How useful is serum 1, 3-β-D-glucan in diagnosing Pneumocystis jiroveci pneumonia and invasive fungal disease?

Serum 1, 3-β-D-glucan (BG) is highly accurate for Pneumocystis jiroveci pneumonia (PJP), but only moderately accurate for diagnosing invasive fungal disease (IFD).

For PJP, a meta-analysis of studies looking at the performance of BG found a pooled sensitivity of 96%, specificity of 84% and area under receiver operating characteristic curve (AUC-ROC) of 0.96. 1 Thus, a negative BG essentially rules out PJP.

For IFD (primarily invasive candidiasis or aspergillosis), data based on 3 separate meta-analyses came to similar conclusions with a pooled sensitivity and specificity of ~80% and AUC-ROC of ~0.89 each.1-3 In some of the studies,2,3 the sensitivity of BG for IFD was between 50% to 60% which makes it difficult to exclude IFD when BG is normal.

Remember that BG may be false-positive in a variety of situations, including patients receiving immunological preparations (eg albumin or globulins), use of membranes and filters made from cellulose in hemodialysis, and use of cotton gauze swabs/packs/pads and sponges during surgery. 1 In addition, although BG is a component of the cell wall of most fungi, there are some exceptions including Zygomycetes and cryptococci.

Bonus pearl: Did you know that BG assay is based on Limulus amoebocyte lysate, extracted from amoebocytes of horseshoe crab species? 3

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References

  1. Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol 2012;50:7-15. https://www.ncbi.nlm.nih.gov/pubmed/22075593
  2. He S, Hang JP, Zhang L, et al. A systematic review and meta-analysis of diagnostic accuracy of serum 1,3–β-D-glucan for invasive fungal infection: focus on cutoff levels. J Microbiol Immunol Infect 2015;48:351-61. https://www.ncbi.nlm.nih.gov/pubmed/25081986
  3. Karageogopoulos DE, Vouloumanou EK, Ntziora F, et al. β-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 2011;52:750-69. https://academic.oup.com/cid/article/52/6/750/361658/

 

How useful is serum 1, 3-β-D-glucan in diagnosing Pneumocystis jiroveci pneumonia and invasive fungal disease?

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

 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?

Is there a connection between trehalose, a natural sugar found in many foods, and Clostridioides difficile disease (CDD)?

There is experimental and epidemiological evidence that trehalose in the diet may enhance the virulence of the epidemic strains (eg. Ribotype 027) of C. difficile (1). 
Many of us may not be familiar with trehalose. It’s a disaccharide composed of 2 glucose molecules and found widely in nature, including bacteria, fungi (eg mushrooms, Brewer’s yeast), plants, insects, other invertebrates, but not vertebrates (2).

Since its approval by the FDA as a natural food additive in 2000, trehalose is increasingly used for its unique properties (including flavor enhancer and moisture stabilizer) in a variety of foods, including ice cream, pasta, ground beef, and sushi. Although in humans trehalose is enzymatically broken down to glucose by the brush borders of intestinal mucosa, intact trehalose is also found in the lower GI tract where C. difficile thrives.

 
In a series of intriguing experiments involving the interaction between trehulose and C. difficile published in Nature in 2018, Collins et al found that RT027 strain of C. difficile had acquired unique mechanisms to metabolize low concentrations of trehalose and that dietary trehalose increased its virulence associated with high mortality in a mouse model of infection even in the absence of antibiotic exposure. They further demonstrated that when human diet was simulated (eg, at concentrations suggested in ice cream), trehalose levels in the cecum of the mice were sufficient to induce production of the enzyme phosphotrehalase by the same strain in vitro by over 400X in the absence of antibiotics and by over 1000X in the presence of antibiotics. Similar results were found in the ileostomy fluid samples of 2 of 3 volunteers consuming normal diet (1). 

 
Equally fascinating is the epidemiological evidence that the timelines of trehalose adoption as a food additive in 2000, subsequent uptick in the number CDDs in the US, as well as the spread of RT027 strain in many countries seem to overlap (1).

 
These observations may at least partially explain the frequently severe nature of CDD during the past 2 decades as well why a significant proportion (up to a-third) of patient with CDD appear to have no recent exposure to antibiotics or hospitalization (3-5).  An epidemiological study examining the dietary habits of patients with CDD without apparent risk factors is in order. Stay tuned!

 
Bonus Pearl: Did you know that trehalose is classified as “generally regarded as safe” (GRAS)  natural food additive by the FDA and may be listed as “added sugar” or “natural flavor” on the food packaging?

 

References
1. Collins J, Robinson C, Danhof H, et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature 2018;553;291-96. https://www.nature.com/articles/nature25178
2. Avonce N, Mendoza-Vargas A, Morett E, et al. Insights on the evolution of trehalose biosynthesis. BMC Evol Biol 2006;6:109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769515/
3. Wilcox MH, Mooney L, Bendall R, Settle CD et al. A case-control study of community-associated Clostridium difficile infection. J Antimicrob Chemother 2008;62:388-96. https://www.researchgate.net/publication/5419268_A_case-control_study_of_community-associated_Clostridium_difficile_infection
4. Severe Clostridium difficile-associated disease in populations previously at low risk. MMWR2005;54:1201-5. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm
5. Halvorson SAC, Cedfeldt AS, Hunter AJ. Fulminant, non-antibiotic associated Clostridium difficile colitis following Salmonella gastroenteritis. J Gen Intern Med 2010;26:95-7.

 

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Is there a connection between trehalose, a natural sugar found in many foods, and Clostridioides difficile disease (CDD)?