My 35 year old patient with Crohn’s disease has peripheral neuropathy but no anemia or macrocytosis. Could he still have vitamin B-12 deficiency?

Absolutely! A significant number of patients with B-12 deficiency are neither anemic nor have macrocytosis but may still have related neurological symptoms.

A large study involving a nationally representative sample of older U.S. adults (aged >50 y) sponsored by the CDC reported a prevalence of B-12 deficiency without anemia or without macrocytosis of about 4% each . 1 Interestingly, in this study,  there was no evidence that mandatory folic acid fortification of certain foods was associated with lower prevalence of B-12 deficiency without anemia or macrocytosis.

In another study, the proportion of subjects with low serum B-12 but without macrocytosis was 70% or higher, irrespective of pre- or post-fortification period.2 Interestingly, in the age group <65 y, the post-fortification was associated with significantly higher proportion of patients without macrocytosis (85% vs. 45% in the prefortification period) in this study.

Younger age groups seem to also be overrepresented among patients with B-12 deficiency but no anemia, with a prevalence of 50% in <60 y age group with B-12 deficiency compared to 38% and 31% among older age groups (60-74 y and >74 y, respectively).3

So, keep B-12 deficiency in mind in the presence of compatible neurological symptoms even in the absence anemia or macrocytosis!

 

References

  1. Qi YP, Do AN, Hamner HC, et al. The prevalence of low serum vitamin B-12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 2014;144:170-76. http://jn.nutrition.org/content/144/2/170.abstract
  2. Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am J Clin Nutr 2007;86:1187-92. https://www.ncbi.nlm.nih.gov/pubmed/17921401
  3. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-7. http://ajcn.nutrition.org/content/77/6/1474.full.pdf+html
My 35 year old patient with Crohn’s disease has peripheral neuropathy but no anemia or macrocytosis. Could he still have vitamin B-12 deficiency?

What does an “indeterminate” result in QuantiFERON Gold in-Tube test for latent tuberculosis really mean?

Anindeterminate” QuantiFeron Gold in-Tube (QFT-IT) simply means the result can’t be interpreted. It does NOT mean “intermediate” or “borderline positive”!

Although there are several reasons for an indeterminate QFT-IT, a common explanation is an immunocompromised state involving inadequate T-cell response (eg, corticosteroids, HIV, cancer). Improper storage of tubes and specimen handling, baseline elevated interferon (IFN)-ɣ due to heterophile antibodies, recovery phase of an infection or vaccination may also be associated with indeterminate QFT-IT results. 1,2 For these reasons, the test should be repeated for confirmation.

It all makes more sense if we understand the basis for the test. QFT-IT involves blood obtained in 3 separate test tubes:

  • Tube 1: Contains only the patient’s blood with nothing added (NIL) (“Negative control”)
  • Tube 2: Contains non-specific mitogens that stimulate patient’s T-cells (“Positive control”)
  • Tube 3: Contains specific TB antigens

Since QFT-IT is an IFN- ɣ release assay, IFN- ɣ is measured in each tube after 16-24 h incubation. A negative QFT-IT is when there is not much difference between IFN- ɣ levels in negative control and TB tubes (“TB-[minus]NIL”) AND the positive control works (“MITOGEN-[minus]NIL” is elevated).

You can now see why a negative result in the TB tube doesn’t mean much (ie, the result is “indeterminate”) when the T-cells don’t respond to non-specific antigens.  This situation is analogous to calling a PPD “negative” when a patient is anergic!

References

  1. Herrera V, Yeh E, Murphy K, et al. Immediate incubation reduces indeterminate results for QuantiFERON-TB Gold in-Tube assay. J Clin Microbiol 2010;48:2672-2676. http://jcm.asm.org/content/48/8/2672.full
  2. Bui DHP, Cruz AT, Graviss EA. Indeterminate QuantiFERON-TB Gold in-Tube assay results in children. Ped Infect Dis J 2014; 33: 220-22. https://www.ncbi.nlm.nih.gov/pubmed/24413410
What does an “indeterminate” result in QuantiFERON Gold in-Tube test for latent tuberculosis really mean?

200 pearls and counting! Take the Pearls4Peers quiz #2!

Multiple choice (choose 1 answer)
1. Which of the following classes of antibiotics is associated with peripheral neuropathy?
a. Penicillins
b. Cephalosporins
c. Macrolides
d. Quinolones

 

 

2. The best time to test for inherited thrombophilia in a patient with acute deep venous thrombosis is…
a. At least 1 week after stopping anticoagulants and a minimum of 3 months of anticoagulation
b. Just before initiating anticoagulants
c. Once anticoagulation takes full effect
d. Any time, if suspected

 

 

3. All the following is true regarding brain MRI abnormalities following a seizure, except…
a. They are observed following status epilepticus only
b. They are often unilateral
c. They may occasionally be associated with leptomeningeal contrast enhancement
d. Abnormalities may persist for weeks or months

 

 

4. Which of the following is included in the quick SOFA criteria for sepsis?
a. Heart rate
b. Serum lactate
c. Temperature
d. Confusion

 

 

5. All of the following regarding iron replacement and infection is true, except…
a. Many common pathogens such as E.coli and Staphylococcus sp. depend on iron for their growth
b. Association of IV iron replacement and increased risk of infection has not been consistently demonstrated
c. A single randomized-controlled trial of IV iron in patients with active infection failed to show increased infectious complications or mortality with replacement
d. All of the above is true

 

True or false

1. Constipation may precede typical manifestations of Parkinson’s disease by 10 years or more
2. Urine Legionella antigen testing is >90% sensitive in legionnaire’s disease
3. Spontaneous coronary artery dissection should be particularly suspected in males over 50 years of age presenting with acute chest pain
4. Urine dipstick for detection of blood is >90% sensitive in identifying patients with rhabdomyolysis and CK >10,000 U/L
5. Diabetes is an independent risk factor for venous thrombophlebitis

 

 

 

Answer key
Multiple choice questions:1=d; 2=a;3=a;4=d;5=c
True or false questions:1=True; 2,3,4,5=False

 

200 pearls and counting! Take the Pearls4Peers quiz #2!

The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Not as well as you might think!

Legionella urine antigens are 60%-80% sensitive (>99% specific) for detecting L. pneumophila serogroup 1 which accounts for about 70%-80% of Legionnaire’s disease (LD) in the US1; there are at least 15 serogroups.2 So as many as 40% or more LD may be missed by urine antigen testing alone. 2 Urine antigen can be excreted as early 3 days after the onset of symptoms and can persist for >300 days which may present a problem in diagnosing a current illness in patients with recurrent pneumonia. 2 One study reported lowest sensitivity (80%) for antigen testing during days 4 to 7 days of symptoms.3Other means of looking for Legionella include culture of respiratory samples for L. pneumophila which can detect all types of Legionella species (sensitivity 20%-80%) but has a lengthy turnaround time. Paired antibody testing may also be performed (sensitivity 70%-80%) in undiagnosed cases of severe pneumonia. 1Take home point: Don’t depend totally on urine antigen testing to rule out LD.

Final fun fact: Did you know that legionellae survive in the aquatic environment by parasitizing free-living protozoa?

References

  1. CDC. Legionellosis: United States, 2000-2009. MMWR 2011;60:1083-86. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6032a3.htm
  2. Fields BS, Benson RF, Besser RE. Legionella and Legionnaire’s disease: 25 years of investigation. Clin Micro Rev 2002;15:506-26. https://www.ncbi.nlm.nih.gov/pubmed/12097254  
  3. Kohler RB, Zimmerman SE, Wilson E, et al. Onset and duration of urinary antigen excretion in Legionnaire’s disease. J Clin Microbiol 20:605-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC271393
The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

There is virtually no utility to obtaining heritable thrombophilia testing in acute hospital setting. In fact, there are potential harms due to false-positive and false-negative results which in turn may lead to increasing anxiety in the patient and added cost due to repeat testing.

As many tests obtained as part of this workup are functional assays—eg, the protein S, C, or antithrombin activity, and activated protein C resistance (often used to screen for factor V Leiden)— they are easily impacted by the physiologic effects of acute thrombosis as well as all anticoagulants.1

More importantly, testing for inherited thrombophilia will not impact management in the acute setting, as decisions regarding duration of anticoagulation are often made later in the outpatient setting. The proper time to evaluate the patient for inherited thrombophilias (if indicated) is at least one week following discontinuation of anticoagulation (minimum 3 months from the time of the index event). 2 

Testing for antiphospholipid syndrome (APS) may be considered in this setting though it should be noted that the lupus anticoagulant assay is impacted by nearly every anticoagulant, resulting in frequent false-positive results1, and therefore should be performed before initiation of these agents (or delayed until later if anticoagulation has already begun). A false-positive result has downstream implications as many patients with acute, uncomplicated venous thromboembolism (VTE) are discharged on a direct oral anticoagulant (DOAC), and antiphospholipid syndrome is currently considered a relative contraindication to the use of DOACs in VTE.

References
1. Moll, S. “Thrombophilia: Clinical-practical aspects.” J Thromb Thrombolysis 2015;39:367-78. https://www.ncbi.nlm.nih.gov/pubmed/25724822
2. Connors JM. “Thrombophilia Testing and Venous Thrombosis.” N Engl J Med 2017; 377:1177-1187. http://www.nejm.org/doi/full/10.1056/NEJMra1700365 

Contributed by Hanny Al-Samkari, MD, Mass General Hospital, Boston, MA

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Continue reading “Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?”

Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

Are two sets of blood cultures adequate for evaluation of bacteremia in my febrile patient?

For great majority of patients, more than 2 sets of blood cultures is not likely to significantly improve the yield of detecting bacteremia. 

Although a 2004 report suggested that 2 sets of blood cultures over 24 h period had a sensitivity of only 80% for bacteremia, several other studies have found much higher sensitivities, ranging from ~90%- 99% 2-3. When broken down by organism, sensitivity of 2 sets of blood cultures may be highest for Staphylococcus aureus (97%), followed by E. coli (91%), and Klebsiella pneumoniae (90%) 2.  The Clinical and Laboratory Standards Institute guidelines recommend paired blood culture sets (each set with 2 bottles, 10 ml of blood in each) to detect about 90-95% of patients with documented bacteremia, and 3 sets for 95-99% detection rate 4.

It seems prudent to strike a balance between drawing more than 2 sets of blood cultures—with its attendant risk of picking up contaminants— and what may be a definite but small incremental increase in the rate of detection of true bacteremia.

Whatever you do,  please don’t order only 1 set of blood cultures! Aside from its generally low yield, when positive it may be difficult to distinguish contaminants from true invaders.

 

References

  1. Cockerill FR, Reed GS, Hughes JG, et al. Clinical comparison of BACTEC 9240 Plus Aerobic/F resin bottles and the Isolator aerobic cultures. Clin Infect Dis 2004;38:1724-30. https://www.ncbi.nlm.nih.gov/pubmed/9163464
  2. Lee A, Mirrett S, Reller LB, et al. Detection of bloodstream infections in adults: how many cultures are needed? J Clin Microbiol 2007; 45:3546-48. http://jcm.asm.org/content/45/11/3546
  3. Towns ML, Jarvis WR, Hsueh PR. Guidelines on blood cultures. J Microbiol Immunol Infect 2010;43:347-49. https://www.ncbi.nlm.nih.gov/pubmed/20688297
  4. Weinstein MP, Reller LB, Murphy JR, et al. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and eipidemiologic observations. Rev Infect Dis 1982;5:35-53. https://www.ncbi.nlm.nih.gov/pubmed/6828811
Are two sets of blood cultures adequate for evaluation of bacteremia in my febrile patient?

What is the utility of urine dipstick for blood in diagnosing rhabdomyolysis?

Although the dipstick method of detecting blood in the urine is convenient, it cannot differentiate between hemoglobin, myoglobin, or red blood cells. 1

Several reviews suggest that urine myoglobin is unstable with subpar performance in rhabdomyolysis1, often defined as creatine kinase (CK) elevation 5 times the upper limit of normal in the proper context (eg, crush injury, hypoxic/ischemic or drug injury). A sensitivity of 71% and a specificity of 54% for urine hemoglobin by dipstick, and a sensitivity of 25% and specificity of 75%  for urine myoglobin  has been reported in patients with serum CK >10,000 U/L. 3  

So while a positive dipstick for blood with few or no RBCs in the urine may make us think about rhabdomyolysis, its absence should not be used to exclude it in a susceptible host.

Final fun pearl: Did you know that consumption of quail has been associated with rhabdomyolysis, possibly due to their feeding on poisonous plants such as hemlock?

References

  1. Rodriguez-Capote Karina, Balion CM, Hill SA, et al. Utility of urine myoglobin for the prediction of acute renal failure in patients with suspected rhabdomyolysis: A systematic review. Clin Chem 2009;55:2190-97. https://www.ncbi.nlm.nih.gov/pubmed/19797717
  2. Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis. Muscle Nerve 2015;51:793-810. https://www.ncbi.nlm.nih.gov/pubmed/25678154
  3. Grover DS, Atta MG, Eustace JA, et al. Lack of clinical utility of urine myoglobin detection by microconcentrator ultrafiltration in the diagnosis of rhabdomyolysis. Nephrol Dial Transplant 2004;19:2634-38. https://www.ncbi.nlm.nih.gov/pubmed/15280520
What is the utility of urine dipstick for blood in diagnosing rhabdomyolysis?