1678 PART 5 Infectious Diseases

classified as acute and subacute, with courses of ≤1 month and 1–3 months,

respectively. More than 80% of cases of invasive aspergillosis involve

the lungs, and most are community acquired. The most common clinical features are no symptoms at all, fever, cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis, and shortness

of breath. Although the fever often responds to glucocorticoids, the

disease progresses. In ventilated patients, screening for Aspergillus

antigen on tracheobronchial lavage fluid is necessary for diagnosis

as radiology is not distinctive. The keys to early diagnosis in at-risk

patients are a high index of suspicion, screening for circulating antigen

(in leukemia), and urgent CT of the thorax. Invasive aspergillosis is one

of the most common diagnostic errors revealed at autopsy.

Invasive Sinusitis The sinuses are involved in 5–10% of cases of

invasive aspergillosis, especially affecting patients with leukemia and

recipients of hematopoietic stem cell transplants. In addition to fever,

the most common features are nasal or facial discomfort, blocked nose,

and nasal discharge (sometimes bloody). Endoscopic examination of

the nose reveals pale, dusky or necrotic-looking tissue in any location.

CT or MRI of the sinuses is essential but does not distinguish invasive

Aspergillus sinusitis from preexisting allergic or bacterial sinusitis early

in the disease process.

Tracheobronchitis Occasionally, only the airways are infected by

Aspergillus. The resulting manifestations seen on bronchoscopy range

from acute or chronic bronchitis to ulcerative or pseudomembranous

tracheobronchitis. These entities are particularly common among lung

transplant recipients and patients on artificial ventilation. Obstruction

with mucous plugs may occur and is called obstructing bronchial

aspergillosis in immunocompromised patients and mucous impaction

in other patients, such as those with ABPA.

Aspergillus Bronchitis Recurrent chest infections that only partially improve with antibiotic treatment and are associated with significant breathlessness or coughing up of thick sputum plugs are typical

features of Aspergillus bronchitis. Patients are not significantly immunocompromised and usually have bronchiectasis or cystic fibrosis.

Occasional patients present with respiratory failure because of airway

obstruction with mucus. Concurrent bacterial bronchitis is common.

The diagnosis rests on recurrent detection of Aspergillus in the airway

by microscopy, culture, or polymerase chain reaction (PCR). Aspergillus

IgG is usually detectable.

Disseminated Aspergillosis In the most severely immunocompromised patients, Aspergillus disseminates from the lungs to multiple

organs—most often to the brain but also to the skin, thyroid, bone,

kidney, liver, gastrointestinal tract, eye (endophthalmitis), and heart

valve. Aside from cutaneous lesions, the most common features are

gradual clinical deterioration over 1–3 days, with low-grade fever and

features of mild sepsis, and nonspecific abnormalities in laboratory

tests. In most cases, at least one localization becomes apparent before

death. Blood cultures are almost always negative.

Cerebral Aspergillosis Hematogenous dissemination to the brain

is a devastating complication of invasive aspergillosis. Single or multiple lesions may develop. In acute disease, hemorrhagic infarction is

most typical, and cerebral abscess is common. Rarer manifestations

include meningitis, mycotic aneurysm, and cerebral granuloma (mimicking a brain tumor). Local spread from cranial sinuses also occurs.

Postoperative infection develops rarely and is exacerbated by glucocorticoids, which are often given after neurosurgery. The presentation can

be either acute or subacute, with mood changes, focal signs, seizures,

and decline in mental status. MRI is the most useful immediate investigation; unenhanced CT of the brain is usually nonspecific, and contrast

is often contraindicated because of poor renal function. Cerebral aspergillosis is disproportionately common in those on ibrutinib.

Endocarditis Most cases of Aspergillus endocarditis are prostheticvalve infections resulting from contamination during surgery. Nativevalve disease is reported, especially as a feature of disseminated infection

and in persons using illicit IV drugs. Culture-negative endocarditis

with large vegetations is the most common presentation; embolectomy

occasionally reveals the diagnosis.

Cutaneous Aspergillosis Dissemination of Aspergillus occasionally results in cutaneous features, usually an erythematous or purplish

nontender area that progresses to a necrotic eschar. Direct invasion

of the skin occurs in neutropenic patients at the site of IV catheter

insertion and in burn patients. Surgical, burn, and trauma wounds may

become infected with Aspergillus (especially A. flavus).

Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (Fig. 217-1) is one or more pulmonary

cavities expanding over a period of months or years in association with

pulmonary symptoms and systemic manifestations such as fatigue and

weight loss. Often mistaken initially for tuberculosis, >90% of chronic

cavitary pulmonary aspergillosis cases occur in patients with prior

pulmonary disease (e.g., tuberculosis, atypical mycobacterial infection,

sarcoidosis, rheumatoid lung disease, pneumothorax, bullae) or lung

surgery. The onset is insidious, and systemic features (weight loss,

fatigue) may be more prominent than pulmonary symptoms. An irregular internal cavity surface and thickened cavity walls are typical and

indicative of disease activity. Irregular material, fluid level, and a wellformed fungal ball are seen in a minority of cavities. Multiple cavities are

more common than a single cavity, and most cavities are in the upper

lobes. Pleural thickening and pericavitary infiltrates are typical and most

obvious if a positron emission tomography scan has been done as part of

the workup. Chronic cavitary pulmonary aspergillosis is usually caused

by A. fumigatus, but A. niger has been implicated, particularly in diabetic

patients, as have other species, rarely. IgG antibodies to Aspergillus are

detectable in ~90% of patients with chronic cavitary pulmonary aspergillosis. Some patients have concurrent infections—even without a fungal

ball—with atypical mycobacteria and/or other bacterial pathogens. The

most significant complication is life-threatening hemoptysis, which may

be the presenting manifestation. If untreated, chronic cavitary pulmonary aspergillosis typically progresses (sometimes relatively rapidly) to

TABLE 217-2 Major Manifestations of Aspergillosis

ORGAN 

TYPE OF DISEASE

INVASIVE (ACUTE AND SUBACUTE) CHRONIC SAPROPHYTIC ALLERGIC

Lung Angioinvasive (in neutropenia),

nonangioinvasive, granulomatous

Chronic cavitary, chronic fibrosing,

bronchitis, Aspergillus nodule

Aspergilloma (single),

airway colonization

Allergic bronchopulmonary, severe asthma with

fungal sensitization, extrinsic allergic alveolitis

Sinus Acute invasive Chronic invasive, chronic

granulomatous

Maxillary fungal ball Allergic fungal sinusitis, eosinophilic fungal

rhinosinusitis

Brain Abscess, hemorrhagic infarction,

meningitis

Granulomatous, meningitis None None

Skin Acute disseminated, locally invasive

(trauma, burns, IV access)

External otitis, onychomycosis None None

Heart Endocarditis (native or prosthetic),

pericarditis

None None None

Eye Keratitis, endophthalmitis None None None described

1679CHAPTER 217 Aspergillosis

unilateral or upper-lobe fibrosis. This end-stage entity is termed chronic

fibrosing pulmonary aspergillosis (destroyed lung).

Aspergilloma Aspergilloma (fungal ball) is a late manifestation of chronic cavitary pulmonary aspergillosis, but some patients

are asymptomatic. The inside of a pulmonary cavity allows fungal

growth that peels off, forming the layers of the fungal ball. Signs and

symptoms associated with single (simple) aspergillomas are minor,

including cough (sometimes productive), hemoptysis, wheezing, and

mild fatigue. More significant signs and symptoms are associated with

chronic cavitary pulmonary aspergillosis and should be treated as such.

About 10% of fungal balls resolve spontaneously (by being coughed

up), but the cavity may still be infected and the patient symptomatic.

Aspergillus Nodule A recently recognized form of chronic pulmonary aspergillosis is the Aspergillus nodule, which may resemble early

lung carcinoma and may cavitate. Nodules may be single or multiple

and 5–50 mm in diameter. Larger mass lesions are rarely seen. Nodules

are usually avid on positron emission tomography. IgG antibodies to

Aspergillus are detectable in ~65% of patients with an Aspergillus nodule.

Chronic Aspergillus Sinusitis Three entities are subsumed under

this broad designation: fungal ball of the sinus, chronic invasive

sinusitis, and chronic granulomatous sinusitis. Fungal ball of the

sinus is limited to the maxillary sinus (except in rare cases involving

the sphenoid sinus) in which the sinus cavity is filled with a fungal

ball. Maxillary disease is associated with prior upper-jaw root canal

work and chronic (bacterial) sinusitis. About 90% of CT scans show

focal hyperattenuation related to concretions; on MRI scans, the

T2-weighted signal is decreased, whereas it is increased in bacterial

sinusitis. Removal of the fungal ball is curative. No tissue invasion is

demonstrable histologically or radiologically.

In contrast, chronic invasive sinusitis is a slowly destructive process that most commonly affects the ethmoid and sphenoid sinuses.

Patients are usually but not always immunocompromised to some

degree (e.g., as a result of diabetes or HIV infection). Imaging of the

cranial sinuses shows opacification of one or more sinuses, local bone

destruction, and invasion of local structures. The differential diagnosis

is wide, including other infections. Apart from a history of chronic

nasal discharge and blockage, loss of the sense of smell, and persistent

headache, the usual presenting features are related to local involvement

of critical structures. The orbital apex syndrome (blindness and proptosis) is characteristic. Facial swelling, cavernous sinus thrombosis,

C

C

C

C

C

FIGURE 217-1 CT scan image of the chest in a patient with long-standing bilateral

chronic cavitary pulmonary aspergillosis. This patient had a history of several

bilateral pneumothoraces and had required bilateral pleurodesis in 1990. CT then

demonstrated multiple bullae, and sputum cultures grew A. fumigatus. The patient

had initially weakly and later strongly positive serum IgG Aspergillus antibody tests.

This scan (2003) shows a mixture of thick- and thin-walled cavities in both lungs

(each marked with C), with a probable fungal ball (black arrow) protruding into

the large cavity on the patient’s right side (R). There is also considerable pleural

thickening bilaterally.

carotid artery occlusion, pituitary fossa, and brain and skull-base invasion are complications.

Chronic granulomatous sinusitis due to Aspergillus is most commonly seen in the Middle East and India and is often caused by

A. flavus. It typically presents late, with facial swelling and unilateral

proptosis. The prominent granulomatous reaction histologically distinguishes this disease from chronic invasive sinusitis, in which tissue

necrosis with a low-grade mixed-cell infiltrate is typical. IgG antibodies

to A. flavus are usually detectable.

Allergic Bronchopulmonary Aspergillosis In almost all cases,

ABPA represents a hypersensitivity reaction to A. fumigatus; rare cases

are due to other aspergilli and other fungi. ABPA occurs in ~2.5% of

patients with asthma who are referred to secondary care, although it

may be less common in the United States and more common in those

from the Indian subcontinent. In cystic fibrosis, up to 15% of teenagers

are affected. Episodes of bronchial obstruction with mucous plugs

leading to coughing fits, “pneumonia,” consolidation, and breathlessness are typical. Many patients report coughing up thick sputum casts,

often brown in color. Eosinophilia commonly develops before systemic

glucocorticoids are given. The cardinal diagnostic test is detection of

Aspergillus-specific IgE (or a positive skin-prick test in response to A.

fumigatus extract) together with an elevated serum level of total IgE

(usually >1000 IU/mL). The presence of hyperattenuated mucus in

airways is highly specific. Bronchiectasis is characteristic, and some

patients develop chronic cavitary pulmonary aspergillosis.

Severe Asthma with Fungal Sensitization (SAFS) Many

adults with severe asthma do not fulfill the criteria for ABPA and yet

are allergic to fungi. Although A. fumigatus is a common allergen,

numerous other fungi (e.g., Cladosporium and Alternaria species) are

implicated by skin-prick testing and/or specific IgE testing. Serum total

IgE concentrations are <1000 IU/mL, and bronchial-wall thickening is

common. ABPA and SAFS are collectively referred to as fungal asthma.

Allergic Fungal Rhinosinusitis Like the lungs, the sinuses

manifest allergic responses to Aspergillus and other fungi. The affected

patients present with chronic (i.e., perennial) sinusitis that is relatively

unresponsive to antibiotics. Many of these patients have nasal polyps,

and all have congested nasal mucosae and sinuses full of mucoid

material. The histologic hallmarks of allergic fungal sinusitis are local

eosinophilia and Charcot-Leyden crystals. Removal of abnormal

mucus and polyps, with local and occasionally systemic administration

of glucocorticoids, usually leads to resolution. Persistent or recurrent

signs and symptoms may require more extensive surgery (ethmoidectomy) and sometimes oral antifungal therapy. Recurrence is common,

often after another bacterial or viral infection.

Superficial Aspergillosis Aspergillus can cause keratitis onychomycosis and otitis externa. The former may be difficult to diagnose

early enough to save the patient’s sight. Natamycin (5%) eye drops are the

optimal therapy for fungal keratitis, often with surgery. Otitis externa usually resolves with debridement and local application of antifungal agents.

■ DIAGNOSIS

Several techniques are required to establish the diagnosis of any form

of aspergillosis with confidence (Table 217-1).

Acute Invasive Aspergillosis Patients with acute invasive aspergillosis have a relatively heavy load of fungus in the affected organ;

thus, antigen detection, PCR, microscopy, culture, and/or histopathology usually confirm the diagnosis. However, the pace of progression

leaves only a narrow window for making the diagnosis without losing

the patient, and some invasive procedures are not possible because of

coagulopathy, respiratory compromise, and other factors. Many cases

of invasive aspergillosis are missed clinically and are diagnosed only at

autopsy. Histologic examination of affected tissue reveals either infarction, with invasion of blood vessels by many fungal hyphae, or acute

necrosis, with limited inflammation and fewer hyphae. Aspergillus

hyphae are hyaline, narrow, and septate, with branching at 45°; no yeast

forms are present in infected tissue. Hyphae can be seen in cytology

1680 PART 5 Infectious Diseases

or microscopy preparations, which therefore provide a rapid means of

presumptive diagnosis.

One Aspergillus antigen test relies on detection of galactomannan

release from Aspergillus organisms during growth, the other a novel

protein antigen. Respiratory sample antigen detection is more sensitive

than serum and is critical in the intensive care unit patient in whom

radiology is nonspecific. Positive serum antigen results usually precede

clinical or radiologic features by several days. The sensitivity of antigen

detection is reduced by antifungal therapy.

A positive culture supports the diagnosis, given that multiple other

(rarer) fungi can mimic Aspergillus species histologically, but only

10–30% of patients with invasive aspergillosis have a positive culture.

Bacterial agar is less sensitive than fungal media for culture; thus, if

physicians do not request fungal culture, the diagnosis may be missed.

High-volume fungal cultures enhance yield. A positive culture may

represent noninvasive forms of aspergillosis or airway colonization.

Both antigen detection and real-time PCR are faster and much more

sensitive than culture of respiratory samples and blood.

Definitive confirmation of a diagnosis of invasive aspergillosis

requires (1) a positive culture of a sample taken directly from an ordinarily sterile site (e.g., a brain abscess) or (2) positive results of both

histologic testing and culture (or molecular confirmation of Aspergillus

spp.) of a sample taken from an affected organ (e.g., sinuses or skin).

Most diagnoses of invasive aspergillosis are inferred from fewer data,

including the presence of the halo sign on a thoracic CT scan—a localized ground-glass appearance representing hemorrhagic infarction

surrounds a nodule or consolidation. Halo signs are present for ~7 days

early in the course of infection in neutropenic patients and are a good

prognostic feature, reflecting an early diagnosis. Nodules with halo

signs are a feature of COVID-19 and do not imply invasive aspergillosis

with supportive evidence. Other characteristic radiologic features of

invasive pulmonary aspergillosis include nodules and pleural-based

infarction or cavitation, but nonspecific consolidation is common

(Fig. 217-2).

Chronic Aspergillosis For chronic aspergillosis, Aspergillus antibody testing combined with characteristic imaging is sufficient for the

diagnosis. Biopsy of Aspergillus nodules reveals hyphae surrounded by

cells of chronic inflammation and sometimes granulomas. Antibody

titers fall slowly with successful therapy. Cultures are infrequently

positive but are important in checking for azole resistance. Real-time

PCR of sputum is often strongly positive. Some patients with chronic

pulmonary aspergillosis also have elevated titers of total serum IgE and

Aspergillus-specific IgE.

ABPA, SAFS, and Allergic Aspergillus Sinusitis ABPA and

SAFS are diagnosed serologically with elevated specific and total serum

IgE levels or with skin-prick tests. Allergic Aspergillus sinusitis is usually diagnosed histologically, accompanied by Aspergillus IgE antibody.

TREATMENT

Aspergillosis

Antifungal drugs active against Aspergillus include voriconazole,

itraconazole, posaconazole, isavuconazole, caspofungin, micafungin, and amphotericin B (AmB). Possible interactions with other

drugs must be considered before azoles are prescribed. In addition,

plasma azole concentrations vary substantially from one patient

to another, and many authorities recommend monitoring levels

to ensure that drug concentrations are adequate but not excessive,

especially with itraconazole and voriconazole. Initial IV administration is preferred for acute invasive aspergillosis and oral administration for all other diseases that require antifungal therapy. Current

recommendations are shown in Table 217-3.

Voriconazole, isavuconazole and posaconazole are the preferred

agents for invasive aspergillosis; caspofungin, micafungin, and lipidassociated AmB are second-line agents. AmB is not active against A.

terreus or A. nidulans; multi-azole resistance in A. fumigatus is present

in <5% of isolates but is increasing, especially in Southeast Asia; and

A. niger is resistant to itraconazole and isavuconazole. An infectious

disease consultation is advised for patients with invasive disease,

given the complexity of management. Immune reconstitution can

complicate recovery. The duration of therapy for invasive aspergillosis varies from ~3 months to several years, depending on the

patient’s immune status and response to therapy. Relapse occurs if the

response is suboptimal and immune reconstitution is not complete.

Voriconazole is currently the preferred oral agent for chronic

aspergillosis with itraconazole or posaconazole as substitutes when

failure, emergence of resistance, or adverse events occur. Because

chronic cavitary pulmonary aspergillosis responds slowly, therapy

for >6 months is necessary, and disease control may require years

of treatment, whereas the duration of treatment for other forms of

chronic and allergic aspergillosis requires case-by-case evaluation.

Glucocorticoids should be used in chronic cavitary pulmonary

aspergillosis only if covered by adequate antifungal therapy. Acute

exacerbations of ABPA respond well to voriconazole, itraconazole,

or a short course of glucocorticoids—long-term azole therapy usually helps minimize corticosteroid exposure and maintain remission. Antifungal response in Aspergillus bronchitis is gratifying, but

relapse after 4 months of therapy is common.

Resistance in A. fumigatus to one or more azoles, although

uncommon, is increasingly found globally. Resistance may be

derived from azole fungicide use for crops. In addition, resistance

arising from multiple mechanisms may develop during long-term

treatment, and a positive culture during antifungal therapy is an

indication for susceptibility testing.

A

B

FIGURE 217-2 Markedly different appearances of invasive aspergillosis on CT scan

of the thorax. A. Patient with myelodysplasia and moderate neutropenia showing

small right-sided nodules with minimal surrounding ground glass and a separate

area of ground glass only on the left laterally. B. Patient with multiple myeloma

undergoing intensive chemotherapy with corticosteroids showing bilateral areas

of consolidation and some nonspecific atelectasis with probable ground glass

surrounding the right-sided lesion. The anterior component of the left-sided lesion

is demarcated by the fissure.

1681CHAPTER 218 Mucormycosis

TABLE 217-3 Treatment of Aspergillosisa

INDICATION PRIMARY TREATMENT PRECAUTIONS SECONDARY TREATMENT COMMENTS

Invasive diseaseb Voriconazole,

isavuconazole,

posaconazole

Drug interactions

(especially with rifampin and

carbamazepine)c

AmB, caspofungin,

posaconazole, micafungin

As primary therapy, voriconazole, isavuconazole, and

posaconazole have a 20% higher response rate than

AmB. Therapeutic drug monitoring is recommended

for voriconazole.

Prophylaxis Posaconazole tablet,

itraconazole solution

SUBA-itraconazole

Vincristine, cyclophosphamide

interaction

Micafungin, aerosolized

AmB

Some centers monitor plasma levels of itraconazole

and posaconazole.

Single aspergilloma Surgical resection Multicavity disease: poor

outcome of surgery, medical

therapy preferable

Itraconazole, voriconazole,

intracavity AmB

Single large cavities with an aspergilloma are best

resected. Relapse reduced by pre- and peri-operative

antifungal therapy.

Chronic pulmonary

diseaseb

Voriconazole,

itraconazole

Poor absorption of itraconazole

capsules with proton pump

inhibitors or H2

 blockers

Posaconazole, IV AmB,

IV micafungin

Resistance may emerge during treatment, especially

if plasma drug levels are subtherapeutic. Resistance

is less common with voriconazole.

ABPA/SAFS (“fungal

asthma”)

Itraconazole Some glucocorticoid

interactions, including with

inhaled formulations

Voriconazole,

posaconazole

Long-term therapy is helpful in most cases. No

evidence indicates whether therapy modifies

progression to bronchiectasis/fibrosis.

a

For information on duration of therapy and drug resistance in certain Aspergillus species, see text. b

An infectious disease consultation is appropriate for these patients. c

Online drug-interaction resource: www.aspergillus.org.uk/content/antifungal-drug-interactions.

Note: After loading doses, the oral dose is usually 200 mg bid for voriconazole and itraconazole, 100 mg bid for SUBA-itraconazole, 300 mg qd for posaconazole tablets, and

200 mg qd for isavuconazole. The IV dose of voriconazole for adults is 6 mg/kg twice at 12-h intervals (loading doses) followed by 4 mg/kg q12h; a larger dose is required

for children and teenagers; a lower dose may be safer for persons >70 years of age. Plasma monitoring is helpful in optimizing the dosage. The IV dose of isavuconazole

is 200 mg tid for 2 days (loading dose) followed by 200 mg qd. Caspofungin is given as a single loading dose of 70 mg and then at 50 mg/d; some authorities use 70 mg/d for

patients weighing >80 kg, and lower doses are required with hepatic dysfunction. Micafungin is given as 50 mg/d for prophylaxis and as at least 150 mg/d for treatment; this

drug has not yet been approved by the U.S. Food and Drug Administration (FDA) for this indication. AmB deoxycholate is given at a daily dose of 1 mg/kg if tolerated. Several

strategies are available for minimizing renal dysfunction. Lipid-associated AmB is given at 3 mg/kg (AmBisome) or 5 mg/kg (Abelcet). Different regimens are available for

aerosolized AmB, but none is FDA approved. Other considerations that may alter dose selection or route include age; concomitant medications; renal, hepatic, or intestinal

dysfunction; and drug tolerability.

Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; AmB, amphotericin B; SAFS, severe asthma with fungal sensitization.

Mucormycosis represents a group of life-threatening infections caused

by fungi of the order Mucorales of the subphylum Mucoromycotina.

Mucormycosis is highly invasive and relentlessly progressive, resulting

in higher rates of morbidity and mortality than many other infections.

The mortality rates from mucormycosis have declined in recent years

as a result of early initiation of more effective antifungal therapies.

However, mortality remains high overall, often driven by progression

of the underlying predisposing condition.

218 Mucormycosis

Brad Spellberg, Ashraf S. Ibrahim

Surgical treatment is important in several forms of aspergillosis,

including fungal ball of the sinus and single aspergillomas, in which

surgery is curative; invasive aspergillosis involving bone, heart

valve, sinuses, and proximal areas of the lung (to avoid catastrophic

hemoptysis); brain abscess; keratitis; and endophthalmitis. In allergic

fungal sinusitis, removal of abnormal mucus and polyps, with local

and occasionally systemic glucocorticoid treatment, usually leads to

resolution. Persistent or recurrent signs and symptoms may require

more extensive surgery (ethmoidectomy) and possibly antifungal

therapy. Surgery is problematic in chronic cavitary pulmonary

aspergillosis, usually resulting in serious complications. Bronchial

artery embolization is preferred for problematic hemoptysis.

■ PROPHYLAXIS

In situations in which moderate or high risk is predicted (e.g., after

induction therapy for acute myeloid leukemia), the need for antifungal prophylaxis for superficial and systemic candidiasis and for

invasive aspergillosis is generally accepted. Fluconazole is commonly

used in these situations but has no activity against Aspergillus species.

Itraconazole solution of SUBA-itraconazole capsules provide enough

bioavailability for modest efficacy, the latter with fewer adverse events.

Posaconazole tablets are more effective in reducing infection rates and

the need for empirical antifungal therapy. Some data support the use of

IV micafungin in those with azole contraindications. No prophylactic

regimen is completely successful.

■ OUTCOME

Invasive aspergillosis is curable if immune reconstitution occurs,

whereas allergic and chronic forms are not. The mortality rate for

invasive aspergillosis is 30–70% if the infection is treated but is 100% if

the diagnosis is missed. Cerebral aspergillosis, Aspergillus endocarditis,

and bilateral extensive invasive pulmonary aspergillosis have very poor

outcomes, as does invasive infection in persons with late-stage AIDS or

relapsed uncontrolled leukemia.

The mortality rate for chronic cavitary pulmonary aspergillosis is

~40% over 5 years and 50–60% over 10 years if the patient is actively

treated with antifungal agents. After 12 months with no antifungal

therapy, 70% of patients have deteriorated, and 10–35% have died.

Therapy fails in ~30% of recipients of antifungal therapy and still more

often if azole resistance is present.

Both ABPA and SAFS patients respond to antifungal therapy; ~60%

respond to itraconazole and ~80% to voriconazole and posaconazole

(if tolerated). Inhaled amphotericin B is effective in and tolerated by

~15% of patients. If the severity of asthma declines, the inhaled glucocorticoid dose can be reduced, and oral glucocorticoids can be stopped.

Relapse after discontinuation is common but not universal.

■ FURTHER READING

Goh KJ et al: Sensitization to Aspergillus species is associated with frequent exacerbations in severe asthma. J Asthma Allergy 10:131-40, 2017.

Lamoth F et al: Incidence of invasive pulmonary aspergillosis among

critically ill COVID-19 patients. Clin Microbiol Infect 26:1706, 2020.

Muldoon EG et al: Aspergillus nodules; another presentation of

chronic pulmonary aspergillosis. BMC Pulm Med 16:123, 2016.

Schauwvlieghe AFAD et al: Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: A retrospective

cohort study. Lancet Respir Med 6:782, 2018.

Ullman AJ et al: Diagnosis and management of Aspergillus diseases:

Executive summary of the 2017 ESCMID-ECMM-ERS guideline.

Clin Microbiol Infect 24:e1ee38, 2018.

1682 PART 5 Infectious Diseases

■ EPIDEMIOLOGY

Mucormycosis typically occurs in patients with diabetes mellitus,

solid-organ transplantation or hematopoietic stem cell transplantation

(HSCT), prolonged neutropenia or corticosteroid use, or malignancy.

As mentioned, the majority of diabetic patients are not acidotic on

presentation with mucormycosis. Furthermore, patients often have no

previously recognized history of diabetes mellitus when they present

with mucormycosis. In these instances, presentation for mucormycosis

may result in the first clinical recognition of hyperglycemia, which

often has been unmasked by recent glucocorticoid use. Thus, a high

index of suspicion of mucormycosis must be maintained, even in the

absence of a known history of diabetes, if hyperglycemia is present. In

patients undergoing HSCT, mucormycosis develops at least as commonly during nonneutropenic as during neutropenic periods, probably because of glucocorticoid treatment of graft-versus-host disease.

Mucormycosis can occur as isolated cutaneous or subcutaneous infection in immunologically normal individuals after traumatic implantation of soil or vegetation (e.g., due to natural disasters, motor vehicle

accidents, or severe injuries in war zones) or in nosocomial settings via

direct access through intravenous catheters, subcutaneous injections,

or maceration of the skin by a moist dressing.

Patients receiving antifungal prophylaxis with either itraconazole or

voriconazole may be at increased risk of mucormycosis. These patients

typically present with disseminated mucormycosis, the most lethal

form of disease. Breakthrough mucormycosis also has been described

in patients receiving posaconazole, isavuconazole, or echinocandin

prophylaxis.

Mucormycosis has also emerged as an important superinfection in

COVID-19 patients, with patients in India being particularly heavily affected. Even before COVID-19, India was hyper-endemic for

mucormycosis, with population-based case rates that were up to 70

times higher than the worldwide rate. Whether or not COVID-19 itself

somehow predisposes to mucormycosis is not clear. Both in India and

the rest of the world, the vast majority of excess cases of mucormycosis during the COVID-19 pandemic have likely been attributable to a

combination of diabetes mellitus and corticosteroid use. In India, onethird of mucormycosis cases during the COVID-19 pandemic were in

patients not infected with COVID-19, underscoring the high baseline

rate there. Furthermore, the large majority of mucormycosis cases in

COVID-19 patients in India and the rest of the world have been of

the rhino-orbital-cerebral variety, and pulmonary infection has been

rare, consistent with diabetes and corticosteroids predisposing to these

cases.

■ CLINICAL MANIFESTATIONS

Mucormycosis presents as one of five well-defined clinical syndromes:

rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, and

disseminated disease. However, infection of any body site can occur.

Patients with specific defects in host defense tend to develop specific

syndromes. For example, patients with diabetes mellitus and/or DKA

typically develop the rhino-orbital-cerebral form and much more

rarely develop pulmonary or disseminated disease. In contrast, pulmonary mucormycosis occurs most commonly in leukemic patients who

are receiving chemotherapy and in patients undergoing HSCT.

Rhino-Orbital-Cerebral Disease Rhino-orbital-cerebral mucormycosis continues to be the most common form of the disease worldwide. Most cases occur in patients with diabetes, although such cases

are also described in the transplantation setting, often along with

glucocorticoid-induced diabetes mellitus. The initial symptoms of

rhino-orbital-cerebral mucormycosis are nonspecific and include eye or

facial pain and facial numbness followed by the onset of conjunctival suffusion and swelling, and blurry vision. In contrast to the acute, bright red,

periocular skin manifestations typical of acute bacterial orbital cellulitis,

periorbital skin in patients with rhino-orbital-cerebral mucormycosis

may take on a more dusky, subacute appearance. Fever may be absent in

up to half of cases. White blood cell counts are typically elevated as long

as the patient has functioning bone marrow. If untreated, infection usually

spreads from the ethmoid sinus to the orbit, resulting in compromise of

TABLE 218-1 Taxonomy of Fungi Causing Mucormycosis

(Subphylum Mucoromycotina, Order Mucorales)

FAMILY GENUS (SPECIES LISTED FOR SOME)

Mucoraceae Rhizopus oryzae

Rhizopus delemar

Rhizopus microsporus

Rhizomucor

Mucor

Actinomucor

Lichtheimiaceae Lichtheimia (formerly Mycocladus, formerly Absidia)

Cunninghamellaceae Cunninghamella

Thamnidiaceae Cokeromyces

Mortierellaceae Mortierella

Saksenaceae Saksenaea

Apophysomyces

Syncephalastraceae Syncephalastrum

■ ETIOLOGY

The fungal order Mucorales consists of seven families that are known

to cause mucormycosis (Table 218-1). Rhizopus oryzae and R. delemar

(both in the family Mucoraceae) are by far the most common causes

of mucormycosis in the Western Hemisphere. Less frequently isolated

species of the Mucoraceae that cause a similar spectrum of infections

include Rhizopus microsporus, Rhizomucor pusillus, Lichtheimia corymbifera (formerly Absidia corymbifera), Apophysomyces elegans, and

Mucor species. Increasing numbers of cases of mucormycosis due to

infection by mold in the family Cunninghamellaceae have also been

reported, particularly in highly immunocompromised patients. Other

Mucorales can be the major cause of disease in certain geographic areas

(e.g., A. elegans in India and Mucor irregularis in China) or in outbreaks following natural disasters (e.g., Apophysomyces trapeziformis

outbreak following the 2011 tornado in Joplin, Missouri). Only rare

case reports have demonstrated the ability of fungi in the remaining

families of the Mucorales to cause mucormycosis.

■ PATHOGENESIS

The Mucorales are ubiquitous environmental fungi to which humans

are constantly exposed. These fungi cause infection primarily in

patients with uncontrolled diabetes, defects in phagocytic function

(e.g., neutropenia or glucocorticoid treatment), and/or elevated levels

of free iron, which supports fungal growth in serum and tissues. In the

past, iron-overloaded patients with end-stage renal failure who were

treated with deferoxamine had a high risk of developing rapidly fatal

disseminated mucormycosis; deferoxamine is an iron chelator for the

human host, but it serves as a fungal siderophore, directly delivering

iron to the Mucorales. Furthermore, patients with diabetic ketoacidosis (DKA) are at high risk of developing rhinocerebral mucormycosis.

The acidosis causes dissociation of iron from sequestering proteins,

resulting in enhanced fungal survival and virulence. The ketoacid

β-hydroxybutyrate also increases expression of host and fungal receptors that result in fungal adherence and penetration into tissues.

Nevertheless, the majority of diabetic patients who present with

mucormycosis are not acidotic, and, even absent acidosis, hyperglycemia directly contributes to the risk of mucormycosis by at least four

likely mechanisms: (1) hyperglycation of iron-sequestering proteins,

disrupting normal iron sequestration; (2) upregulation of a mammalian

cell receptor (GRP78) that binds to Mucorales, enabling tissue penetration (due to both a direct effect of hyperglycemia and increasing levels

of free iron); (3) induction of poorly characterized defects in phagocytic

function; and (4) enhanced expression of CotH, a Mucorales-specific

protein that mediates host cell invasion by binding to GRP78 (due

to hyperglycemia and the resulting free iron). More recently, the

mucoricin toxin—with structural and functional similarities to ricin—

was found to be responsible for host cell death and tissue necrosis. The

toxin is a key virulence factor of Mucorales fungi and is a promising

therapeutic target.

1683CHAPTER 218 Mucormycosis

A B

FIGURE 218-1 Histopathology sections of Rhizopus delemar in infected brain. A. Broad, ribbon-like,

nonseptate hyphae in the parenchyma (arrows) and a thrombosed blood vessel with extensive intravascular

hyphae (arrowhead) (hematoxylin and eosin). B. Extensive, broad, ribbon-like hyphae invading the

parenchyma (Gomori methenamine silver).

extraocular muscle function and proptosis, typically with chemosis. From

the orbit, the fungus can spread contiguously or hematogenously to the

frontal lobe of the brain and/or via venous drainage to the cavernous

sinus. Onset of signs and symptoms in the contralateral eye, with resulting

bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is ominous, suggesting the development of cavernous sinus thrombosis.

Upon visual inspection, infected tissue often has a normal appearance

during the earliest stages of fungal spread, which can make diagnosis

difficult; blind biopsies of normal-appearing sinus tissue are warranted

when suspicion for mucormycosis is high. Tissue then progresses

through an erythematous phase, with or without edema, before the

onset of a violaceous appearance and finally the development of a black

necrotic eschar. Infection can sometimes extend from the sinuses into the

mouth and produce painful necrotic ulcerations of the hard palate, but

this is a late finding that suggests extensive, well-established infection.

One common misperception about mucormycosis is that it is always

rapidly progressive. In fact, the rate of progression is extremely variable

and is possibly dependent on the immune status of the patient, the

infectious inoculum, and the causative Mucorales species, some of

which are more virulent and/or have faster growth rates than others.

Patients may go from initial symptoms to death in days; alternatively, it

can take months or even a year or more for lethal progression to occur.

Pulmonary Disease Pulmonary mucormycosis is the second most

common manifestation. Symptoms include dyspnea, cough, and chest

pain; fever is often but not invariably present. Angioinvasion results in

necrosis, cavitation, and/or hemoptysis. Lobar consolidation, isolated

masses, nodular disease, cavities, or wedge-shaped infarcts may be seen

on chest radiography. High-resolution chest CT is the best method for

determining the extent of pulmonary mucormycosis and may demonstrate evidence of infection before it is seen on chest x-ray. In the

setting of cancer, where mucormycosis may be difficult to differentiate

from aspergillosis, the presence of ≥10 pulmonary nodules, pleural

effusion, or concomitant sinusitis makes mucormycosis more likely. It

is important to distinguish mucormycosis from aspergillosis because

treatments for these infections may differ. Indeed, voriconazole—the

first-line treatment for aspergillosis—exacerbates mucormycosis in

mouse and fly models of infection. Isavuconazole and posaconazole

were noninferior to voriconazole for the treatment of aspergillosis in

randomized controlled trials, and also have activity against Mucorales.

Hence if there is doubt about whether infection is caused by a septated

mold (e.g., Aspergillus) or a Mucorales, inclusion of isavuconazole or

posaconazole in a treatment regimen is a reasonable consideration.

Consideration must also be given to the possibility of dual infection

with both a septated mold and Mucorales; dual infection is not infrequently encountered in highly compromised patients.

Cutaneous Disease Cutaneous mucormycosis may result from

external implantation of the fungus or from hematogenous dissemination. External implantation–related infection has been described in the

setting of soil exposure from trauma (e.g., in a motor vehicle accident,

a natural disaster, or combat-related injuries), penetrating injury with plant material (e.g., a thorn),

injections of medications (e.g., insulin), catheter

insertion, contamination of surgical dressings, and

use of tape to secure endotracheal tubes. Cutaneous disease can be highly invasive, penetrating into

muscle, fascia, and even bone. Necrotizing fasciitis

caused by mucormycosis carries a mortality rate

approaching 80%. Necrotic cutaneous lesions in

the setting of hematogenous dissemination also are

associated with an extremely high mortality rate.

However, with prompt, aggressive surgical debridement, isolated cutaneous mucormycosis has a

favorable prognosis and a low mortality rate.

Gastrointestinal Disease In the past, gastrointestinal mucormycosis occurred primarily in premature neonates in association with disseminated

disease and necrotizing enterocolitis. However,

there has been a marked increase in case reports describing adults

with neutropenia, glucocorticoid use, or other immunocompromising

conditions. In addition, gastrointestinal disease has been reported as

a nosocomial process following administration of medications mixed

with contaminated wooden applicator sticks. Nonspecific abdominal

pain and distention associated with nausea and vomiting are the most

common symptoms. Gastrointestinal bleeding is common, and fungating masses may be seen in the stomach at endoscopy. The disease may

progress to visceral perforation, with extremely high mortality rates.

Disseminated and Miscellaneous Forms of Disease Hematogenously disseminated mucormycosis may originate from any primary site of infection. The most common site of dissemination is the

brain, but metastatic lesions may also be found in any other organ.

Mortality rates for widely disseminated mucormycosis exceed 90%;

however, these high rates are likely to be due in part to the underlying

predisposing condition leading to the infection and the inability to

surgically remove the infected foci.

Mucormycosis may affect any body site, including bones, mediastinum, trachea, kidneys, peritoneum (in association with dialysis), scalp

(causing a kerion), and even isolated infection of teeth.

■ DIAGNOSIS

A high index of suspicion is required for diagnosis of mucormycosis.

Unfortunately, autopsy series have shown that up to half of cases are

diagnosed only postmortem. Because the Mucorales are environmental

isolates, definitive diagnosis requires a positive culture from a sterile

site (e.g., a needle aspirate, a tissue biopsy specimen, or pleural fluid) or

histopathologic evidence of invasive mucormycosis. A probable diagnosis of mucormycosis can be established by culture from a nonsterile

site (e.g., sputum or bronchoalveolar lavage) or the detection of Mucorales on the surface of histopathology samples (without visualization

of evidence of invasion) when a patient has appropriate risk factors

as well as clinical and radiographic evidence of disease. In such cases,

given the urgency of administering therapy early, the patient should be

treated while confirmation of the diagnosis is awaited.

Biopsy with histopathologic examination remains the most sensitive

and specific modality for definitive diagnosis (Fig. 218-1). Biopsy

reveals characteristic wide (≥6- to 30-μm), thick-walled, ribbon-like,

aseptate hyphal elements that branch at right angles. Other fungi,

including Aspergillus, Fusarium, and Scedosporium species, have septa,

are thinner, and branch at acute angles. However, artificial septa may

result from folding of tissue during processing (which may also alter

the appearance of the angle of branching), which can make Mucorales

appear to have septa. Thus, the width and the ribbon-like form of the

fungus are the most reliable features distinguishing mucormycosis

from other pathogenic molds. The Mucorales are visualized most

effectively with periodic acid–Schiff or hematoxylin and eosin; in

contrast to many other fungi, methenamine silver may not result in

optimal staining. While histopathology can identify the Mucorales,

1684 PART 5 Infectious Diseases

species can be identified only by culture. Several studies showed that

polymerase chain reaction (PCR) of Mucorales-specific targets is useful in diagnosing mucormycosis. However, the U.S. Food and Drug

Administration (FDA) has not approved any of these PCR-based assays

for this purpose.

Unfortunately, cultures are positive in fewer than half of cases of

mucormycosis. Nevertheless, the Mucorales are not fastidious organisms and tend to grow quickly (i.e., within 48–96 h) on culture media.

The likely explanation for the low sensitivity of culture is that the

Mucorales form long filamentous structures that are killed by tissue

homogenization—the standard method for preparing tissue cultures

in the clinical microbiology laboratory. Thus, the laboratory should be

advised when a diagnosis of mucormycosis is suspected, and the tissue

should be cut into sections and placed in the center of culture dishes

rather than homogenized. Because there is also substantial variability

among isolates in optimal growth temperature, growth at both room

temperature and 37°C is advisable.

Imaging techniques often yield subtle findings that underestimate

the extent of disease. For example, the most common finding on CT or

MRI of the head or sinuses of a patient with rhino-orbital mucormycosis is sinusitis that is indistinguishable from bacterial sinusitis.

While sinusitis is almost always seen on CT scans in patients with the

rhino-orbital-cerebral disease, erosion through the sinus bones and

into the orbit is rarely seen on CT even when it is clinically present.

MRI is more sensitive (~80%) for detecting orbital and central nervous

system (CNS) disease than is CT. High-risk patients should always

undergo endoscopy and/or surgical exploration, with biopsy of the

areas of suspected infection. If mucormycosis is suspected, initial

empirical therapy with a polyene antifungal agent should be initiated

while the diagnosis is being confirmed.

■ DIFFERENTIAL DIAGNOSIS

Other mold infections, including aspergillosis, scedosporiosis, fusariosis, and infections caused by the dematiaceous fungi (brownpigmented soil organisms), can cause clinical syndromes identical

to mucormycosis. Histopathologic examination usually allows distinction of the Mucorales from these other organisms, and a positive

culture permits definitive species identification. As stated above, it

is important to distinguish the Mucorales from these other fungi, as

the preferred antifungal treatments differ (i.e., polyenes for the Mucorales vs expanded-spectrum triazoles for most septate molds). The

entomophthoromycoses caused by Basidiobolus and Conidiobolus also

can cause identical clinical syndromes. These fungi cannot be readily

distinguished from the Mucorales by histopathology but can be reliably distinguished by culture. Fortunately, entomophthoromycoses are

uncommon in developed countries and can be treated with polyenes; it

is not urgent to distinguish them from mucormycosis.

In a patient with sinusitis and proptosis, orbital cellulitis and cavernous sinus thrombosis caused by bacterial pathogens (most commonly

Staphylococcus aureus, but also streptococcal and gram-negative species) must be excluded. Klebsiella rhinoscleromatis is a rare cause of

an indolent facial rhinoscleroma syndrome that may appear similar

to mucormycosis. Finally, the Tolosa-Hunt syndrome causes painful

ophthalmoplegia, ptosis, headache, and cavernous sinus inflammation; biopsies and clinical follow-up may be needed to distinguish the

Tolosa-Hunt syndrome from mucormycosis by the lack of progression

of the former entity.

TREATMENT

Mucormycosis

GENERAL PRINCIPLES

Optimizing the chances for successful treatment of mucormycosis

requires four steps: (1) early initiation of therapy; (2) surgical debridement, when possible; (3) rapid reversal of underlying predisposing risk factors, if possible; and (4) proceeding to treat underlying

malignancy, if present, without waiting to complete antifungal

therapy first.

Early initiation of antifungal therapy requires maintaining a high

index of suspicion for at-risk patients. Multiple studies have found

that earlier initiation of polyene-based therapy improves survival

of patients with mucormycosis. Because the disease can present

subtly at first and confirmation of the diagnosis can take days,

therapy often must be started empirically before the diagnosis is

established. When there is a reasonable suspicion of mucormycosis,

clinicians should not hesitate to initiate therapy with a lipid polyene

as soon as possible since the toxicity of lipid polyenes (unlike that

of amphotericin B [AmB] deoxycholate) is rarely substantial after

one or two doses.

Blood vessel thrombosis and resulting tissue necrosis during

mucormycosis can result in poor penetration of antifungal agents

to the site of infection. Therefore, debridement of all necrotic

tissues can help eradicate the disease. Surgery has been found (by

logistic regression and in multiple case series) to be an independent

variable for favorable outcome in patients with mucormycosis.

However, these data are confounded by the fact that sicker patients

are often unable to tolerate surgical procedures. Thus, a moderated

approach where tissue is debrided when and to the extent it is

safe to do so is advisable. Limited data from a retrospective study

support the use of intraoperative frozen sections to delineate the

margins of infected tissues, with sparing of tissues lacking evidence

of infection.

Rapidly reversing hyperglycemia, acidosis, or iron overload and

lowering corticosteroid doses are important to improving cure.

Indeed, a recent study confirmed that resolution of acidosis in mice

with DKA via the administration of sodium bicarbonate (used in

the mice in lieu of insulin) improved survival. Administration of

glucocorticoids predisposes animals to death from mucormycosis

in experimental models. Similarly, iron administration to patients

with active mucormycosis should be avoided as iron exacerbates

infection in experimental models. Blood transfusion typically

results in some liberation of free iron due to hemolysis, so a conservative approach to red blood cell transfusions is advisable.

One of the most common errors made in management of

mucormycosis is the belief that mucormycosis must be eradicated

before an underlying malignancy can be treated. This belief can

result in halting or delaying treatment for the underlying disease

(e.g., chemotherapy or transplantation) until the mucormycosis

is cured. Three fallacies belie this concern. First, mucormycosis

will not be definitively eradicated until near-normal immunity is

restored; the antifungals provide a holding action and are unlikely

to be curative until the underlying disease is treated. Second, modern antifungals can halt progression of mucormycosis temporarily,

enabling aggressive chemotherapy or transplantation to be administered to cure the underlying disease. Finally, the primary driver

of death in such patients is typically progression of the underlying

disease due to failure to treat it appropriately.

Initially, some consideration can be given to moderating the level

of aggressiveness of the chemotherapy and resulting duration and

depth of neutropenia. The aggressiveness of immune suppression

and antifungal therapy can then be adjusted during the course of

treatment in response to changes in clinical status. Chemotherapy

should be given sufficiently aggressively to attempt cure of the

underlying disease. These patients are extremely complex, and

multidisciplinary, team-based care is advisable.

ANTIFUNGAL THERAPY

Primary therapy for mucormycosis should be based on a polyene

antifungal agent (Table 218-2), except perhaps in mild localized

infection (e.g., isolated suprafascial cutaneous infection) that has

been eradicated surgically in an immunocompetent patient. Lipid

formulations of AmB are significantly less nephrotoxic than AmB

deoxycholate, can be administered at higher doses, and are probably

more effective for this purpose. Liposomal amphotericin B (LAmB)

is preferred to amphotericin B lipid complex (ABLC) for management of brain infection on the basis of retrospective survival data

and superior brain penetration; there is no clear efficacy advantage