike1. In 1994, another study found no significant difference between the yield of simultaneous and serial (separated by a few hrs) BCs2, supporting the current practice of collecting ≥2 sets of BCs simultaneously.

In 2008, a multicenter retrospective study found that the likelihood of detecting bacteremia was not significantly enhanced by collecting BCs at the time of fever3.  Instead, obtaining an adequate blood volume (~40 – 60mL for each episode), and collecting ≥2 sets of BCs under strict aseptic technique were emphasized4. BCs should be obtained prior to antibiotic administration.

So in our patient, BCs should be obtained if sepsis is suspected, irrespective of fever.

 

References

  1. Thomson RB, et al. Timing of blood culture collection from febrile patients. Abstr. C-227. 89th Annual Meeting American Society of  Microbiology, Washington, DC, 1989. 
  2. Li J, et al.  Effects of volume and periodicity on blood cultures. J Clin Microbiol. 1994; 32:2829-2831. 
  3. Riedel S, et al. Timing of specimen collection for blood cultures from febrile patients with bacteremia. J Clin Microbiol. 2008;46:1381-1385.
  4. Clinical and Laboratory Standards Institute (CLSI). Principles and Procedures for Blood Cultures: Approved Guideline. 2007. CLSI document M47-A. Clinical and Laboratory Standards Institute, Wayne, PA

 

Contributed by Henrietta Afari, MD, Mass General Hospital, Boston, MA

When is the best time to obtain blood cultures (BCs) from my patient admitted with recent fevers?

What is the significance of smudge cells (SCs) on peripheral blood smear?

SCs (Photo), also known as “basket cells”, are remnants of B lymphocytes ruptured during slide preparation. Although at low numbers (~0-5% of lymphocytes), SCs may be observed in healthy individuals, when found at higher numbers (>10%)they are associated with chronic lymphocytic leukemia (CLL) and other lymphoproliferative diseases1; the percentage of SCs may not discriminate between these malignancies, however2.

For nearly a century, SCs were thought to be just an artifact of slide preparation resulting from the fragility of CLL cells3. Although the mechanism accounting for the appearance of SCs is still unclear, their formation is inversely correlated with B cell content of vimentin, a cytoskeletal protein essential for rigidity and integrity of lymphocytes 3-5. High vimentin expression is associated with an aggressive variant of CLL and shorter survival times3-5. Therefore, higher number of SCs at the time of CLL diagnosis (>20% or >30%) may actually indicate a better prognosis4-6!

smudgecellsarrow

Photo courtesy of U.S. National Library of Medicine

References

  1. Petrakis NL, Lieberman E, Fullerton J. The dead leukocyte content of the blood in normal and leukemic patients. Blood. 1957 Apr;12:367-72.
  2. Matos DM, Perini G, Kruzich C, Rego EM, Falcao RP. Smudge cells in peripheral blood smears did not differentiate chronic lymphocytic leukemia from other B-cell chronic lymphoprolipherative diseases. Rev Bras Hematol Hemoter. 2009;31:333–6.
  3. Nowakowski GS1, Hoyer JD, Shanafelt TD, et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J Clin Oncol. 2009;27:1844-9.
  4. Nowakowski GS, Hoyer JD, Shanafelt TD, et al. Using smudge cells on routine blood smears to predict clinical outcome in chronic lymphocytic leukemia: a universally available prognostic test. Mayo Clin Proc. 2007;82:449-53.
  5. Johansson P, Eisele L, Klein-Hitpass L, et al. Percentage of smudge cells determined on routine blood smears is a novel prognostic factor in chronic lymphocytic leukemia. Leuk Res. 2010;34:892-8.
  6. Gogia A, Raina V, Gupta R, et al. Prognostic and predictive significance of smudge cell percentage on routine blood smear in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2014;14(6):514-7.

 

Contributed by Khin-Kyemon Aung, medical student, Harvard Medical School, Boston.

 

 

 

 

 

 

 

 

 

What is the significance of smudge cells (SCs) on peripheral blood smear?