Aspergillosis differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Haytham Allaham, M.D. [2]; Serge Korjian M.D.

Overview

Aspergillosis must be differentiated from other diseases that cause fever, chest pain, dyspnea, sinusitis, allergic symptoms, and elevated IgE concentrations. Differential diagnosis includes other infections (fungi, bacteria, viruses, and parasites), non-infectious pulmonary diseases (such as asthma, COPD, interstitial lung disease, bronchiectasis, and lung tumors), cardiac diseases (such as pericarditis, endocarditis, or myocarditis), facial diseases (such as infectious sinusitis, sinus tumor, or nasal polyps), systemic diseases (such as Hyper IgE syndrome, Churg-Strauss syndrome, granulomatosis with polyangiitis, Goodpasture's syndrome), congenital diseases (such as cystic fibrosis or ciliary dyskinesia), transplant-related complications (such as GVHD), diseases with cutaneous manifestations (such as eczema, scabies, deep vein thrombosis, cellulitis), and adverse drug reactions.

Diffential Diagnosis

Aspergillosis must be differentiated from other diseases that cause fever, chest pain, dyspnea, sinusitis, allergic symptoms, and elevated IgE concentrations. Differential diagnosis includes:

• Actinomycosis
• Acute Respiratory Distress Syndrome
• Aspiration (e.g. foreign body)
• Asthma
• Arteriovenous malformation
• Blastomycosis
• Bronchiectasis and mucoid impaction
• Bronchocentric granulomatosis
• Cellulitis
• Churg-Strauss syndrome
• Coccidiomycosis
• COPD exacerbation
• Cryptococcosis
• Ciliary dyskinesia
• Cystic fibrosis
• Deep vein thrombosis
• Drug - adverse reaction
• Eczema
• Endocarditis
• Eosinophilia
• Eosinophilic pneumonia
• Goodpasture's syndrome
• Granulocytopenia
• Granulomatosis with polyangiitis (Wegener's granulomatosis)
• Graft vs. host disease
• Heart failure
• Hemosiderosis
• Hemothorax
• Histoplasmosis
• Histiocytosis
• Hypereosinophilic syndrome
• Hypersensitivity Pneumonitis
• Hyper IgE syndrome (Job's syndrome)
• Impetigo
• Infectious sinusitis
• Interstitial lung disease
• Leishmaniasis
• Leproma (leprosy nodule)
• Leukemia
• Loffler's syndrome
• Lung Abscess
• Lung tumor (primary or metastatic)
• Lymphoma
• Malaria
• Mucormycosis
• Myeloproliferative disorder
• Myocardial abscess
• Myocarditis
• Nasopharyngeal polyp
• Nocardiosis
• Paracoccidioidomycosis
• Pericarditis
• Pneumonia
• Pneumothorax
• Pulmonary embolism
• Pulmonary eosinophilia
• Pulmonary arterial hypertension
• Sarcoidosis
• Scabies
• Scedosporiosis (pulmonary infection caused by the fungus Scedosporium)
• Sporotrichosis
• Sinus tumor
• Trauma
• Tuberculosis (including tuberculoma)
• Zygomycosis

Pathogen	Disease	Geographic distribution	High risk Groups	Differentiating features		Microscopic findings
				Physical exam	Laboratory findings
Fungal	Histoplasmosis	Mississippi and Ohio River valleys	Cave dwellers Soil that contains bird or bat dropping	Palate and oral ulcers Splenomegaly	Pancytopenia Urine antigen testing	Yeast are typically smaller, with narrow-based budding, found intracellularly within macrophages
	Coccidioidomycosis	Southwestern US region	Opportunistic infection seen in AIDS	Rash on upper body or legs Night sweats	Serologic tests( enzyme immune assay )more sensitive	Characteristic spherule appearance
	Paracoccidioidomycosis	Central and South america	Opportunistic infection seen in AIDS	Lymphadenopathy Hepatosplenomegaly Bone marrow dysfunction	Elevated liver enzymes Hyperbilirubinemia Hypoalbuminemia	Smaller fungi with thin cell walls, forming mariner wheel appearance, circumferentially surrounding the parent cell.( Captain wheel appearance )
	Sporotrichosis	Ubiquitous	Gardeners	Extremities Lymphadenitis (nodular)	+ Sporotrichin skin test	Finger or cigar shaped yeast.
	Aspergillosis	Ubiquitous	Cystic fibrosis or asthma. tuberculosis. Immunocompromised	Wheezing Stuffiness, runny nose Hemoptysis Weight loss	Cell wall detection using galactomannan antigen detection, Beta-D-glucan detection test.	Septated hyphae with acute angle branching
Bacterial	Anthrax	Ubiquitous	Live stock handlers	Painless skin ulcer with a black center  Bloody diarrhea	Thrombocytopenia Hyponatremia ↑ BUN Hypoalbuminemia ↑ Troponin.	Nonmotile, Gram-positive, aerobic or facultatively anaerobic, endospore-forming, rod-shaped bacterium
	Legionella	Ubiquitous	Chronic lung disease Building water systems	Diarrhea Confusion	+ Urine Antigen Hyponatremia	Gram negative bacterium
	Tuberculosis	Asia,Africa	Ill contact individuals	Night sweats Hemoptysis	Hypercalcemia Elevated alkaline phosphatase levels fluorescence microscopy (auramine-rhodamine staining)+ for baccilli.	Aerobic, non-encapsulated, non-motile, acid-fast bacillus
	Listeriosis	Ubiquitous	Pregnant women Adults > 65 Immunocompromised.	Pregnancy can lead to miscarriage, stillbirth, premature delivery, Non-pregnant : headache, stiff neck, confusion, loss of balance, and convulsions	Elevated titers of listeriolysin O CSF analysis :Pleocytosis lymphocytes  ↑CSF protein   ↓ CSF glucose	flagellated, catalase-positive, facultative intracellular, anaerobic, nonsporulating, Gram-positive bacillus
	Brucellosis	Mexico, South and Central America	People who take unpasteurized dairy products	Arthritis Testicular and scrotal swelling Endocarditis	Antibody production against lipopolysaccharide and bacterial antigens Relative lymphocytosis and thrombocytopenia.	Gram-negative bacteria,non-motile, encapsulated coccobacilli.
	Scrub typhus	Asia-Pacific region Australia Afghanistan	Hikers	Maculopapular rash	Indirect immunofluorescence + Weil-Felix test	a Gram-negative α-proteobacterium  intracellular parasite
	Leptospirosis	Temperate, tropical climates.	People who work with animals	Jaundice Red eyes Kidney failure	Antibodies labelled with fluorescent markers positive for leptospires. Microscopic agglutination test +	Spiral-shaped bacteria with hooked ends on dark-field.
	Cat scratch fever	Ubiquitous	cat licking a person's open wound, or bites or scratches a person	Lymphadenopathy Papule or pustule at the infected site	enzymatic immunoassay positive for antibody to B henselae lymphocytosis	Gram-negative bacteria. facultative intracellular parasites
Viral	Chickenpox	−	Pregnant women. Infants born at less than 28 weeks gestation Immunocompromised persons	conjunctival and catarrhal symptoms Spots appearing in two or three waves	Whole infected cell (wc) ELISA for IgG.	−
	Coxsackie A virus	−	Children attending day care	Painful blisters in the mouth, palms and on the feet. Rash, appears after episode of high fever.	Clinically diagnosed	−
Others	Primary lung cancer	−	Age >65	Weight loss H/o smoking Hemoptysis	CT guided bronchoscopy + for malignant cells	−

Differentiating Aspergillosis in immunocompromised host

Aspergillosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases:

Disease	Differentiating signs and symptoms	Differentiating tests
CNS lymphoma	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli CXR shows cavitations
Aspergillosis	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl's eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.

Differentiating invasive aspergillosis from other diseases

Invasive aspergillosis must be differentiated from other conditions with similar presentation. Invasive fungal disease should be considered in any immunocompromised patient presenting with a new cranial neuropathy or ocular motility abnormality for example, mucormycosis. The differentials include:

Disease	General features	Signs and Symptoms			Radiological abnormalities	Histopathological abnormalities	Other differentiating characters
		Facial/Sinus swelling and ulceration	Cranial neuropathy	Disturbance in ocular motility
Mucormycosis	Agents found in: decaying vegetation Soil Acquired by: Inhalation Ingestion contamination of wounds with sporangiospores from the environment. Air-conditioning systems, particularly during construction Use of contaminated adhesive bandages or tape in surgical wound dressings Susceptible individuals: Immunocompromised patients Diabetics Patients receiving deferoxamine therapy Injection drug users Patients with no apparent immune impairment Invasive mucormycosis is clinically similar to aspergillosis and is marked by angioinvasion and tissue infarction	+ (Mucosal thickening on the paranasal sinuses is more common in rhinocerebral mucormycosis(ROCM) than bacterial orbital cellulitis(BOC)	+ (Specially if there is invasion of the cavernous sinus)	+ (Limited eye movement is more common in patients with rhino-cerebral mucormycosis (ROCM) than in those with bacterial orbital cellulitis)	CT scan: Reverse halo sign (characterized by central ground-glass opacity (GGO) which is surrounded by a partial or complete rim of consolidation) is more common in patients with pulmonary mucormycosis than in those with invasive pulmonary aspergillosis	Nonpigmented, wide (5- to 20-μm), thin-walled, ribbon-like hyphae with few septations (pauciseptate) and right-angle branching In lesions exposed to air, thick-walled spherical structures can form at the ends of the hyphae Fungal elements invading the blood vessel wall or inside their lumen	Mucormycosis is generally more commonly observed in immunocompromised patients Patients with orbital fungal infections are more likely to be infected with mucormycosis compared with Aspergillus The prognosis of pulmonary mucormycosis has not improved significantly over the last ten years
Invasive aspergillosis	Aspergillosis is a heterogenous group of infectious diseases caused by Aspergillus(commonly A. fumigatus) Classified into: Allergic bronchopulmonary aspergillosis (ABPA)  Aspergilloma  Chronic pulmonary aspergillosis   Invasive aspergillosis  Cutaneous aspergillosis  Trasmitted by: Inhalation of airborne conidia (usually during dust exposure during building renovation or construction) Contaminated biomedical devices, but not from one individual to another. Susceptible individuals: Immunocompromised status (e.g. organ or stem cell transplant recipient) History of prior lung disease	+	+	+ (There may be painful ophthalmoplegia if there is invasion of the cavernous sinus)	CT scan: Reverse halo sign Allergic bronchopulmonary aspergillosis (ABPA) are not specific, the demonstration of bronchial dilatation, wall thickening, and centrilobular nodules in an asthmatic patient should suggest the diagnosis	Microscopic observation under ultraviolet light shows that the hyphae of aspergillus have characteristic dichotomous branching, parallel walls, and numerous septa. These septa structure is clearly different from those of the mucor Clusters of centrilobular nodules, peribronchial consolidations, and bronchial wall thickening, are more common in patients with invasive pulmonary aspergillosis
Orbital cellulitis	Orbital cellulitis is an inflammation of the soft tissues of the eye socket behind the orbital septum, a thin tissue which divides the eyelid from the eye socket Infection isolated anterior to the orbital septum is considered to be preseptal cellulitis Orbital cellulitis most commonly refers to an acute spread of infection into the eye socket from either the adjacent sinuses, skin or from spread through the blood The most common pathogens in orbital cellulitis are streptococcus and staphylococcus	+	+	+ (The ocular symptoms of bacterial orbital cellulitis (BOC) , such as facial edema, pain, and blepharoptosis, are similar to those of rhino-cerebral mucormycosis (ROCM) soon after infection onset, therefore it maybe difficult to distinguish the two during the initial phase of infection. Eye lid swelling is more common in BOC than ROCM)	CT scan: Cross-sectional imaging demonstrates diffuse soft-tissue thickening anterior to the orbital septum and obliteration of the adjacent fat planes in pre-septal cellulitis	Biopsy may show a neutrophilic infiltration of the tissues due to acute inflammation
Extra nodal T cell lymphoma	These tumors are more clearly classified as nasal-type extranodal T-cell/natural killer (T/NK) cell lymphoma and natural killer cell leukemia Epstein bar virus (EBV) has been found to be one of the major causes. They are characterized immunophenotypically by the expression of CD2, CD3ϵ (but not CD3 and the T-cell receptor), and CD56 The lesion produced are destructive and involve the nasal cavity, oropharynx, upper palate, and larynx Immunophenotyping shows these lesions to be lymphoid in nature	+	+ (Primary CNS NK/Tcell lymphoma of the nasal type)	+/-	CT scan: The CT and MR imaging appearances are nonspecific and do not allow reliable distinction of this disease from other nasal cavity tumors such as squamous cell carcinoma or from minor salivary gland tumor.	“Angiocentric” invasion of lymphoid cells is Angiocentricity is seen in about half of all cases but is also found in other lymphoma subtypes. Invasion of vascular walls by lymphoid cells causes occlusion of the lumen. The vascular occlusion is usually associated with prominent ischemic necrosis of both tumor cells and normal tissue.
Cutaneous Anthrax	Cutaneous anthrax is extremely rare in developed countries Usually patient history points towards the diagnosis of cutaneous anthrax Patient develops a painless ulcer with vesicles, edema, and has a history of exposure to animals or animal products; whereas patients with cutaneous mucormycosis are mainly debilitated (diabetics, hematological malignancies, organ transplant recepients) and present as a black necrotic eschar	+			Imaging modalities are not indicated in cutaneous anthrax	Epithelium is edematous with loss of continuity. Sub-epidermal, chronic and acute infiltrates involving adipose tissue and capillaries, with areas of necrosis. Gram stain shows large solid and beaded gram-positive rods, particularly beneath the epithelium. The bacilli are not visible on the hematoxylin and eosin stain.