Distinguishing Mucormycosis from Aspergillosis – A Clinical Perspective

February 24, 2024

Back
Featured image for “Distinguishing Mucormycosis from Aspergillosis – A Clinical Perspective”

Invasive mold infections caused by organisms like Aspergillus or the Mucorales order have emerged as deadly complications in the critically ill following COVID-19 treatment involving immunosuppression and oxygen therapy.

Prompt identification of the exact pathogen guides appropriate antifungal selection in these aggressive angioinvasive diseases where delays prove fatal. This article examines key features differentiating pulmonary aspergillosis from rhino-orbital mucormycosis with insights on special stains assisting diagnosis.

Understanding Mold Infections

In healthy individuals, molds like Aspergillus present in environment seldom cause issues – our immune defenses eliminate occasional spores inhaled or ingested. However, in disease states compromising immunity like :

  • Uncontrolled diabetes
  • Steroid treatment
  • Organ failure
  • Neutropenia
  • Metabolic acidosis

These opportunists assume pathogenic forms – either by fungal overproliferation (aspergillosis) or vascular invasion (mucormycosis). Clinical disease represents the tip of an iceberg, its genesis extending back weeks through low-grade colonization.

High risk categories include:

  • Long term ICU cases with secondary infections
  • Post-transplant / chemotherapy cases
  • Severe COVID pneumonia treated with tocilizumab / high flow oxygen

Manifestations encompass a spectrum – from mild allergic stimulus to localized sinusitis through disseminated multiorgan failure with sepsis. Mortality exceeds 50% in advanced cases. Hence identifying causal species is vital for survival.

70

Overview of Aspergillosis

Aspergillus represents a ubiquitous mold – over 250 species are known. Fortunately, only a handful cause human disease. Key culprits are:

  • A. fumigatus – most common variant causing 90% of infections
  • A. flavus
  • A. niger
  • A. terreus

Inhalation of conidia (spores) allows their germination within lung tissue – this remains the foremost site affected. However Aspergillus also spreads hematogenously to other organs in disseminated cases.

Immunocompetent hosts limit invasive disease through macrophage phagocytosis of spores combined with neutrophil fungicidal activity. However where such responses fail, uncontrolled fungal proliferation into tissue occurs manifesting as:

Clinical Forms

  • Chronic pulmonary aspergillosis – Cavitary lesions, nodules, fibrosis post-tuberculosis scars
  • Aspergilloma – Fungus ball in existing lung cavity causing hemoptysis
  • Allergic bronchopulmonary aspergillosis (ABPA) – Asthmatic attacks, eosinophilic pneumonitis following sensitization
  • Invasive aspergillosis – Vascular invasion into lungs or dissemination with multiorgan failure

This spectrum highlights Aspergillus’ pathophysiology – interference in immune regulation, toxin-mediated necrosis and angioinvasion with infarcts.

Severe forms have mortality exceeding 80% if undiagnosed – demanding accurate identification both through culture and special stains. Management requires both antifungal therapy and immunotherapy modulation for lasting recovery.

Mucormycosis Pathophysiology

The term mucormycosis broadly refers to invasive mold infections by fungi of the Mucorales order from genera like Rhizopus, Mucor, Rhizomucor etc. They produce ribbon-like pauciseptate hyphae with right angle branching.

While spore inhalation or inoculation can occur after trauma, uncontrolled diabetes with ketoacidosis seems particularly vulnerable owing to the acidic, hyperglycemic environment favoring uninhibited sporangiospore growth.

As fungi proliferate, they invade vessels – both arteries and veins. This triggers thrombosis and tissue infarction with black necrotic eschars allowing further rapid spread. The predilection for vascular rather than airway invasion sets mucormycosis apart and underlies its aggressive course.

Common sites affected are:

  • Rhino-orbital – Facial swelling, sinusitis with dark bloody discharge
  • Pulmonary – Breathlessness, hypoxia, diffuse alveolar infiltrates
  • Cutaneous – Wound infections with necrosis following trauma
  • Disseminated – Multiorgan failure with shock

Delays beyond 2 weeks of symptom onset lead to mortality exceeding 80%. Hence clinical suspicion must be followed by confirmatory tests that differentiate causative species for guiding therapy.

Key Diagnostic Differences

Given their angioinvasive potential, isolating Aspergillus or Mucorales on culture alone lacks sufficient sensitivity in invasive disease. Culture positivity ranges 30-50% – further limited by prior antifungal exposure.

Alongside, biopsies for histopathology and fungal staining provide vital visual confirmation within tissues. Imaging reveals suggestive lesions. And serological markers add supporting evidence of mold infection.

Histopathology

Microscopic morphology can quickly differentiate the two molds:

FeatureAspergillusMucormycosis
SeptationRegular, dichotomous branching septate hyphaeBroad non-septate hyphae
Width3-6 μm6-25 μm
BranchingAcute angles ~45°Right angles ~90°
StainingGMS positiveWeakly positive on GMS / H&E
VesselsArterial wall invasionArterial + venous invasion with thrombosis

Aspergillus hyphae are uniform in diameter with regular septation whereas Mucorales have ribbon-like folds and minimal cross walls. Branching morphology also differs – Mucorales at perpendicular whereas Aspergillus shows acute angles.

Silver stains like GMS highlight Aspergillus cell walls brown but Mucorales stain weakly requiring careful examination.

Culture

Both organisms grow well on routine media at 25°C. Sabouraud agar with antibiotics detects mejority of cases. However some species like A. terreus need specific media.

Aspergillus shows fast-growing wooly colonies initially white then black conidia. Microscopy reveals characteristic biseriate conidiophores.

Whereas Mucor has a more fluffy cotton-like growth habit on media. Rhizoids fuse to form sporangiophores releasing many spherical sporangiospores unique to Mucorales.

Molecular tests like PCR offer 100% specificity but have limited sensitivity in culture-negative cases. Multiplex platforms can detect multiple gene targets from lower burden infections.

Imaging Patterns

Thin-section CT offers vital clues differentiating invasive fungal disease:

AppearanceAspergillosisMucormycosis
NodulesMultiple solid nodules +/- cavitationRare, peripheral cavities
InfarctsWedge-shaped, peripheralReverse halo, central cavitation
OtherHalo sign, air crescent signEffusion more common

Aspergillosis manifests as solid pulmonary nodules with occasional central break down. However mucormycosis shows multiple pulmonary infarcts with surrounding ground glass opacity and effusion – the reverse halo sign.

Crescentic peripheral cavities in aspergillosis indicate immune recovery. However central necrosis in mucormycosis reflects invasive progression.

Biomarkers

Certain serological tests support invasive fungal disease through detection of cell wall components released during tissue invasion:

MarkerOriginUtility
GalactomannanAspergillus cell wallSensitive, specific for aspergillosis
1,3-Beta-D-glucanMost fungiLow levels in mucormycosis
Mucorales DNABlood PCRConfirms mucormycosis

Platelia Aspergillus galactomannan EIA shows excellent sensitivity and specificity for detecting aspergillosis. However it is negative in case of mucormycosis.

Conversely beta-d-glucan, though elevated in over 70% of aspergillosis, proves less useful in mucormycosis with low levels.

Hence the combined picture from histopathology, culture, imaging and serology achieved maximal diagnostic accuracy. Molecular assays further validate difficult cases.

Treatment Considerations

Correct speciation determines antifungal drug choice and influences adjunctive measures like immunotherapy or surgical debridement.

55

Antifungal Agents

European guidelines recommend:

DiseaseFirst lineAlternatives
Invasive aspergillosisVoriconazoleL-AmB, posaconazole, isavuconazole
MucormycosisLiposomal amphotericin BPosaconazole, isavuconazole combinations

Azoles like voriconazole show excellent penetration into lung and brain tissue making them suitable for aspergillosis. However Mucorales display innate resistance to voriconazole – requiring polyene amphotericin B.

Newer agents like isavuconazole offer oral step-down therapy in stable patients. Combinations overcome toxicity and prevent emergence of further antifungal resistance.

Host Modulation

Immunomodulation for improving outcomes involves:

ConditionApproach
AspergillosisReduce steroid exposure < 0.7 mg/kg < 12 weeks < 20 mg/day < 6 months < 10 mg/day
MucormycosisStrict diabetic control – insulin drips, hydration, electrolyte correction

Steroid tapering aims to preserve sufficient host immunity for fungal control while preventing rebound inflammation.

For mucormycosis, achieving euglycemia is vital as persistence of high blood sugars despite antifungals leads to treatment failure and progression.

Debridement

Unlike aspergillosis, mucormycosis requires urgent surgical debridement of visible necrosis and involved sinus tissue to decrease fungal burden and vascular spread. This is often extensive given angioinvasion.

Plastic surgery later allows grafting to cover resultant defects esp. in rhino-orbital disease. However such reconstruction can only succeed after infection is controlled with systemic antifungals.

Prevention Strategies

Preventing healthcare associated mold infections involves multifaceted efforts:

  • Protecting immunocompromised patients from nosocomial exposure
  • Avoiding blind corticosteroid therapy without infection assessment
  • Limiting broad spectrum antimicrobial overuse
  • Strict diabetic monitoring in high-risk subgroups
  • Prompt investigation of suggestive lesions

Wider environmental strategies like better indoor air standards in healthcare facilities, fungal spore monitoring and food/water safety regulations also help by reducing community acquisition.

Conclusion

Invasive aspergillosis and mucormycosis demand early consideration in critically ill patients with risk factors like uncontrolled diabetes, steroid use or immunocompromised states.

Careful comparison of histopathologic morphology, culture characteristics, imaging and biomarkers accurately determines the causal species – guiding choice of antifungal agent as well as adjunctive surgical or immunologic support needed to prevent mortality exceeding 50% seen with delays.

Integrating conventional and molecular diagnostic modalities is vital for maximizing outcomes. This must be followed by personalized therapy incorporating patient factors and institutional epidemiology.

With prevalence projected to increase post-pandemic, physicians will need heightened vigilance and protocols supporting rapid evidence-based management of angioinvasive mold infections.

Frequently Asked Questions

How do you confirm mucormycosis versus aspergillosis?

Definitive diagnosis of mucormycosis versus aspergillosis requires culture and histopathology from infected tissuecombined with tests like PCR, imaging and fungal antigen assays to distinguish the two entities based on microscopic and radiologic features along with biomarker profiles.

What is the best initial test for invasive aspergillosis?

Galactomannan antigen testing shows high sensitivity and specificity exceeding 85% for detecting invasive aspergillosis among at-risk patients. Levels > 0.5 by the Platelia EIA assay indicate probable disease.

How do you treat mixed mold infections?

Combined infections by Aspergillus and Mucorales are complex – requiring broader spectrum antifungals like liposomal amphotericin B along with both surgical debridement of mucor lesions plus immunotherapy modulation for aspergillosis. Species-specific PCR guides tailored secondary antifungal regimens.

What are the symptoms of invasive mucormycosis?

Rhino-orbital mucormycosis presents with facial pain and swelling, black bloody nasal discharge and tissue necrosis signaling vascular invasion. Disseminated disease causes sepsis-like pictures with shock, DIC and end-organ failure though pulmonary cases may show breathlessness.

Why is voriconazole not used for mucormycosis?

Unlike Aspergillus, the Mucorales order displays intrinsic resistance to voriconazole due to differences in ergosterol synthesis pathways. Hence azoles prove ineffective with reported failure rates over 60% – demanding alternate broad spectrum amphotericin B therapy to control mucor infections.

Key Takeaways

  • Invasive aspergillosis and mucormycosis display key differences in risk factors, histopathologic morphology, culture characteristics and biomarker profiles.
  • Galactomannan antigen assays are useful for diagnosing aspergillosis while Mucorales PCR provides specificity in differentiating mucormycosis.
  • Choice of first line antifungal agent relies on accurately identifying inciting species – voriconazole for aspergillosis while liposomal amphotericin B forms essential therapy for mucormycosis.
  • Control of underlying diabetes along with extensive surgical debridement of infected tissue supplements medical management of mucormycosis whereas steroid sparing and immunotherapy modulation improves aspergillosis outcomes.
  • Further research into novel fungal antigens, multiplex PCR platforms and adjunctive immunotherapies can enhance the ability to tackle these aggressive angioinvasive diseases.

Prompt diagnosis and tailored therapy based on the causative mold remains key to survival in invasive fungal disease.

71

References

  1. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
  2. Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405-e421.
  3. Skiada A, Lanternier F, Groll AH, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica. 2013;98(4):492-504.
  4. Chang DC, Olczak-Kowalczyk D, Das S, et al. Toward Optimization of Imaging Strategies for Invasive Pulmonary Aspergillosis in the Immunocompromised Host. J Thorac Imaging. 2017;32(4):228-244.
  5. Gavaldá J, Meije Y, Fortún J, et al. Invasive Fungal Infections in Solid Organ Transplant Recipients. Clin Microbiol Rev. 2014;27(4):522-547.
Rate this post

Related articles



Image
Image

MIRARI®
Cold Plasma System

The world's first handheld cold plasma device

Learn More


Made in USA

Image