Brief
in
Invasive Aspergillosis
Bethany A. Darling, MD,* Edmund A. Milder, MD, MSCE*
*Naval Medical Center San Diego, San Diego, CA
AUTHOR DISCLOSURE Drs Darling and
Milder have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device.
Practice Guidelines for the Diagnosis and
Management of Aspergillosis: 2016 Update
by the Infectious Disease Society of
America. Patterson TF, Thompson GR III,
Denning DW, et al. Clin Infect Dis. 2016;63(4):
e1–e60
Aspergillosis. In: Kimberlin DW, Brady MT,
Jackson MA, Long SS, eds. Red Book: 2015
Report of the Committee on Infectious Diseases.
30th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2015:249–252
Aspergillus Species. Steinbach WJ. In: Long
SS, Pickering LK, Prober CG, eds. Principles and
Practice of Pediatric Infectious Diseases. 4th ed.
Philadelphia, PA: Saunders Elsevier;
2012:1203–1209
Aspergillus Species, Patterson TF, Bennet JE,
Bolin R, Blaser MJ, Mandell GL. Mandell,
Douglas, and Bennett’s Principles and Practice
of Infectious Diseases. 7th ed. Philadelphia, PA:
Elsevier Health Sciences; 2010:2895–2908
476 Pediatrics in Review
Aspergillus species are ubiquitous molds found in the environment, most abun-
dantly in soil and on decaying vegetation. The genus contains more than 200
species, with more than 30 species now reported to cause infections in humans.
Aspergillus infection can present with a range of clinical syndromes, from localized
colonization of the respiratory tract to devastating invasive disease. This In Brief
focuses on invasive aspergillosis (IA). Although Aspergillus infection in immu-
nocompetent patients is rare, it remains a significant cause of morbidity and
mortality in immunocompromised patients. The incidence of IA infections has
been increasing, likely related to more aggressive immunosuppressive therapies
for certain conditions and increased survival in chronically immunosuppressed
patients.
The incidence and severity of IA corresponds directly to a patients’ degree of
immunosuppression. Patients with prolonged neutropenia are particularly at risk,
with reports of an incidence of up to 70% in patients with neutropenia for greater
than 30 days. In pediatric populations, the highest rates of IA occur in patients
with hematologic malignancy, especially acute myelogenous leukemia. Hemato-
poietic stem cell transplant patients have 2 peaks of infection: one in the first 40
days after transplant and another 100 days or more after transplant. Later-onset
infections are often related to high-dose corticosteroid therapy for graft-versus-
host disease. Also, IA is seen in patients with chronic granulomatous disease and
other inherited immunodeficiency conditions.
Aspergillus is transmitted through the inhalation of conidia (spores). Studies
suggest that most people inhale several hundred Aspergillus conidia daily, but
infection is avoided through the effective action of pulmonary macrophages
and neutrophils. In patients who develop IA there is often a history of a potential
exposure in the community, such as gardening or nearby construction. Health-care–
associated outbreaks have also been reported and linked to nearby construction,
faulty ventilation, or contaminated water sources. Occasionally, cutaneous Aspergil-
lus arises in an at-risk patient by direct inoculation at a site of skin injury, such as an
intravenous catheter site or under an adhesive dressing (Fig 1). Person-to-person
transmission does not occur. The incubation period between exposure and clinical
manifestations is unknown but is estimated to be from 2 days to several months
depending on species pathogenicity and host factors.
Clinical presentation varies widely and reflects the underlying risk factors of
the individual patient. The first presentation may be an unremitting fever in a
high-risk patient. Unfortunately, the most immunosuppressed patients have the
highest risk of rapid progression but often have minimal symptoms. Invasive
disease most commonly involves the respiratory tract due to inhalation of conidia,
presenting as pneumonia, tracheobronchitis, or sinusitis. A hallmark of invasive
Aspergillus disease is the organism’s propensity to invade blood vessels, which can
lead to thrombosis, dissemination to other organs, and in some cases catastrophic

Figure 1. Aspergilloma at the intravenous line site in a 9-year-old boy
with acute lymphoblastic leukemia. (Reprinted with permission from
Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report
of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL:
American Academy of Pediatrics; 2015.)
hemorrhage. Central nervous system disease is the most
dreaded of IA syndromes because it is associated with
mortality as high as 80% to 90%. Less commonly involved
sites of infection include skin, bones, joints, eye/orbit, heart,
spleen, kidney, liver, esophagus, and intestine.
Aspergillus infection is notoriously difficult to diagnose.
Maintaining a high index of suspicion in high-risk patients
is critical. Even in disseminated disease, Aspergillus species
are usually not recoverable in blood cultures. Tissue biopsy
demonstrating hyaline, septate hyphae with acute branch-
ing on histologic examination, and growth on fungal culture
media are the gold standard of diagnosis. The pathologist
may also identify the sporulating conidiophore, whose
Figure 2. Aspergillus fumigatus microscopic image. (Reprinted with
permission from Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. AAP
Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk
Grove Village, IL: American Academy of Pediatrics; 2015.)
resemblance to the aspergillum religious device gave rise
to the genus name in the 1700s (Fig 2). Obtaining a biopsy is
often not feasible due to a high risk of bleeding or secondary
infection in patients with AI. Fortunately, adjunctive tests
are available to aid in diagnosis. The most frequently used
and best studied is a serologic enzyme immunoassay
for galactomannan (GM), a component of the cell wall
of Aspergillus. Results are reported as positive or negative
and are not quantitative. A positive test result is suggestive of
IA, especially in high-risk patients, but false-positives can
occur due to dietary GM (rice, pasta), medications (piper-
acillin), or other fungi. The GM assay is not reliable in
patients with chronic granulomatous disease or Job syn-
drome. The test has been shown to turn positive approx-
imately a week before radiographic changes or clinical signs
develop, leading some centers to prospectively track GM
levels in high-risk patients. Other fungal markers, such as 1/
3-beta-d-glucan, may be useful for diagnosis, but there are
limited data on their accuracy in children and they are less
able to differentiate between Aspergillus and other fungi.
Polymerase chain reaction tests have been developed for
serum and bronchoalveolar lavage specimens. Their role in
the diagnosis and management of IA is an active area of
research.
Due to the rapidly progressive nature of the disease,
treatment should not be delayed until definitive diagnosis
is made but should begin as soon as IA is suspected.
Voriconazole is the treatment of choice for nearly all
forms of IA as outlined in the Infectious Diseases Society of
America’s 2016 practice guideline. Amphotericin B was
historically first-line therapy, but several randomized
clinical trials have confirmed voriconazole’s superiority.
Voriconazole is generally well-tolerated but can interact with
immunosuppressive drugs such as tacrolimus and cyclo-
sporine. Treatment duration should be individually tailored
for each patient, but generally a minimum of 6 to 12 weeks is
required. There are significant differences in metabolism
between patients, and serum drug levels should be moni-
tored to ensure safety and efficacy. Other antifungal agents
have been studied as alternative options for patients who
cannot tolerate voriconazole or for refractory disease, but
there is no clear second-line agent of choice. When possible,
decreasing the degree of immunosuppression by lowering
the dose of immunosuppressive agents or treating pro-
longed neutropenia with granulocyte colony-stimulating
factor or granulocyte infusion is an important adjunct to
antifungal therapy. Surgical resection of localized and easily
Vol. 39 No. 9 SEPTEMBER 2018 477
 accessible lesions should be considered but in pulmonary
disease surgery is reserved for cases where there is signif-
icant hemoptysis or lesions are impinging on major airways
or vessels.
Prognosis for invasive disease depends on the site of
infection, extent of disease, and host factors. Untreated IA
has mortality of nearly 100% in most patient groups. An
inability to achieve decreased immunosuppression is a
significant risk factor for disease progression and death.
Although overall survival rates have improved, mortality
still exceeds 75% for the highest-risk patients and those
with most severe disease. Central nervous system disease
outcomes are particularly grave, with rapid progression
and greater than 80% mortality.
Due to the high morbidity and mortality associated with
IA, there is ongoing effort to find ways to improve outcomes.
Early diagnosis and treatment, including periodic monitor-
ing of at-risk patients with GM assays and empirical treat-
ment with voriconazole when IA is suspected, have been
shown to improve survival. Prevention efforts for high-risk
patients include providing HEPA-filtered, positive-pressure
isolation rooms for inpatients and counseling on avoiding
gardening or exposure to construction for outpatients.
Although there is limited evidence at this time, some have
proposed the use of prophylactic antifungal therapy during
periods of highest risk. Because patients with IA often
have significant underlying comorbidities, treatment of
IA should always include consultation with a pediatric
infectious disease specialist.
Note. The views expressed herein are those of the authors
and do not necessarily reflect the official policy or position of
the Department of the Navy, the Department of Defense, or the
US Government.
COMMENT: This In Brief reviews a medical entity that
primary care pediatricians need to be familiar with in pa-
tients they may care for who are immunosuppressed. Be-
cause protection against aspergillosis is afforded through
neutrophils and alveolar macrophages, patients who do not
have these well-functioning protective mechanisms will be
at risk. It is important to remember that patients taking cor-
ticosteroids may not always present with fever and that as-
pergillosis may be the first presentation of patients with
chronic granulomatous disease. Primary care providers will
want to partner with an infectious disease specialist to
assist with evaluation and treatment when aspergillosis is
a possibility.
– Janet R. Serwint, MD
Associate Editor, In Brief

Correction
An error appeared in the print version of the August 2018 review “Group A Streptococcus” (Dietrich ML, Steele, RW.
Pediatr Rev. 2018;39(8):379-391; DOI: 10.1542/pir.2017-0207). In the Summary, the end of the fourth bullet point should
read “methicillin-resistant Staphylococcus aureus” instead of “methicillin-resistant Streptococcus aureus.” The online
version of the article has been corrected, and a correction notice has been posted with the online version of the article.
The journal regrets the error.

ANSWER KEY FOR SEPTEMBER 2018 PEDIATRICS IN REVIEW

Pediatric Cervical Lymphadenopathy: 1. D; 2. D; 3. D; 4. A; 5. E.
Pediatric Solid Tumors in Children and Adolescents: 1. E; 2. E; 3. A; 4. E; 5. E.
Pediatric Hip Disorders: Slipped Capital Femoral Epiphysis and Legg-Calvé-Perthes Disease: 1. C; 2. E; 3. C; 4. B; 5. C.

478 Pediatrics in Review