A Quick Introduction to the Pathogenesis, Diagnosis, Pathology and Treatment of Aspergillosis with case study for the Physician

Aspergillosis is a non contagious disease caused by fungi of the genus Aspergillus (usually A. fumigatus). Other potentially pathogenic species are A. flavus, A. nidulans, A. deflectus, A. niger and A. terreus . These fungi occur widely in nature and the usual mode of infection is by inhalation (3-5 u) with the resulting production of granulomatous lesions and nodules in the respiratory tract from which there may be dissemination to other tissues and organs. A. fumigatus is thermophillic (+ 37 C). In the immuocompetent host the pulmonary defense mechnisim is generally very effective in defending against its invasion. An exception to this is after damage to the lungs by influenza. Spores  are ingested by macrophages of the immune system and hypahe extracelluarly by neutrophils. Infections may also, but less frequently, begin in the alimentary tract. Disseminated aspergillosis originating from pulmonary or intestinal aspergillosis is a rare disease. It is more common in immunosuppressed humans and in those under prolonged antibiotic treatment.

Diagnosis -  In general diagnosis is usually based on the isolation and identification of the Aspergillus species from appropriate clinical specimens and the demonstration of typical septate hyphae in biopsies or tissue sections.  Disseminated aspergillosis is probably most often diagnosed following necropsy. *More recent reports indicate that fungal sinusitis is more common than previously thought. Fulminant Aspergillosis is usually seen in immunosuppressed patients, and chronic invasive Aspergillus sinusitis, allergic Aspergillus sinusitis and Aspergilloma are seen in the non-immunocompromised individual

Treatment - If diagnosed antemortem it is treated long term with itraconazole or amphotericin B.

Atlas of Clinical Fungi, S. DeHoog, J. Guarro,  R. Samson, CBS 2004,   Fungal Disease of the Lung - Sarosi, Davies  -  Lippincott 2000*British Journal of Radiology, Vol 66, Issue 783 260-263, 1993, Mayo Clinic Proceedings in September, 1999

Patient Case Study- Christopher N. Prichard, M.D. December 9, 2004 **

59-year-old Hispanic female who presented  with several days of nausea, vomiting, blurry vision, and increasing peri-orbital pain. She denied cough, fevers, chills, sweats or recent weight loss. She also denied headache, nasal congestion or rhinorrhea. Her vision had been worsening for the previous five days.

Past medical history is notable for type II diabetes mellitus, a left above-knee amputation, and bilateral cataract surgery. She currently controls her diabetes with glucovance. She has no history of alcohol, tobacco, or recreational drug use.

Physical examination revealed a pleasant female with notable right eye proptosis and peri-orbital edema. She was afebrile with stable vital signs. Cranial nerve examination revealed significant deficits of CN III, IV and VI on the right. Pupillary response was not detected secondary to post-surgical change. There was no maxillary sinus tenderness. Nasal endoscopy revealed right middle turbinate edema without discoloration or eschar. There was mild purulence from the posterior nasal cavity/ethmoid region.

Admission laboratory data revealed sodium of 111, potassium of 3.3, and BUN/ creatinine of 13/0.6. Her glucose was 137. WBC was 4.8 with 69% neutrophils. Hemoglobin/hematocrit was 9.7/27.8, and platelet count was 308,000. An HIV test was negative.

A diagnosis of SIADH was established, and the patient was admitted to the medical intensive care unit for fluid and electrolyte management. Ophthalmologic evaluation revealed visual acuity of only light discrimination.

CT and MRI of the brain revealed a soft tissue mass density in the right sphenoid sinus with possible erosion of the inferolateral sinus wall as well as inflammatory change in the right orbit.

The patient was taken to the operating room for right sphenoid sinusotomy with debridement of the sphenoid sinus. There was edematous mucosa and minimal purulence in the right spheno-ethmoid recess and thick, yellow-brown debris in the right sphenoid with no palpable dehiscence of the sphenoid wall.

Biopsy specimens revealed fungal hyphae in the submucosa, confirming a diagnosis of invasive fungal sinusitis with subsequent orbital apex syndrome. Culture was inconclusive but revealed likely aspergillus species. Post-operatively the patient was started on high-dose IV liposomal amphotericin-B and voriconazole. Her sodium improved, and follow-up examination revealed a well-aerated sphenoid sinus with slightly improved ocular motility, but no significant change in vision.

**Baylor College of Medicine- http://www.bcm.edu/oto/grand/12_09_04.htm

Cerebral Aspergillosis – Gross Pathology

Section though unfixed brain showing large pale area of infarction deep in the parietal cortex, in which Aspergillus sp. hyphae were seen histologically. The patient developed disseminated aspergillosis after a prolonged stay in intensive care after contracting severe community acquired pneumonia.

Lung, Aspergillus Infection

Aspergillus is an opportunistic fungus. It is an ascomycete and therefore is characterized by dimorphism (yeast forms and hyphae forms), septate hyphae, sexual spores found in an ascus and asexual spores (conidia) found on conidiophores. Aspergillus can be identified quickly by its septated hyphae and the 45 degree angle branching of its hyphae.

Aspergillus niger - Fungal ball

Gross section of lung at autopsy showing a discrete, well-demarcated dark/black mass surrounded by a fibrotic capsule. No evidence of local invasion, or infarction. The patient had had acute myeloid leukaemia (M1) and responded poorly to chemotherapy. He developed A.niger endocarditis and disseminated disease to the kidneys, lumbar disc and heart, probably arising from this lesion. It is unclear whether this lung lesion was a partially cured ‘mycotic lung sequestrum’ following antifungal therapy, or originated as an aspergilloma. The confirmation of genus and species was obtained by PCR on blood and vegetations.

Lung, Aspergillosis

Arrow one indicates a conidiophore which is the stalk which supports a conidia as seen at arrow 2. The conidia are the spores of the ascomycete. The conidiophore and the conidia are part of the asexual stage of the life cycle of the ascomycete. Arrow 3 highlights a hypha. No septae are visible in this example. Arrow 4 shows a mycelium which is in a mat of hyphae.

Sphenoid Sinusitis in AIDS

Base of skull at autopsy showing pus in the sphenoid sinus and destruction of the lateral wall of the sinus, as demonstrated on the CT scan. Cultures from the sinus and brain abscess grew Aspergillus fumigatus

Allergic Fungal Sinusitis

Also as eosinophilic fungal rhinosinusitis, light microscopy of mucus sections. Histological sections of formalin fixed and paraffin embedded mucus, from patients suffering from allergic fungal sinusitis (eosinophilic fungal rhinosinusitis).

MRI Fungal Sinusitus

Calicifications in imaging. Allergic fungal sinusitis (AFS) is commonly caused by Aspergillus. Patients often have associated asthma. The MRI in addition to radiological abnormalities, thick pus or a clay-like substance was found in the sinuses. There was no allergic mucin, but dense hyphae are found. An inflammatory response in the mucosa was noted.. Upon looking into the sinus, the fungus ball can vary in size from 1 mm or smaller to a size which completely occupies the sinus. It may have a greenish-black appearance.

Removal of the fungus ball is the typical treatment.

Corneal Ulcer - Gram Stain

Corneal scrapings were taken from a 67 yr old farmer presenting with a corneal ulcer of the right eye. A piece of vegetable matter was embedded in the cornea and scrapings were done. Gram stain (500x magnification) showed numerous septate hyphae. Cultures grew a small amount of A fumigatus

Kindly provided by Dr Ken Stottler (© Fungal Research Trust)

Aspergillus Keratitis

Endocarditis

Macroscopic view of the heart at autopsy, showing an infracted lesion on the papillary muscle of the mitral valve in the left ventricle. In addition the patient had large vegetations, which are not shown here. The confirmation of genus and species was obtained by PCR on blood and vegetations; the pericarditis was a manifestation of disseminated aspergillosis.

Reported in association with with infection of long-standing central venous catheters.

Chest X-Ray - Enocarditis Diagnosis

This (normal) chest X-ray was taken about 6 weeks before endocarditis was diagnosed, and 3 months before death due to disseminated aspergillosis. No CT scan was done (a chest radiograph has a 10% false negative rate in leukaemic patients, compared with CT)

Pericardits - Aspergillus niger

Myocarditis and pericarditis are complications of disseminated disease.

Macroscopic view of the pericardium at autopsy, showing gross chronic haemorrhagic pericarditis. The confirmation of genus and species was obtained by PCR on blood and vegetations; the pericarditis was a manifestation of disseminated aspergillosis.

Three patients have been reported to have survived when treated. One with  amphotericin B and the other two with Itraconazole.

Lumbar Discitis

Macroscopic lesion of a lumbar intervertebral vertebral at autopsy, showing haemorrhagic necrosis, caused by hyphal invasion and infarction. The confirmation of genus and species was obtained by PCR on blood and vegetations; the discitis was a manifestation of disseminated aspergillosis.

Wound Mycotic Infection

Neonatal Primary Cutaneous Aspergillosis – Buttocks Lesion

Neonatal primary cutaneous aspergillosis usually presents as an erythematous plaque with pustules that evolve into an eschar. Immunocompromised patients and premature neonates are at risk of developing this disease. Early diagnosis and treatment are critical in preventing progression to a systemic illness.

Woodruff CA, et al. Pediatr Dermatol 2002;5:439-44.

This photo shows extensive infection of the burn wound on the leg of a 7 year old boy, acquired about 3 weeks after the injury. Despite medical therapy he died

Aspergillus onychomycosis

Although Candida sp. yeast infections are common in onychomycosis, in this case was caused by Aspergillus terreus known to be resistant to AMB.

Aspergillus onychomycosis

Onychomycosis caused by Aspergillus fumigatus

Double Diffusion test for Aspergillosis.

Central well contains Aspergillus fumigatus antigen and wells in the top and bottom contain control antiserum. The three peripherals wells with precipitin bands contain sera from patients with A. fumigatus fungus ball (FB). More bands present in the upper right cases is characteristic of FB. The well in the bottom left position is negative.

Images supplied by LC Severo, with the help of AC Pasqualotto, at Santa Casa Complexo Hospitalar, Porto Alegre, Brazil