Saving the Horseshoe Crab: Why We Should Rethink BDG Testing

Today I want to wade into a probably controversial topic in diagnostics — the famous 1,3-β-d-Glucan (BDG).
I call it “controversial” because I think its utility is limited, and in most situations, it probably shouldn’t be ordered at all — especially now that blood culture yields for candidemia have improved and molecular testing in serum for fungi (including PJP) is more accessible.

First, what is BDG?

BDG is a polysaccharide that makes up much of the cell wall in most fungi.

Classic ID board question: Which fungi don’t have BDG?
Common answer: Cryptococcus spp., Blastomyces, and mucorales (Rhizopus, Mucor).
Reality:

• Cryptococcus does have BDG, but in very small amounts compared to other glucans (α-1,3-glucan, β-1,6-glucans), so most assays won’t detect it.

• Mucorales have cell walls mainly made of chitin, with BDG present in only trace quantities.

And here’s the twist — BDG tests don’t measure BDG directly. They detect BDG-mediated activation of the coagulation cascade in horseshoe crab amoebocyte lysate (yes, actual crab blood). Different assays even use different crab species.

The Evidence: Where BDG Fits (and Mostly Doesn’t)

The study by Lamoth et al. summarized BDG performance in invasive fungal infections (IFIs — mostly Candida and Aspergillus).
Results vary hugely depending on the patient group because performance is tied to pretest probability, immune status, comorbidities, and exposure history.

We’ll cover:

1. Hematologic malignancies / HSCT

2. Solid Organ Transplant (SOT)

3. ICU / invasive candidiasis

4. PJP

1. Hematologic malignancies / HSCT

• Study design: Main evidence comes from a European group led by Lamoth as well: six studies (mostly cohorts), five of which measured BDG once or twice weekly as part of a screening strategy.

• Patient population:

  • Allogeneic HSCT recipients or patients with acute leukemia undergoing prolonged chemotherapy-induced neutropenia (>10 days).

  • BDG compared to diagnosis of IFI by EORTC-MSG criteria, meaning they had not just host risk factors but also radiologic signs concerning for IFI such as halo sign, crescent sign, or cavitary lesions.

  • In other words, this was an extremely high pretest probability group before BDG was even sent.

• Results:

  • Sensitivity 61%, specificity 91%.

  • Specificity increased to 99% when two consecutive positives were required.

  • Another meta-analysis (White et al.) found much lower specificity (63%) in similar populations.

Clinical meaning:

• A positive BDG in this very high-risk population may support starting antifungals if clinical and imaging features fit.

• A negative BDG cannot reliably rule out IFI — sensitivity is low, so decisions still depend on clinical judgment.

2. Solid Organ Transplant (SOT)

• Available data: Mostly lung and liver transplant cohorts.

• Patient profile:

  • Post-transplant immunosuppression varies widely.

  • Many have complex post-operative courses with frequent infectious and non-infectious complications.

• Example: Duke lung transplant study (cutoff 60 pg/ml):

  • Sensitivity 64%, specificity 9%, PPV 14%, NPV 50%.

  • 92% of patients without IFI still had at least one BDG ≥60 pg/ml; 90% had ≥80 pg/ml.

• Interpretation: False positives are common — possibly due to colonization, frequent exposure to medical devices for Renal Replacement Therapy (RRT), transfusions, and antibiotics.

Clinical meaning:

• In SOT patients, BDG results (positive or negative) rarely change management — pretest probability is too variable and specificity is too low.

3. ICU

• Context: Most ICU BDG testing focuses on suspected invasive candidiasis.

• Patient profile:

  • High rates of colonization, frequent exposure to medical devices for RRT, transfusions, and broad-spectrum antibiotics.

  • Frequent comorbidities (renal replacement therapy, major surgery, trauma requiring multiple gauzes).

• False positive sources:

  • One of my favorite cautionary tales is a case report of a patient who underwent CABG with blood conservation techniques — blood aspirated from the surgical sponges was reinfused. When they tested the sponge, BDG concentrations were more than 10,000 times higher than human serum levels. No fungus, just a whole lot of glucan.

  • Hemodialysis cellulose membranes.

  • Albumin or platelet transfusions.

  • Piperacillin-tazobactam and possibly other penicillins.

• Performance: Most studies find NPV >90%, PPV <70%.

Clinical meaning:

• A negative BDG can be used to justify stopping antifungals in high-risk ICU patients who are already on antifungal therapy. (Discussion on why someone is already on antifungal therapy for invasive candidiasis to be discussed in another post).

• A positive BDG generally should not trigger antifungals — unless maybe in very high-risk post-abdominal surgery patients (recurrent GI perforation, hepatobiliary leaks, necrotizing pancreatitis, or Candida score ≥3) with two consecutive positive BDG, where PPV rises to 70–80%.

• No role for invasive mold infection (mainly aspergillus) diagnosis in ICU patients.

4. PJP (Pneumocystis jirovecii pneumonia)

• Meta-analysis (Karageorgopoulos): Sensitivity 94.8%, specificity 86.3%.

• Patient profile:

  • High pretest probability in HIV/AIDS with bilateral infiltrates, hematologic malignancy with lung infiltrates, solid tumor patients on prolonged steroids, and other profoundly immunocompromised hosts.

• Use case:

  • A negative BDG in low-suspicion cases can help rule out PJP and shift focus to other diagnoses.

  • A positive BDG in moderate/high suspicion cases supports diagnosis if clinical and imaging findings align.

Take-Home Decision Guide

General

• Limited utility in most settings.

• Best reserved for patients with an already high pretest probability for IFI or PJP — not routine ordering.

Hematologic malignancies / HSCT

• Positive BDG may support starting antifungals ONLY if patient already has very high clinical/radiologic suspicion.

• Negative BDG should not be used to rule out IFI.

Solid Organ Transplant

• Test performance too poor to meaningfully guide therapy; avoid using BDG for IFI decisions.

ICU

• Negative BDG can help stop antifungals in high-risk patients who are already on therapy.

• Positive BDG should not trigger antifungals maybe except in very high-risk post-abdominal surgery cases (recurrent gastro-intestinal tract perforation or hepatobiliary anastomotic leakage, necrotizing pancreatitis or Candida score ≥ 3) with repeat positive BDG.

• No role for invasive mold infections

PJP

• Negative BDG can help rule out PJP when suspicion is low.

• Positive BDG in moderate/high suspicion cases supports diagnosis if clinical and radiologic findings match.

MUSICAL CODA 🎶

This is my longest post yet — thanks for sticking with me!
If we all use BDG more thoughtfully, maybe we can even turn this into a conservation project: save the horseshoe crab, order less BDG.