Less Common Fungal Infections: Pneumocystis and Other

34 Pneumocystis and Other
Less Common Fungal

Infections
FRANCIS GIGLIOTTI, TERRY W. WRIGHT, and DAMIAN J. KRYSAN
CHAPTER OUTLINE Pneumocystis jirovecii (Formerly Known as Epidemiology and Transmission

Pneumocystis carinii) Infection Pathogenesis
History Pathology
The Organism Clinical Manifestations
Epidemiology and Transmission Diagnosis
Pathology Treatment
Pathogenesis Prognosis
Clinical Manifestations Cryptococcosis
Diagnosis The Organism
Treatment Epidemiology and Transmission
Prognosis Pathogenesis
Prevention Pathology
Aspergillosis Clinical Manifestations
The Organism Diagnosis
Epidemiology and Transmission Treatment
Pathogenesis Prognosis
Pathology Malassezia
Clinical Manifestations The Organism
Diagnosis/Differential Diagnosis Epidemiology and Transmission
Therapy Pathogenesis
Prognosis Clinical Manifestations
Prevention Diagnosis
Blastomycosis Treatment
The Organism Prognosis
Epidemiology and Transmission Prevention
Pathogenesis Zygomycosis
Pathology The Organism
Clinical Manifestations Epidemiology and Transmission
Diagnosis Pathogenesis
Therapy Pathology
Prognosis Clinical Manifestations
Prevention Treatment
Histoplasmosis Prognosis
The Organism Dermatophytoses
Epidemiology and Transmission The Organism
Pathogenesis Epidemiology and Transmission
Pathology Pathogenesis
Clinical Manifestations Pathology
Diagnosis Clinical Manifestations
Treatment Diagnosis
Prognosis Treatment
Coccidiodomycosis Prognosis
The Organism Prevention
1080
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34 • Pneumocystis and Other Less Common Fungal Infections 1081
Fungal infections, other than those caused by Candida a sexual stage in the life cycle of the trypanosome and not
spp., rarely are considered in the differential diagnosis for a different organism. Carini,2 an Italian working in Brazil,
an acutely ill newborn infant because disorders of bacte- saw the same organism-like cysts in the lungs of rats experi-
rial and viral etiology are vastly more common. Neverthe- mentally infected with Trypanosoma lewisi. His slide mate-
less, fungal infections do occur in neonates, especially in rial subsequently was reviewed by P. and M. Delanoë and
premature infants and those of very low birth weight (less their colleagues3 at the Pasteur Institute in Paris. They rec-
than 1500 g), and can cause serious and frequently fatal ognized that these alveolar cysts were present in the lungs
disease. As with any other infectious disease, the risk of fun- of local Parisian sewer rats and thereby established that the
gal infection depends on the host and risk of exposure. The “organisms” were independent of trypanosomes. They pro-
neonate has some risk of exposure to either Malassezia furfur posed the name Pneumocystis carinii for the new species.
or Pneumocystis jirovecii (previously Pneumocystis carinii), At about this time, Chagas may have unwittingly
has a limited risk of exposure to Aspergillus spp., and has an described the first human case of pneumocystosis when
extremely low risk of exposure to other fungi, especially in he reported the presence of similar organisms in the lungs
the neonatal intensive care unit (NICU) setting. Therefore it of a patient with interstitial pneumonia who had died of
is not surprising that the most common fungal infection in American trypanosomiasis.4 Nevertheless, no definite etio-
neonates is candidiasis. logic connection was made between P. carinii and human
Although much has been learned regarding the patho- pneumonic disease for another 30 years. The reason for this
genesis, immune response, and treatment of fungal infec- delay was the belief during this period that infantile syphi-
tions in older children and adults, studies to determine lis was responsible for virtually all instances of interstitial
the cause of increased susceptibility or resistance to infec- plasma cell pneumonia. In 1938, Benecke5 and Ammich6
tion with fungi, especially in neonates, are incomplete. identified a histologically similar pneumonic illness in non-
The intent of this chapter is to review current knowledge syphilitic children that was characterized by a peculiar
regarding fungal diseases, other than those caused by Can- honeycombed exudate in alveoli. Subsequent scrutiny of
dida, in the neonate and infant. Infections caused by Candida photomicrographs in their reports revealed the presence
are reviewed in Chapter 33. of Pneumocystis organisms,7 but it was not until 1942 that
Van der Meer and Brug,8 in the Netherlands, unequivo-
cally recognized the organism in lungs from two infants
Pneumocystis jirovecii (Formerly and one adult. The first epidemics of interstitial plasma cell
pneumonia were reported shortly thereafter among prema-
Known as Pneumocystis carinii) ture debilitated babies in nurseries and foundling homes in
Infection central Europe. In 1952, Vanek and Jirovec7 in Czechoslo-
vakia provided the most convincing demonstration of the
P. jirovecii, a fungus with a history of unsettled taxon- etiologic relationship of Pneumocystis to this disease in an
omy, was discovered in the lungs of small mammals and autopsy study of 16 cases.
humans in Brazil more than 100 years ago. Today it is a Pneumocystosis was first brought to the attention of
cause of often fatal pneumonia in patients with primary pediatricians in the United States in 1953 by Deamer and
immunodeficiencies or secondary immunodeficiencies, such Zollinger,9 who reviewed the pathologic and epidemiologic
as those resulting from the treatment of hematologic malig- features of the European disease. In 1957, Gajdusek10 pre-
nancies, collagen-vascular disorders, or organ allografts, sented an in-depth perspective on the history of the infec-
and in those who receive corticosteroids and immunosup- tion that included an extensive bibliography. This review
pressive drug therapy. Although congenital infection with was particularly timely because the next decade was to see
Pneumocystis is unproven, it does occur in infants younger the disturbing emergence of P. carinii pneumonia in the
than 1 year in two well-defined epidemiologic settings: Western world—even while the epidemic disease in central
(1) in epidemics in nurseries located in impoverished areas Europe was waning—to the degree that it would become
of the world and (2) in isolated cases in which the infected preeminent among the so-called opportunistic pulmonary
child has an underlying primary immunodeficiency disease infections in the immunosuppressed host. In 1988, DNA
or acquired immunodeficiency syndrome (AIDS). analysis demonstrated that Pneumocystis was not a proto-
This section of the chapter reviews the problem of Pneu- zoan but a fungus.11 Most recently, a change in nomencla-
mocystis infection in the newborn. Much of our knowledge ture from P. carinii to P. jirovecii, a name chosen in honor
of the epidemiologic, pathologic, and clinical features of of the parasitologist Otto Jirovec, who now is credited by
pneumocystosis, however, is drawn from observations of some with the original description of this organism, has
the infection in older children and adults, as well as from been put forth.12 The rationale for this change is the unique
animal models. As a result, we have elected to include data antigenic, genetic, and restricted infectivity profile of the
derived from such observations to present a more com- Pneumocystis organisms associated with each mammalian
plete picture of the infectious process caused by this unique species.12-15
organism.
THE ORGANISM
HISTORY
The taxonomic status of P. jirovecii as a fungus has been
In 1909 in Brazil, Chagas1 first described the morphologic defined on the basis of molecular analysis.11,12 Because the
forms of Pneumocystis in the lungs of guinea pigs infected organism cannot be adequately propagated in vitro, efforts
with Trypanosoma cruzi. He believed the forms to represent to classify it and to elucidate its structure and life cycle
1082 SECTION IV • Protozoan, Helminth, and Fungal Infections
have been based exclusively on morphologic observations

of infected lungs from animals and humans. The earliest of
these investigations was performed by parasitologists; in
accordance, the terminology applied to the forms of Pneu-
mocystis seen in diseased tissue has been that reserved for
protozoal organisms.
Three developmental forms of this presumably unicellular
microbe have been described: a thick-walled cyst, an intracys-
tic sporozoite (intracystic body), and a thin-walled trophozo-
ite (trophic form).4 The form of Pneumocystis that assists with
diagnosis is the cyst, which may contain up to eight sporozo-
ites. Each sporozoite is round to crescent shaped, measures 1
to 2 μm in diameter, and contains an eccentric nucleus. This
cystic unit with its intracystic bodies is seen well in Giemsa-
stained imprint smears of infected fresh lung.10,16 Giemsa
stain, however, results in staining of background alveoli and
Figure 34-1 Cysts of Pneumocystis jirovecii in a smear from bronchoal-
host cell fragments and does not stain empty cysts. Gomori veolar lavage. (Gomori methenamine silver stain, ×400.) (Courtesy Dr.
methenamine silver stain (GMS), which highlights only the Russell K. Brynes, Centers for Disease Control and Prevention Public Health
cyst wall of Pneumocystis, is preferable to Giemsa stain when Image Library.)
tissues must be screened for the presence of organisms.17 The
cysts stained with silver have a black cell wall and appear
round, crescentic, or disk shaped. Cysts measure 4 to 6 μm in without intracystic bodies (“precysts”), partly empty cysts,
diameter and must be distinguished from erythrocytes. The and collapsed cystic structures have been identified. The
cysts often occur in clusters within an alveolus. collapsed cysts are crescentic and presumably are the same
The typical honeycombed intraalveolar exudate of crescentic forms seen frequently in silver-stained specimens
Pneumocystis pneumonia is a result of negative staining of under light microscopy.
clumps of cysts held together by proteinaceous debris. The Life cycles for P. jirovecii have been proposed. They have
internal structure of the silver-stained cyst is variable. In been based on the variant forms of the fungus detected by
the lighter-staining round cysts, there are sometimes vis- light18,28,29 and electron microscopy.26,30 One scheme sug-
ible thickenings in the cell wall that are circular or comma gests that the thick-walled round cyst undergoes dissolu-
shaped (Fig. 34-1).18 The significance of these cell wall vari- tion or “cracking,” whereupon the intracystic bodies pass
ations is unknown, but they are helpful in confirming the through tears in the wall (Fig. 34-2).26 It is not known
identification of Pneumocystis. whether the bodies escape from the cyst by active motility
Staining procedures, other than those using Giemsa or whether they are extruded passively as a consequence of
and methenamine silver, have been used less frequently to cyst collapse. At this stage, the intracystic bodies resemble
delineate the cyst form of the organism. The cyst wall stains free thin-walled trophozoites. The small trophozoites evolve
red with periodic acid–Schiff (PAS) stain.19 A modified to larger forms, their walls thicken, and a precyst develops
Gram-Weigert method stains both the cyst wall and the that is devoid of intracystic bodies. The cyclic process is
intracystic sporozoites.20 Gridley fungus stain may identify completed when formation of the mature cyst, containing
cyst outlines. More reliable stains for this purpose are the eight daughter cysts, is achieved.
modified toluidine blue stain of Chalvardjian and Grawe21 Classification of Pneumocystis as a protozoan or as a
and the crystal violet stain,22 which color the cyst wall fungus was complicated by the inability to maintain the
purple. Electron microscopy has been an invaluable tool organism in culture to further characterize the biochemical
in morphologic studies of P. jirovecii.23-26 It has helped to nature of the organism. Arguments in favor of a protozoan
confirm that the structures regarded as Pneumocystis under taxonomy were based mainly on the resemblance of its
light microscopy are, in fact, typical microorganisms and structural features to those of other protozoa. The organism
not just degradation products of host cells. has cystic and trophozoite stages, pseudopodia in cell walls,
The trophozoite is thin walled and measures between 1.5 and pellicles around intracystic sporozoites. In addition, the
and 2.0 μm in diameter. It has numerous evaginations or disease caused by Pneumocystis responds to antiprotozoal
pseudopodia-like projections that appear to interdigitate medications, such as pentamidine, atovaquone, fansidar,
with those of other organisms in the alveolar space.25,26 The trimethoprim-sulfamethoxazole (TMP-SMX), while not
projections have been postulated to allow for attachment of responding to many antifungal drugs, namely, amphoteri-
Pneumocystis, but the prevailing opinion, however, is that cin, azoles, 5-flucytosine, and Nystatin. On the other hand,
no specialized organelle of attachment exists. Rather, the like fungi, P. jirovecii contains a paucity of cellular organ-
surfaces of P. jirovecii and alveolar cells (specifically, type elles, its nucleus is not visibly prominent, and its cell mem-
I pneumonocytes) are closely opposed, without fusion of brane is layered throughout an entire life cycle. Finally,
cell membranes.27 This adherence of P. jirovecii to alveolar there is a high degree of homology between “housekeeping”
lining cells may explain why organisms are not commonly genes of Pneumocystis and other fungi.11,31,32
found in expectorated mucus or tracheal secretions.25 The question of host species specificity of Pneumocystis
The intracystic bodies (sporozoites) measure 1.0 to 1.7 μm remained similarly unanswered until the development of
across and bear a marked similarity to small trophozoites.26 highly specific monoclonal antibodies provided the tools to
In addition, thick-walled cysts rich in glycogen particles but demonstrate the uniqueness of Pneumocystis isolated from
A B
G E
Figure 34-2 Probable life cycle of Pneumocystis within pulmonary alveoli. A, Mature cyst with intracystic bodies. B, Empty cyst and recently escaped
intracystic body. C, Small trophozoite. D, Larger trophozoite. E, Possible budding or conjugating form. F, Large trophozoite undergoing thickening of
pellicle. G, Precyst.
different mammalian hosts.13,33,34 Subsequent genetic elicits pneumonia in healthy rats. A prospective, longitu-
analyses confirmed the host species specificity of Pneumo- dinal study of infants bled every 2 months from birth to 2
cystis.15,35-39 The initial demonstration that Pneumocystis years demonstrated 85% of the infants seroconverted by 20
could not be transmitted between different host species pro- months of age.45 Authors of a number of autopsy reviews
vided biologic confirmation for the observed host-defined have attempted to determine the incidence of Pneumocys-
phenotypic and genotypic differences among Pneumocystis. tis infection, but the results have been divergent, because
of the heterogeneity of the populations studied.46-52 Those
studies conducted in central Europe after World War II47 or
EPIDEMIOLOGY AND TRANSMISSION
in cancer referral centers in the United States52 have yielded
The distribution of human infection is worldwide, and a higher rates of infection.
wide variety of wild and domestic animal species has been Few published reports have been devoted exclusively to
demonstrated to be infected by Pneumocystis. The natural the descriptive epidemiology of Pneumocystis pneumonia in
habitat of P. jirovecii is unknown, but what is known of the the United States. In a literature review of the subject, Le
biology of Pneumocystis strongly supports the idea that it is Clair53 accumulated 107 accounts of the disease recorded
maintained in the population through subclinical or mild from 1955 through 1967. The male-to-female ratio of
infection of immunologically normal persons, especially infected persons was in excess of 2:1, but ethnic distribution
infants.40 The prevalence of infection with Pneumocystis was even. The disease was reported from diverse geographic
remains to be determined because studies to detect latent locales (21 of the 50 states). The largest number of cases33
carriage of the organism in large populations have not been occurred in infants younger than 1 year. Proved or pre-
performed. Serologic surveys, however, indicate that infec- sumptive congenital immunodeficiencies were identifiable
tion is widespread and acquired in early life. Meuwissen and in virtually all of the children in this group. In patients 1 to
colleagues,41 in the Netherlands, noted that antibodies to P. 10 years of age, who constituted the next largest group,26
jirovecii are first detectable in healthy children at 6 months only six had a primary immune deficit, whereas most of
of age, and by age 4 years, nearly all children are sero- the other children had an underlying hematologic malig-
positive. Pifer and associates,42 in the United States, found nancy. The remaining patients, ranging in age from 10 to
significant titers of antibody to Pneumocystis in healthy 81 years, were persons with assorted malignancies or renal
7-month-old infants and in two thirds of normal children by allografts, who almost always had had prior exposure to
age 4 years. Gerrard and coworkers,43 in England, detected corticosteroids, radiation, or cytotoxic drugs. The mortality
P. jirovecii antibodies in serum from 48% of 94 young rate for the entire group of patients was 95%.
healthy children. Pifer44 also found that serologic evidence The Centers for Disease Control and Prevention (CDC)
of Pneumocystis infection is present before immunosuppres- updated Le Clair’s study by investigating the epidemiologic,
sive therapy with corticosteroids and that Pneumocystis clinical, and diagnostic aspects of all confirmed cases of
pneumocystosis reported to its Parasitic Disease Drug Ser- A role for Pneumocystis in the pathogenesis of the sud-
vice between 1967 and 1970.54,55 The first of these reports den infant death syndrome (SIDS) has been postulated. The
has particular relevance because it focused only on the cause of SIDS, the unexplained death of previously healthy
infectious episodes in infants and young children. A total of infants, remains a mystery. In 1999, Vargas and col-
194 documented cases of P. jirovecii pneumonia were ana- leagues,68 in Santiago, Chile, reported finding Pneumocystis
lyzed, and 29 occurred in infants younger than 1 year. The in the lungs of many infants whose death was diagnosed as
attack rate for this group (8.4 per million) was more than SIDS. Shortly thereafter, this observation was confirmed in
five times higher than that for other age groups. Eighty- SIDS cases occurring in the Northeast United States.69 Inter-
three percent of these infants had an underlying primary preting these observations presented two problems: defining
immunodeficiency disease. Moreover, because the inheri- appropriate case controls for the presence of Pneumocystis
tance of the primary immunodeficiency state often was sex in infants without SIDS and explaining the mechanism of
linked, the preponderance of infection (88%) occurred in death, given the light infections and lack of demonstrable
males. The mean age at diagnosis in the immunodeficient pathology in these infants. After a series of investigations,
infants was 7.5 months, whereas the epidemic form of which included control infants, Vargas and colleagues70
the infection in European and Asian infants was associ- clearly established the presence of Pneumocystis in infants
ated with peak morbidity in the third and fourth months dying of SIDS but came to the conclusion that Pneumocystis
of life.10,16 Twenty-four percent of the infected children was not likely the cause of SIDS. More recently, Vargas and
with immunodeficiencies had at least one sibling with an colleagues71 reported finding near-universal focal Pneu-
identifiable immune deficiency in whom P. jirovecii pneumocystis that was associated with upregulation of mucus
monia also developed. expression in the lung of SIDS cases. Whether and how this
After this analysis of cases indigenous to the United observation relates to the role of Pneumocystis in the patho-
States was complete, it became evident that infantile pneu- genesis of SIDS is yet to be determined.
mocystosis could be introduced into the United States from The mode of transmission of P. jirovecii is difficult to
epidemics abroad. The first such case was reported in 1966, prove, but animal studies provide unequivocal evidence for
when a 3-month-old Korean infant died of Pneumocystis animal-to-animal transmission via the airborne route.72-74
infection after being brought to the United States from an Epidemiologic studies support a similar mode of transmis-
orphanage in Korea.56 The potential for imported pneumo- sion among humans. For example, Pneumocystis infections
cystosis received renewed publicity with the cessation of the among transplant patients have been shown to increase as
war in Vietnam. Surveillance for Pneumocystis infection in their exposure to patients with or at risk for Pneumocystis
American-adopted Vietnamese orphans was urged when it pneumonia increases.75-79 Furthermore, using molecular
was recognized that large numbers of infants exposed to the probes, it is possible to demonstrate that clusters of Pneumo-
hardships of war and malnutrition in Indochina had expe- cystis pneumonia appear to be caused by the same organ-
rienced fulminant Pneumocystis pneumonia.57,58 In quick ism.75,77,78 Occurrence of pneumocystosis among family
succession, multiple cases of Pneumocystis infection among members also has been reported with pneumonia devel-
these refugee Vietnamese were reported.59 Most of the oping in three family members in a strikingly related time
affected infants were approximately 3 months of age; this sequence.64 More commonly, cases within a family emerge
was exactly the age at which pneumocystosis had emerged over a period of several years, and affected members almost
in the marasmic children infected during the earlier nurs- always are infant siblings with either proven or suspected
ery epidemics in central Europe and Asia. underlying immunodeficiencies. In at least three fam-
The epidemiology of P. jirovecii infection has changed as ily studies, no fewer than three siblings succumbed to the
cases of human immunodeficiency virus (HIV) infection have infection.80-83 It is unlikely, however, that direct patient-
occurred in infants.60 As is true in adults with acquired AIDS, to-patient transfer of the organism occurred in any of these
infants with AIDS are at high risk for this opportunistic infec- settings because, in almost all instances, development of
tion. Among children with perinatally acquired HIV infec- disease in the sibling occurred months or years later. Con-
tion, P. jirovecii pneumonitis occurs most often among infants tagion could still be implicated in the family milieu if a res-
3 to 6 months of age.61 Another important change in the ervoir of asymptomatic infection with P. jirovecii existed
epidemiology of Pneumocystis pneumonia relates to the use among healthy family members. Supporting evidence sug-
of more potent immunosuppressive therapies, which places gests that infants may serve in the role of reservoir.40,45
new patient groups at risk for Pneumocystis pneumonia. For Maternal transfer of Pneumocystis to infants from colostrum
example, it is now suggested that patients with inflammatory or from the genital tract at parturition also might main-
bowel disease who are receiving anti–tumor necrosis factor tain Pneumocystis within a family, but it is difficult to test
(TNF) treatment should be considered for Pneumocystis pneu- this hypothesis. The paucity of documented cases of overt
monia prophylaxis because of the recognized risk of Pneumo- Pneumocystis pneumonia in stillborn infants or in the early
cystis infection in these patients.62 neonatal period, however, argues against frequent intra-
It has been suggested63-67 that P. jirovecii may be an uterine passage of the organism. Congenital infection has
important cause of pneumonitis in immunologically intact been suggested based on very few case reports, but the data
infants. As noted above, primary infection with Pneumocystis presented is inconclusive.84-86
occurs in most healthy infants by 2 years of age.45 However, The possibility that Pneumocystis pneumonia is a zoonotic
seroconversion occurred for the most part without a recog- disease and that infestation of rodents or even domesticated
nizeable clinical illness. More cases need to be confirmed pets could provide a sizable reservoir for human infec-
histologically before it is established that Pneumocystis infection has been postulated based on the frequent finding of
tion produces morbidity in previously healthy infants. Pneumocystis in animals. For example, abundant infection
of rodents with Pneumocystis was discovered in patients’

homes in many of the index cases in ward epidemics in
Czechoslovakia.87 However, with only microscopy, it is not
possible to distinguish animal from human Pneumocystis.
The development of reagents that could distinguish Pneu-
mocystis from one host species from that infecting a different
host allowed for definitive experiments to address host spe-
cies specificity. Controlled experiments demonstrated that
Pneumocystis from ferrets could not infect severe combined
immunodeficient (SCID) mice.14 These results were quickly
confirmed using Pneumocystis from different hosts, includ-
ing P. jirovecii from humans.88-90 Thus the concept of Pneu-
mocystis pneumonia as a zoonosis is not tenable.
PATHOLOGY
Figure 34-3 Section of lung tissue obtained at autopsy showing the
The gross and microscopic pathologic features of P. jirovecii amorphous, proteinaceous intraalveolar infiltrate characteristic of
pneumonitis caused by Pneumocystis jirovecii. Hematoxylin and eosin
pneumonia have been elucidated in a number of excellent stain, ×160. (From Remington JS: The compromised host, Hosp Practice
reviews.9,10,16,20,91-93 At autopsy in typically advanced 7:59-70, 1972.)
infection, both lungs are heavy and diffusely affected. The
most extensive involvement often is seen in posterior or
dependent areas. At the lung margins anteriorly, a few occasionally.9 Septal cell hyperplasia, a nonspecific reac-
remaining air-filled alveoli may constitute the only portion tion of lung tissue to injury induced by infections of diverse
of functioning lung at the time of death.9 Subpleural air etiology, is also seen.96
blebs not infrequently are seen in these anterior marginal Hughes and colleagues97 studied the histologic progres-
areas. On occasion, prominent mediastinal emphysema or sion of typical Pneumocystis pneumonia based on the num-
frank pneumothorax can be noted. The color of the lungs ber and location of organisms and the cellular response in
is variously described as dark bluish purple, yellow-pink, pulmonary tissue. The lung samples were from children
or pale gray-brown. The pleural surfaces are smooth and with underlying malignancy who had received intensive
glistening, with little inflammatory reaction. Hilar adenop- chemotherapy. The authors categorized three sequential
athy is uncommon. Necrosis of tissue is not a feature of the stages in the course of the disease. In the first stage, no sep-
disease. tal inflammatory or cellular response is seen, and only a
Although these gross features of widespread infection few free cyst forms are present in the alveolar lumen; the
are strikingly characteristic, focal or subclinical pneumo- remainder are isolated on the alveolar septal wall. The sec-
cystosis presents a less recognizable picture. In this condi- ond stage is characterized by an increase in the number of
tion, the lung has tiny 3- to 5-mm reddish brown retracted organisms within macrophages fixed to the alveolar wall
areas contained within peribronchial and subpleural lob- and desquamation of these cells into the alveolar space;
ules, where hypostasis is greatest.16,19 Even these features, again, only minimal septal inflammatory response is seen
however, may be absent because of variable involvement of at this time. Finally, a third stage is identified, in which
adjacent lung tissue by concomitant pathologic processes. extensive reactive and desquamative alveolitis can be seen.
The microscopic appearance of both the contents and Such diffuse alveolar damage may be the major pathologic
the septal walls of pulmonary alveoli in Pneumocystis pneu- feature in certain cases.98 Variable numbers of cysts of the
monia are virtually pathognomonic of the infection. The organism, presumably undergoing dissolution, are present
outstanding histologic finding with hematoxylin and eosin within the alveolar macrophages. These findings under-
stain is an intensely eosinophilic, foamy, or honeycomb-like score the thought that the so-called foamy exudate within
material uniformly filling the alveolar sacs (Fig. 34-3). This alveoli is neither foamy edema fluid nor the product of an
intraalveolar material is composed largely of Pneumocystis, exudative inflammatory reaction but largely a collection of
host cells, immunoglobulin, and proteinaceous debris.94,95 coalesced alveolar cells and macrophages that contain siz-
Typical cyst forms of the organism within alveoli are vis- able digestive vacuoles and remnant organisms.
ible only after application of special stains such as methe- The mechanism of spread of Pneumocystis throughout
namine silver. pulmonary tissue is not completely understood. Direct
The type and degree of cellular inflammatory responses invasion by the organism through septal walls into the
provoked by the intraalveolar cluster of Pneumocystis interstitium or the lymphatic or blood vascular spaces
organisms vary based on host response (see “Pathogen- of the lung is considered unlikely,19,97 except in rare
esis”). The descriptive histologic term for pneumocystosis— instances when systemic dissemination of the organism
interstitial plasma cell pneumonia—is derived from the occurs.
pronounced plasma cellular infiltration of the interalveolar Interstitial fibrosis is a distinct but infrequently reported
septa observed almost exclusively in newborns in European complication of Pneumocystis pneumonia in older children and
nursery epidemics. Distention of alveolar walls to 5 to 10 adults but has been reported in infants only rarely.92,93,99-101
times the normal thickness, with resultant compression Nowak,100 in Europe, first emphasized that fibrosis was not
of alveolar spaces and capillary lumens, typically is noted unusual in the lungs of infants at autopsy who had especially
in this form of the disease. Hyaline membranes develop protracted infection with P. jirovecii. Pneumocystis-infected
lungs sometimes demonstrate, in addition to fibrosis, other inescapable conclusion of these carefully designed studies
pathologic features compatible with a more chronic destruc- was that Pneumocystis infection is latent in rats and rabbits
tive inflammatory process. Multinucleate alveolar giant cells and becomes clinically manifest only when host resistance
occasionally accompany alveolar cell proliferation.16,19,93 is altered or that Pneumocystis is ubiquitous in the environ-
Whether presence of these cells is more often a response to ment and capable of infecting a susceptible host.
undetected concomitant viral infection is unknown. Typi- The issue of latency is an important one in defining the
cal granulomatous reactions with organisms visible in the pathogenesis of Pneumocystis pneumonia. To determine
granulomas also have been described.93,102,103 Extensive whether Pneumocystis establishes latency after infection,
calcification of Pneumocystis exudate and adjacent lung tissue SCID mice, which resolve naturally acquired Pneumocystis
may ultimately develop.93 carinii pneumonia (PCP) after reconstitution with immuno-
competent spleen cells, were observed for evidence of a latent
PATHOGENESIS Pneumocystis infection.108 Neither P. carinii nor amplified P.
carinii DNA was detected in the lungs of SCID mice killed
The clinical conditions that predispose patients to the devel- 21 days after spleen cell reconstitution. Furthermore, SCID
opment of Pneumocystis pneumonia are associated with mice that recovered from P. carinii infection failed to reac-
impaired immune responses, leading to the presumption tivate the infection after they were either depleted of CD4+
that Pneumocystis causes disease, not because it is intrinsi- cells for up to 84 days or depleted of CD4+ cells and treated
cally virulent but because the host’s immune mechanisms with corticosteroid for 35 days. These results indicate that
fail to contain it. The severity of P. jirovecii pneumonia in an immune response to P. carinii can completely clear the
infants with AIDS illustrates this phenomenon dramati- organism from the host. This supports the hypothesis that
cally. The primary role of immunocompromise also would P. carinii pneumonia that develops in immunocompromised
explain, in part, why Pneumocystis pneumonia did not patients is due to exposure to an exogenous source of P. cari-
emerge as a serious health problem until more than 30 nii rather than reactivation of latent infection. Experiments
years after the disease was first recognized. European epi- using the steroid-treated rat model of Pneumocystis infec-
demics of Pneumocystis arose out of the devastation of World tion demonstrated similar findings.109
War II and widespread use of antibacterial drugs. Each of In 1966, Frenkel and colleagues110 published a hallmark
these two seemingly unrelated events served ultimately to study of rat pneumocystosis. They showed that clinical and
disrupt the normal host-organism immunologic interaction histopathologically significant involvement with Pneumo-
in favor of the organism. The war resulted in institutional- cystis is regularly inducible in rats by “conditioning” them
ization of inordinate numbers of orphans under conditions with parenteral cortisone over a period of 1 to 2 months.
of overcrowding and malnutrition. At the same time, anti- Premature death from complicating bacterial infection
bacterial therapy dramatically enhanced survival rates of was prevented by simultaneous administration of antibac-
these institutionalized infants, who would otherwise have terial agents. Of interest is their finding that regression of
succumbed to bacterial sepsis during the first days or weeks established interstitial pneumonitis occurs if cortisone con-
of life. In addition, it was realized that Pneumocystis infec- ditioning is stopped early enough; on the other hand, rats
tion appeared in these marasmic children at an age when continuing to receive cortisone die of coalescent alveolar
their immunoglobulin G (IgG) levels reached a physiologic Pneumocystis infiltration, and the infiltrate is almost devoid
nadir. By 1960, the orphanage epidemics had abated in of inflammatory cells. These histologic changes are, in
Europe as environmental conditions improved, but they fact, an exact replica of those observed in sporadic cases of
persisted in Asia, where poverty and overcrowding con- human Pneumocystis infection developing in congenitally
tinued.84,104 Subsidence of the epidemic disease and more immunodeficient and exogenously immunosuppressed
widespread antibacterial drug therapy, as well as sophis- patients. Attempts to precipitate clinical pneumocystosis
ticated immunosuppressive drug treatment, contributed with a variety of immunosuppressants other than cortisone
thereafter to awareness in Europe and North America of were also explored. Of eight cytotoxic agents and antime-
isolated instances of Pneumocystis infection among children tabolites tested, only cyclophosphamide was shown to make
suffering from a variety of identifiable immunodeficiencies. the rats susceptible to infection by Pneumocystis. Total-body
Weller,105,106 in Europe, was among the first to experi- irradiation and lymphoid tissue ablation (splenectomy, thy-
mentally induce Pneumocystis pneumonia in animals. His mectomy) by themselves were incapable of inducing overt
crucial observation relative to pathogenesis of the infection Pneumocystis pneumonia.
was that in rats pretreated with cortisone (and penicillin) The clinical association between pneumocystosis and
and exposed to suspensions of Pneumocystis-containing protein-calorie malnutrition also has been reproduced in a
lung tissue, Pneumocystis pneumonia develops with the rat model.111 Healthy rats given either a regular or a low-
same frequency and severity as in corticoid-treated ani- protein diet gain weight and exhibit little to no evidence
mals that were not subsequently inoculated with organ- of pneumocystosis postmortem. By contrast, in rats fed a
isms. The intensity of such artificially induced animal protein-free diet, which produces weight loss and hypoal-
infection also was noted to be less marked than that in buminemia, fatal infection regularly developed; adminis-
spontaneous human pneumocystosis of the epidemic tration of corticosteroid only foreshortened their median
variety. Comparable observations in the rabbit model survival time.102
were made by Sheldon107 in the United States. He showed None of the experimental models described thus far permit
that cortisone and antimicrobial agents were sufficient a precise appraisal of the relative importance of the cellular
to induce Pneumocystis infection without direct exposure and humoral components of host defense against Pneumocys-
of animals to an exogenous source of organisms. The tis. Although corticosteroids, cytotoxic drugs, and starvation
interfere primarily with cell-mediated immunity, they do not pulmonary inflammation and the severity of PCP was noted
always induce purely functional cellular defects. Rather, the and suggested that the host response to infection affects
immunosuppressive effects of chemotherapeutic agents or the clinical manifestation of PCP.120,121 Before the AIDS
of malnutrition are far more complex, and ultimately both epidemic, the majority of PCP cases occurred in patients
cellular and humoral arms of the immune system may be with hematologic malignancies, and often it was noted
impaired by them. that the onset of PCP coincided with cessation of corticoste-
The production of pneumocystosis in the nude mouse roid treatment. Similarly, the onset of PCP in bone marrow
without the use of exogenous immunosuppressants implies transplant recipients often coincided with engraftment. In
that susceptibility to the infection relates most to a defect both examples, Pneumocystis infection likely occurred dur-
in thymic-dependent lymphocytes.112 The role of anti- ing the period of immunosuppression, but the clinical mani-
body deficiency is less clear. A role for antibody in control festation was not evident until a degree of immune function
of infection with the organism has been shown in vitro by was restored, suggesting that the host-driven pulmonary
demonstrating that Pneumocystis organisms adherent to rat immune response contributed to the disease process. The
alveolar macrophages become interiorized only after anti- onset of the AIDS epidemic offered a distinct subset of PCP
Pneumocystis serum is added to the culture system.113 patients who suffered from profound immunosuppression.
That primary humoral immune deficits could predis- Comparison of patients with AIDS-related PCP to patients
pose to sporadic pneumocystosis was first reported, unwit- with non-AIDS PCP revealed that AIDS patients had a more
tingly, by Hutchison114 in England in 1955. He described subtle onset of symptoms with better pulmonary func-
male siblings with congenital agammaglobulinemia who tion and better prognosis, despite harboring higher lung
died of pneumonia of “similar and unusual” histology. P. fungal burdens. Furthermore, the severity and prognosis
jirovecii was implicated as the etiologic agent of these fatal for PCP patients was found to correlate with the degree of
infections only when the pathologic sections were reviewed pulmonary inflammation but not with organism burden.
by Baar.115 Burke and colleagues116 stressed what was to Together, these findings suggest that the host response to
be regarded as a typical histologic finding in Pneumocys- Pneumocystis infection contributes to lung injury and respi-
tis-infected agammaglobulinemic children, namely, the ratory impairment during PCP.
absence or gross deficiency of plasma cells in pulmonary The development of animal models of Pneumocystis
lesions (and in hematopoietic tissues). This deficiency con- infection has proved invaluable for elucidating the immu-
trasted sharply with the extensive plasmacytosis seen in nopathogenesis of PCP.122-126 SCID mice lack functional
epidemic infections. lymphocytes and are highly susceptible to Pneumocystis
Pneumocystis been reported in association with a pure infection. An early study found that when Pneumocystis-
T-cell deficiency, namely, in DiGeorge syndrome.117 That infected (SCID) mice were immune reconstituted by the
the integrity of the cellular immune system is critical for adoptive transfer of functional lymphocytes, the mice suf-
resistance to Pneumocystis may be inferred from the steroid- fered from rapid deterioration and high mortality rates.
induced and congenitally athymic animal models of pneu- Subsequent studies found that immune reconstitution of
mocystosis described earlier. Most Pneumocystis infections Pneumocystis-infected SCID mice induced a rapid increase
occurred in infants with SCID, a state characterized by pro- in the pulmonary expression of proinflammatory cytokines
found depression of both cellular and humoral immunity. and chemokines and the recruitment of cellular infiltrates
For many years it had not been possible to study in vitro into the lungs. Although immune reconstitution provided
the cellular immune response to P. jirovecii because of the the benefit of restoring an effective CD4+ T-cell–depen-
impurity of available antigens. Preliminary experiments dent immune response against Pneumocystis infection, it
with an antigen derived from a cell culture suggested that also had profound effects on physiology, including severe
specific cell-mediated immunity may be depressed in chil- weight loss, tachypnea, hypoxia, and decreased lung com-
dren with active Pneumocystis pneumonia. Lymphocytes pliance. Of importance, nonreconstituted SCID mice with
from two such children failed to transform in the presence similar fungal burdens appeared physiologically normal
of the antigen,118 whereas lymphocytes from healthy, sero- and showed little evidence of PCP-related disease, suggest-
positive adults were, in most cases, stimulated specifically to ing that Pneumocystis itself is not the direct cause of pulmo-
undergo blastogenesis.118,119 nary damage, at least early in the evolution of the disease
Although PCP was clearly defined as an opportunistic process. The immune-reconstituted SCID mouse model
pathogen causing clinical disease in patients suffering from of PCP is similar to the clinical syndrome termed immune
primary or, more commonly, secondary immunodeficien- reconstitution inflammatory syndrome (IRIS), which has
cies, for many years the pathogenic mechanisms by which been reported in AIDS patients after institution of combined
Pneumocystis caused lung injury and respiratory impair- antiretroviral therapy. The rapid recovery of CD4+ T lym-
ment remained mostly undefined. Histologic observations phocytes causes an intense pathologic pulmonary immune
of infected lung tissue demonstrated that Pneumocystis response to preexisting pulmonary infections, including
attaches to alveolar epithelial cells in the distal lung and Pneumocystis. Patients with PCP-related IRIS suffer severe
that these cells are preferentially damaged during severe pulmonary decompensation and have poorer survival rates
PCP. However, the nature of the injury was unclear, and than patients with a classic AIDS-related presentation of
progress in understanding this organism and identify- PCP. These observations highlight the contribution of the
ing potential toxins or virulence factors was hampered immune response to PCP pathogenesis.
by the lack of an axenic culture system. Clinical observa- Classic AIDS-related PCP has also been effectively
tions offered some insight into the nature of PCP-associated modeled in mice. Continual administration of anti-CD4
lung injury. A positive correlation between the degree of monoclonal antibody maintains mice in a chronic CD4+
T-cell–depleted state. CD4-depleted mice are susceptible requires, above all, a high index of suspicion whenever
to Pneumocystis infection and develop a clinical syndrome interstitial pneumonia occurs in settings known to pre-
very similar to AIDS-related PCP in humans. Several stud- dispose to infection with the organism. It may be inferred
ies have demonstrated that in the absence of CD4+ lympho- from these observations that pneumocystosis is not
cytes, large numbers of CD8+ T cells are recruited to the merely an end-stage infection in a host with a pretermi-
lung in response to Pneumocystis infection.122-124 These nal illness but, on the contrary, often represents a poten-
lymphocytes are unable to control Pneumocystis infec- tially treatable cause of death in patients whose primary
tion but directly contribute to lung injury and PCP-related immunodeficiency or malignancy is being controlled.
pathogenesis. Mice depleted of both CD4+ and CD8+ lym-
phocytes are much healthier compared with mice depleted Symptoms and Signs
of only CD4+ lymphocytes. Together, these findings support Epidemic Infection in Infants. The onset of epidemic-type
the immunopathogenic features of PCP. Although infec- infection, essentially nonexistent in developed countries, in
tion is necessary to cause pneumonia, certain aspects of infants is reported to be slow and insidious. Initially, nonspecific
the immune response cause disease symptoms. Differences signs of restlessness or languor, poor feeding, and diarrhea
in the degree of immunosuppression among PCP patients are common. Tachypnea and periorbital cyanosis gradually
likely affect their ability to produce an immunopathogenic develop. Cough productive of sticky mucus, although not
response to infection and may account for variability in the prominent, may appear later.10,19 Respiratory insufficiency
severity of PCP between different patient groups. progresses over 1 to 4 weeks, and patients exhibit increasingly
The mechanisms of PCP-related immunopathogenesis are severe tachypnea, dyspnea, intercostal retractions, and flaring
not clearly defined. Although both CD4+ and CD8+ lympho- of the nasal alae. Fever is absent or of low grade.133 Physical
cyte-driven events have been implicated in immunopatho- findings are strikingly minimal and consist primarily of fine
genesis, the specific mechanisms have not been elucidated. crepitant rales with deep inspiration. Chest radiographs, how-
The appearance of neutrophils and neutrophil chemotactic ever, typically demonstrate pulmonary infiltrates early in the
factors in the lung correlate with a poorer prognosis for illness. The duration of untreated disease is 4 to 6 weeks, but
PCP patients.120,121 However, these cells do not appear to it often is difficult to determine an exact date of onset of illness.
directly contribute to either host defense against Pneumo- Before the introduction of pentamidine therapy, the mortal-
cystis infection or to PCP-related immunopathogenesis.126 ity rate for such epidemic infant infection is estimated to have
The proinflammatory cytokine TNF appears to be required been between 20% and 50%.134
for successful host defense against Pneumocystis infection,
and signaling through TNF receptors is also a major con- Sporadic Infection in Infants. The typical clinical
tributor to immunopathogenesis.127 A possible physiologic syndrome is less evident in sporadic cases of pneumo-
consequence of PCP-driven inflammation is pulmonary cystosis occurring in infants with acquired or con-
surfactant dysfunction.128,129 Surfactant is critical to nor- genital immunodeficiency and in older children with
mal gas exchange and proper lung function. Pulmonary acquired immunodeficiency. In infants with primary
inflammation elicited during Pneumocystis infection was immunodeficiency diseases, the onset of clinical infection
found to directly disrupt surfactant function, contributing can be insidious, and illness can extend over weeks or pos-
to PCP-related respiratory impairment. Although the spe- sibly months,135 a course not unlike that seen in epidemic
cific mechanisms of immunopathogenesis are not defined, pneumocystosis. By contrast, in most infants with con-
the contribution of inflammation and the immune response genital immunodeficiency or AIDS and in older children
to this disease process is recognized, and standard treatment with acquired immune deficits, Pneumocystis pneumonia
of moderate-to-severe PCP typically includes corticosteroids manifests abruptly and is a more symptomatic, short-lived
as adjunctive therapy to dampen inflammation. disease.50,55,97,135 Among infants with HIV infection, the
median age at onset is 4 to 5 months, and the mortality rate
is between 39% and 59%.136 High fever and nonproductive
CLINICAL MANIFESTATIONS cough are initial findings, followed by tachypnea, coryza,
and, later, cyanosis. Death may supervene within a week or
General Considerations so. If no treatment is given, essentially all patients with this
With the exception of hypoxia, no clinical features are form of pneumocystosis die.
pathognomonic for P. jirovecii infection. As discussed ear-
lier, the clinical presentation of PCP is influenced by the Radiologic Findings
patient’s residual capacity to mount an immune response. Because the extent of pulmonary involvement in P. jirovecii
For example, severely immunosuppressed AIDS patients pneumonia rarely is detectable by physical examination, a
often have a very subacute onset of PCP with a lower mor- chest radiograph showing diffuse infiltrative disease is the
tality than a patient being treated for a hematologic malig- most useful indicator of infection in a susceptible host.137
nancy who develops PCP while receiving maintenance Although certain characteristic patterns of radiographic
chemotherapy. Clinical syndromes ascribable to Pneumo- involvement have been ascribed to Pneumocystis pneumo-
cystis may be simulated by other infections (cytomega- nitis, it is worth emphasizing that the findings may vary
lovirus10), or by inflammatory processes (drug-induced depending on the presence of coincident pulmonary infec-
pulmonary toxicity,130 radiation fibrosis131) and neopla- tion as well as on the nature of the underlying disease state.
sia (pulmonary leukemia132) capable of producing inter- The radiographic findings of mild (“focal”) Pneumocystis
stitial pulmonary infiltrates in older children and adults. pneumonia described by Vessal and associates138 in infants
Thus recognition of pneumocystosis on clinical grounds from an Iranian orphanage included hilar interstitial
infiltrate, thymic atrophy, pulmonary hyperaeration, and Concentration of organisms within alveoli and inflamma-
scattered lobular atelectasis. Although none of these signs tion of the surrounding alveolar septa not unexpectedly
is specific for Pneumocystis infection, they persist longer lead to interference in gas transfer, whereas persistence of
(3 weeks-2 months) in serologically proven cases. Indeed, areas of normal lung parenchyma and lack of significant
surviving infants may exhibit focal interstitial infiltrates airway obstruction account for the usual absence of carbon
after organisms are cleared from the lung and for as long as dioxide retention.
1 year.133,139
In infants, especially those with immunodeficiency syn- Concurrent Infection
dromes, the initial radiograph often shows haziness spread- The clinical presentation of pneumocystosis may be altered
ing from the hilar regions to the periphery, which assumes by simultaneous infection with other organisms. Certainly,
a finely granular, interstitial pattern. An antecedent gross infection with a variety of opportunistic pathogens is not sur-
alveolar infiltrate usually is not seen. The peripheral granu- prising in patients with broadly compromised immunologic
larity may progress to coalescent nodules. These changes defense mechanisms. Infection with one or more organ-
resemble the “atelectatic” radiographic abnormalities of isms was found in 56% of Pneumocystis-infected infants and
hyaline membrane disease. In both conditions, aeration children with primary immunodeficiency disease reported
is absent peripherally. Pneumothorax with subcutaneous to the CDC.54 Comparable rates of multiple infections also
and interstitial emphysema and pneumomediastinum are have been noted in several large series of patients with
not uncommon and are associated with a poor progno- acquired immune defects and pneumocystosis.96,135,143
sis.140 Even with therapy, radiographic clearing can lag far Infection with cytomegalovirus appears to be the most
behind clinical improvement. common “unusual” infection associated with pneumocys-
As experience with Pneumocystis has broadened, espe- tosis. Indeed, in his 1957 review, Gajdusek10 already was
cially in older children and adults, a number of atypical able to cite numerous published studies referring to the
radiographic abnormalities have been described.141 These “unexpectedly high frequency of association” of the two
atypical findings include hilar and mediastinal adenopathy, infections. He conceded that one infection most probably
pleural effusions, parenchymal cavitation, pneumatoceles, predisposed the affected patient to the other. On the basis
nodular densities, and unilateral or lobar distribution of of electron micrographic observations of cytomegalovirus-
infiltrates. By contrast, the chest radiographic appearance like particles within pneumocysts, histopathologic exami-
can remain essentially normal well after the onset of fever, nation of lung biopsy specimens from infants with AIDS
dyspnea, and hypoxemia. The presence of such radiograph- often demonstrates concomitant cytomegalovirus and
ically silent lung disease can be visualized as abnormal P. jirovecii infections.144,145
findings by pulmonary computed tomography.
Laboratory Studies DIAGNOSIS
Routine laboratory studies yield little diagnostic information The diagnosis of Pneumocystis pneumonia remains difficult.
in Pneumocystis infection. Abnormalities in hemoglobin con- The organism must be visualized in the respiratory tract
centration or white blood cell count are more likely to result of ill persons, and often this can be accomplished only by
from an underlying disease of the hematopoietic system or bronchoalveolar lavage (BAL) or, in infants, a lung biopsy.
cytotoxic drug effect. Neither laboratory value is consis- Recently, polymerase chain reaction (PCR) assay has been
tently altered by secondary pneumocystosis. Nevertheless, a used for diagnosis in fluid specimens obtained by BAL. Nev-
subgroup of infants with primary immunodeficiency disease ertheless, this technique is still not generally available for
and infection caused by P. jirovecii can exhibit significant routine clinical use. Attempts to isolate Pneumocystis from
eosinophilia.19,83,134,135 Jose and associates 83 first empha- clinical specimens on synthetic media or in tissue culture
sized the association of peripheral blood eosinophilia and have not been successful, and serologic techniques to detect
pneumocystosis in a report describing three infected male active infection have been too insensitive.
siblings with infantile agammaglobulinemia. In one of the
infants, eosinophilia developed very early in the course of Examination of Pulmonary Secretions
the illness, and the differential eosinophil count peaked at Diagnosis of sporadic cases of pneumocystosis by examina-
42% as the respiratory disease worsened. In accordance, it tion of sputum or tracheal and gastric aspirates has never
has been suggested that the combination of cough, tachy- been rewarding. The rate of recovery of Pneumocystis from
pnea, diffuse haziness on chest radiographs, and eosino- upper airway secretions in the cases compiled by the CDC
philia in an infant with immunodeficiency can be indicative was estimated to be only about 6%.55 Japanese investigators
of Pneumocystis pneumonia. A constant pathophysiologic have described a method of concentrating sputum samples
finding in pneumocystosis, as well as in other interstitial with acetyl-l-cysteine in 0.2 N sodium hydroxide solution,
pulmonary diseases, is that of ventilation and perfusion which permits filtration and centrifugation of a pellet of
defects most compatible with an “alveolar-capillary block” Pneumocystis.146 Ognibene and associates147 reported the
syndrome.135,142 Arterial blood gas determinations in use of induced sputa in the diagnosis of pneumonia in 18
infected patients show severe hypoxemia and hypocapnia, children with HIV infection or malignancy. Nine sputum
often before profound subjective respiratory insufficiency or samples were positive for P. jirovecii by immunofluores-
even radiologic abnormalities supervene. Less commonly, cent antibody testing. Four of the patients with negative
modest hypercapnia with respiratory acidosis is recorded. findings by examination of sputum samples subsequently
This respiratory pathophysiology correlates well with the underwent BAL; BAL fluid was negative for P. jirovecii in
anatomic pulmonary lesion in Pneumocystis pneumonia. all four. The remaining five patients received treatment for
bacterial pneumonia and responded to therapy. This tech- of antibodies are present in sera of diseased infants during
nique required ultrasonic nebulization in the children, and the first weeks of pneumonia, but only IgG antibodies per-
the youngest patient in this report was 2 years of age. sist during convalescent periods or in cases of protracted
infection.161
Percutaneous Lung Aspiration The worth of immunofluorescent antibody tests in the
The need to obtain lung tissue for a more accurate assess- diagnosis of sporadic pneumocystosis was examined subse-
ment of the presence of Pneumocystis pneumonia has been quently in the United States by Norman and Kagan162 at the
appreciated for some time. Percutaneous needle aspira- CDC. They observed low rates of serologic reactivity among
tion of the lung was successfully used in infected infants patients with suspected and confirmed cases, positive results
and children with underlying primary and acquired in sera from patients who seemed to have only cytomega-
immunodeficiencies.148,149 The procedure is performed lovirus and other fungal infections, and negative results in
without general anesthesia so that the child’s respiratory sera from six infants with primary immunodeficiency dis-
function is not further compromised. Under fluoroscopy, a eases and documented pneumocystosis. Although it is pos-
20-gauge spinal needle with syringe in place is guided into sible to increase the specificity and sensitivity of these tests
the midportion of the lung. The resultant aspirate (usually for Pneumocystis,163,164 such tests detect background levels
< 0.1 mL) may be transferred directly to slides, allowed to of Pneumocystis antibody in clinically healthy persons and,
air dry, and then stained with Gram, GMS, and toluidine as a result, fail to discriminate between patients with active
blue O stains. Children with platelet counts of less than disease and those with past unrecognized infection.
60,000/mm3 receive fresh whole-blood or platelet trans- To avoid the problem posed by the insensitivity of anti-
fusions before the procedure. Pneumothorax appears to body determinations per se in pneumocystosis, Perera
be the major complication encountered. In one series, it and colleagues52 developed a counterimmunoelectropho-
occurred in 37% of the patients, and evacuation of air by retic assay for detecting circulating Pneumocystis antigen
thoracotomy tube was required in 14%.149 in suspected cases. In an initial evaluation of the test,
antigenemia was demonstrated in up to 95% of children
Lung Biopsy with Pneumocystis pneumonia and was absent in normal
It has been argued that aspiration is inferior to biopsy in control children. Antigen also was found in the sera of
that the former does not permit histologic examination 15% of oncology patients who did not have pneumonia,
of lung tissue. Open lung biopsy has been proposed as the however. Unfortunately, this ability to detect circulating
most reliable method for identifying and estimating the antigens has not been duplicated by other laboratories
extent of Pneumocystis infection, as well as for demonstrat- and as a result detection of antigenemia is not used to
ing the presence of complicating pathologic conditions, diagnose PCP.
such as coexistent infection, malignancy, or interstitial
fibrosis.150-152 It may be hazardous, however, to perform
a thoracotomy using general anesthesia in patients with TREATMENT
marginal pulmonary reserve. Although the procedure has
been associated with an acceptably low incidence of seri- Specific Therapy
ous complications in critically ill children,153-156 deter- Hughes and coworkers,165 in 1974, first demonstrated that
mination of its risk-to-benefit ratio based on the infant’s the combination of TMP-SMX was effective in treatment
underlying disease, expected life span, and clinical condi- of cortisone-induced rat pneumocystosis. This combina-
tion is appropriate in individual cases. Unfortunately, these tion was shown to be as efficacious as pentamidine in chil-
analyses have not yet been applied rigorously to infants and dren infected with Pneumocystis who also had underlying
young children with suspected pneumocystosis. Technical malignancy.166 Several uncontrolled trials of TMP-SMX in
modification in the performance of open biopsy that would congenitally immunodeficient infants and in older immu-
avoid general anesthesia and endotracheal intubation (e.g., nosuppressed children and adults confirmed the efficacy
using thoracoscopy) may be particularly advantageous for and low toxicity of this combination agent.167,168 The dos-
diagnosis of Pneumocystis pneumonia in small children.157 age used was 20 mg of TMP and 100 mg of SMX/kg body
Once obtained, there are a variety of acceptable staining weight/day, given orally in four divided doses for 14 days.
techniques that can be used to identify Pneumocystis. The This daily dose was two to three times that used in treat-
most commonly used staining methods include methena- ment of bacterial infections. The equivalent efficacy of TMP-
mine silver, toluidine blue O, Diff-Quick, calcofluor white, SMX and of pentamidine has been confirmed in pediatric
and immunofluorescence.158,159 cancer patients with P. jirovecii pneumonia.169
TMP-SMX is the drug of choice for treatment of P. j irovecii
Serologic Tests pneumonia in infants and children. The oral route of
It is clear that sensitive and specific serologic methods are administration can be used in mild cases, for which the
desirable to detect active Pneumocystis infection. It is disap- recommended dosage is 20 mg TMP plus 100 mg SMX/kg/
pointing that despite extensive investigation, no method day in divided doses every 6 to 8 hours apart. Infants with
has been proved to be entirely satisfactory. moderate or severe disease require treatment by the intra-
Serodiagnosis of P. jirovecii infection in infants by detec- venous route, with 15 to 20 mg TMP plus 75 to 100 mg
tion of immunofluorescent antibodies was first reported in SMX/kg/day in divided doses 6 to 8 hours apart. In general,
1964 in Europe.160 It was found that IgM and IgG anti-Pneu- treatment is given for 3 weeks. Adverse reactions to TMP-
mocystis immunofluorescent antibodies appear sequentially SMX will develop in approximately 5% of infants and chil-
in sera during the course of clinical infection. Both classes dren without HIV infection and 40% of children with HIV
infection; most commonly seen is a maculopapular rash Local reactions at injection sites, namely, pain, erythema,
that clears after discontinuation of the drug. Other adverse and frank abscess formation, developed in 10% to 20% of
reactions are uncommon and include neutropenia, anemia, patients.55,175 Elevation in serum glutamic-oxaloacetic
renal dysfunction, and gastrointestinal symptoms or signs. aminotransferase levels was frequently recorded and may
In infants who do not respond to TMP-SMX or in whom have resulted partly from this local trauma. Hypoglycemia
serious adverse reactions develop, pentamidine isethionate ensued not uncommonly after the fifth day of pentamidine
in a single daily dose of 4 mg/kg given intravenously may therapy but often was asymptomatic.174 Hypoglycemia
be used. Other drugs have been tested in limited studies in also was observed in pediatric patients with AIDS who were
infants and young children with HIV infection and P. jirovecii given pentamidine for treatment of P. jirovecii pneumonia.178
pneumonia, including atovaquone, trimetrexate-leucovorin, Pentamidine-associated pancreatitis also has been reported
oral TMP-dapsone, pyrimethamine-sulfadoxine, clindamy- in children and adults with HIV infection.179-181 Although
cin plus primaquine, and aerosolized pentamidine. overt anemia was rare, megaloblastic bone marrow changes
The ease with which TMP-SMX can be administered and or depressed serum folate levels were noted.174
its lack of adverse side effects make it an attractive combi-
nation for empirical therapy for suspected pneumocystosis. Supportive Care
Such treatment is reasonable in infants who are gravely ill A critical component in the management of Pneumocystis
and whose outlook for recovery from underlying disease is pneumonia is oxygen therapy. Because hypoxemia can be
bleak. Several objections to the universal adoption of this profound, the fraction of inspired oxygen should be adjusted
approach have been raised. In at least half of the immuno- to maintain the arterial oxygen tension at 70 mm Hg or
suppressed children with typical clinical and radiographic greater. The inspired oxygen concentration should not
features of Pneumocystis pneumonia, the illness is in fact not exceed 50%, to avoid oxygen toxicity. Assisted or controlled
related to infection with P. jirovecii.170 Identification of the ventilation may be required.
etiologic agent and proper management of the disorder can The use of early adjunctive corticosteroid therapy in the
be accomplished only by first performing appropriate diag- treatment of P. jirovecii pneumonia in adults with AIDS can
nostic procedures. increase survival and reduce the risk of respiratory fail-
Until 1958, no therapy specific for P. jirovecii infection ure.182,183 A national consensus panel has recommended
was available. In that year, Ivady and Paldy171 in Hun- the use of corticosteroids in adults and adolescents with HIV
gary recorded the first successful use of several aromatic infection and documented or suspected P. jirovecii pneumo-
diamidines, including pentamidine isethionate, in 16 of 19 nia.184 Two studies have supported the use of corticoste-
infected infants. By 1962, the Hungarian investigators had roids in decreasing the morbidity and mortality associated
used pentamidine therapy in 212 patients with epidemic with P. jirovecii pneumonia.185,186
Pneumocystis pneumonia.172 During the next several years,
favorable responses to this drug were observed in infants
and children with both the epidemic and the sporadic forms PROGNOSIS
of the infection.97,135 Treatment effected a dramatic reduc-
tion in the mortality rate for the epidemic disease from 50% Chronic Sequelae
to less than 4%.169,173 In the cases of sporadic infection Little is known about the residual effects of successfully
reported to the CDC,55,174,175 survival rates ranged from treated Pneumocystis pneumonia on pulmonary function.
42% to 63% for those patients who received the drug for 9 Patients may suffer additional “pulmonary” morbidity from
or more days. In cases confined largely to young children other opportunistic infections or from noninfectious com-
and managed at a single institution, cure rates were noted plications of underlying disease or its therapy. Hughes and
to be as high as 68% to 75%.97,166 Because spontaneous coworkers97 evaluated 18 children with underlying malig-
recovery from Pneumocystis pneumonia in immunode- nancies over periods of 1 to 4 years after surviving Pneumo-
pressed persons is rare, it is clear that pentamidine therapy cystis infection. Although pulmonary function tests were
reduced the mortality rate in such patients to nearly 25%. not performed, none of the subjects demonstrated clinical
The recommended dose of the drug is 4 mg/kg intra- or radiographic evidence of residual pulmonary disease. In
venously once daily for 14 days. Clinical improvement a subsequent study from the same institution, pulmonary
becomes evident 4 to 6 days after initiation of therapy, function was assessed serially in surviving children.187
but radiographic improvement may be delayed for several Significant improvement in function was noted within
weeks. 1 month of the infection, and all abnormalities resolved by
Pentamidine toxicity from intravenous and intramuscular 6 months.
use has been reported. Although toxicity from pentamidine It seems inevitable that respiratory dysfunction can
apparently was not a significant problem in the marasmic result from severe episodes of Pneumocystis pneumonia that
infants with Pneumocystis infection treated during the Euro- provoke interstitial fibrosis or extensive calcification (as
pean epidemics,176 the CDC determined that 189 (47%) of discussed earlier under “Pathology”). Cor pulmonale has
404 children and adults given the drug for confirmed or sus- been observed in infants with such protracted infection.135
pected Pneumocystis infection suffered one or more adverse In one notably well-studied patient, an adult with biopsy-
effects.55 Immediate systemic reactions, such as hypoten- proven fibrosis that appeared 4 months after curative
sion, tachycardia, nausea, vomiting, facial flushing, pru- pentamidine therapy, serial tests of pulmonary function
ritus, and subjective experience of unpleasant taste in the revealed persistent ventilatory defects of the restrictive type
mouth, were noted particularly after intravenous adminis- and impairment of carbon monoxide–diffusing capacity.101
tration of the drug. Herxheimer reactions occurred rarely.177 Although a possible link between pentamidine therapy
per se and lung fibrosis was suggested by earlier observa- (or autopsy material) 10 to 20 days after institution of drug
tions in rat pneumocystosis,110,188 healthy animals given treatment. Richman and associates192 demonstrated nor-
the drug exhibit no histologic abnormalities.97 Moreover, mal-appearing Pneumocystis organisms in a lung aspirate
pulmonary fibrosis has been described after Pneumocystis from a clinically cured patient 3 days after completion of his
pneumonia in patients who received treatment with pyri- 14-day course of pentamidine. Similarly, Fortuny and col-
methamine and sulfonamide189 and TMP-SMX.190 leagues196 recovered organisms from induced sputa on each
of 11 days of pentamidine injections.
Recurrent Infection TMP-SMX appears to have only a limited and nonlethal
Recurrence of Pneumocystis pneumonia after apparently effect on organisms. Experiments have shown that short-
curative courses of therapy has been documented in infants term treatment with the drug combination ultimately fails
and children with underlying congenital immunodeficiency to prevent emergence of recrudescent Pneumocystis infec-
or malignancy. As early as 1966, Patterson191 reported tion. In one study, a therapeutic dosage of TMP-SMX was
the case of an infant with probable SCID who experienced given prophylactically to children with acute lymphocytic
one presumptive and two substantiated bouts of pneumo- leukemia for a 2-week period beginning 28 days after initia-
cystosis at approximately 5-month intervals; treatment tion of antineoplastic treatment.197 Although the incidence
with pentamidine resulted in “cure” on each occasion, of Pneumocystis infection in these children after TMP-SMX
although radiographic abnormalities persisted. A few years was discontinued was not different from that observed in
later, Richman and associates192 and then Saulsbury and persons who did not receive the drug, the time interval
colleagues193 described recurrent pneumocystosis in two to development of infection was lengthened. Reinfection
children with hypogammaglobulinemia. In the first case, rather than relapse may have accounted for the late infec-
three proven attacks responded to pentamidine, and in tions, but relapse seems more likely in view of the follow-
the second child, two separate episodes of infection were ing results in experimental animals.198 Immunocompetent
treated successfully with TMP-SMX. At St. Jude Children’s rats were given TMP-SMX for as long as 6 weeks and then
Research Hospital, a study of 28 children with malignancy placed in individual isolator cages to exclude the possibil-
whose pneumocystosis was treated with pentamidine ity of acquisition of new organisms from the environmen-
revealed that 4 (14%) suffered a second infection.97,194 The tal air. After 12 weeks of immunosuppressive therapy with
clinical manifestations, radiographic findings, and response prednisone, P. jirovecii was still found in the lungs of at least
to therapy were similar for each child in both infectious epi- 90% of both the animals given TMP-SMX and the control
sodes. In addition, no differences in host factors were dis- animals (given no treatment). These human and animal
cernible in those patients who had recurrent infection and data are particularly relevant to the design of prophylac-
those who did not. Other examples of recurrent pneumo- tic regimens to prevent Pneumocystis infection in humans.
cystosis emerging rather soon after clinical recovery have They provide a compelling argument for the need to con-
been observed in patients given either pentamidine or TMP- tinue prophylaxis for as long as host defenses are consid-
SMX.195 Whether recurrences of Pneumocystis pneumonia ered to be too compromised to keep patients protected from
result from reinfection or from relapse of previously treated Pneumocystis infection. Survival and permanent immunity
infection is not known. to reinfection relate not to chemotherapy but to specific
Clinical and morphologic studies provide conflicting anti-Pneumocystis immunity in the affected infants. Unfor-
views on the completeness of Pneumocystis killing by specific tunately, the congenitally immunodeficient or exogenously
drugs. The Hungarian workers, who first used pentamidine immunosuppressed child does not possess such normal
in epidemic pneumocystosis among infants, witnessed pro- immune responsiveness and thus is subject to recurrent
gressive degeneration of P. jirovecii in tracheal mucus from infection.
the sixth day of therapy; by the tenth day, the organisms
had almost entirely disintegrated.172 In their review of spo- PREVENTION
radic pneumocystosis in the United States, Western and
associates174 similarly concluded that pentamidine proba- The first successful attempts to prevent pneumocystosis
bly eliminates organisms from the lung. In two patients, no with drugs were reported in infants with the epidemic form
microscopically visible P. jirovecii organisms were present of the infection. In a controlled trial conducted in an Iranian
at 5 and 14 days, respectively, after initiation of therapy. orphanage where the infection was endemic (attack rate
Also, none of 11 patients who died more than 20 days after of 28%), the biweekly administration of a pyrimethamine
receiving pentamidine had demonstrable organisms in their and sulfadoxine combination to marasmic infants before
lungs, even though they survived an average of 189.5 days the second month of life entirely eradicated Pneumocystis
after administration of the drug. In ultrastructural studies, pneumonia from the institution.16 In a children’s hospi-
Campbell26 detected what he believed to be the destructive tal in Budapest, Hungary, pentamidine given every other
effects of pentamidine on the organisms. In a lung biopsy day for a total of seven doses to premature infants from the
specimen obtained surgically 16 hours after onset of ther- second week of life provided equally effective prophylaxis.
apy, structurally normal trophozoites or mature cysts with During the 6 years of the study, Pneumocystis infection did
intracystic bodies were absent. A few apparent “ghosts” of not develop among 536 premature babies who received this
trophozoites were noted within phagosomes of intraalveo- treatment, whereas 62 fatal cases were recorded elsewhere
lar macrophages. in the city.199
By contrast, pentamidine does not promptly eradicate On the basis of promising results in a rat model of infec-
potentially viable forms of the organism. Hughes and tion, TMP-SMX was evaluated in a randomized, double-
coworkers97 identified intact P. jirovecii in lung aspirates blind, controlled trial in children with cancer who were at
extremely high risk for Pneumocystis pneumonitis.200 The although pulmonary aspergillosis occurs in term and pre-
daily dosage for prophylaxis was 5 mg of TMP plus 20 mg term infants, primary cutaneous aspergillosis (PCA) com-
of SMX/kg body weight, administered orally in two divided prises a much larger proportion of aspergillosis in this age
doses. Seventeen (21%) of 80 children receiving placebo group compared with older children and adults.207 For
acquired pneumocystosis, whereas the infection developed example, a large case series of invasive aspergillosis in chil-
in none of 80 patients given TMP-SMX. No adverse effects dren younger than 3 months (44 cases) reported by Groll
of TMP-SMX administration were observed, although oral and coworkers208 found that the number of children with
candidiasis was more prevalent among the patients in the pulmonary aspergillosis (10) was nearly identical to those
treatment group than among the control patients. In a with PCA.11 The most common underlying condition asso-
subsequent uncontrolled trial, the prophylactic efficacy of ciated with invasive aspergillosis in this series was prematu-
TMP-SMX was confirmed; cases of infection developed only rity (43% of patients), followed by chronic granulomatous
in those children in whom the TMP-SMX was discontin- disease (14%). Of interest, whereas 10 of 11 patients with
ued while they were still receiving anticancer chemother- PCA were preterm, only 2 of 10 patients with pulmonary
apy.201 More recently, a regimen of TMP-SMX prophylaxis aspergillosis were preterm; 5 of 10 term infants with pulmo-
given 3 days per week was shown to be as effective as daily nary aspergillosis were later diagnosed with chronic granu-
administration.202 lomatous disease, indicating that it would be reasonable to
The gratifying success of TMP-SMX prophylaxis in pre- evaluate infants who develop pulmonary aspergillosis for
vention of Pneumocystis infection has been duplicated in chronic granulomatous disease.
other medical centers caring for children with underlying Aspergillus spp. are ubiquitous environmental molds and
malignancy.203 Administration of the drug for the duration are an opportunistic pathogen in that the vast majority of
of antineoplastic therapy has become standard practice. exposed people do not develop disease. In the hospital set-
Congenitally immunodeficient children and infants with ting, there have been numerous reports of outbreaks or
AIDS who have had a prior episode of Pneumocystis pneu- clusters of aspergillosis within specific units or in groups
monia would appear to be prime candidates for preventive of at-risk patients. For example, a number of outbreaks in
therapy. The CDC issues a set of guidelines for chemopro- NICUs have been associated with construction or renova-
phylaxis against P. jirovecii pneumonia in children with tion projects at the hospitals housing these units.209 Pre-
HIV infection.204 These guidelines recommend promptly sumably, the disruption of dirt and soil caused by these
identifying infants and children born to HIV-infected projects increases the burden of exposure and, correspond-
women, initiating prophylaxis at 4 to 6 weeks of age for ingly, the likelihood of disease in high-risk patients. How-
all of these children, and continuing prophylaxis through ever, it is important to note that clusters of cases in preterm
12 months of age for HIV-infected children and offer new infants have also been linked to contaminated equipment
algorithms based on clinical and immunologic status to within the units themselves. For example, Etienne and
continue prophylaxis beyond 12 months of age. Although associates210 described a cluster of invasive aspergillosis in
no chemoprophylactic regimens for P. jirovecii pneumonia a NICU that was ultimately linked to contaminated humid-
among HIV-infected children have been approved as label- ity chambers. Invasive aspergillosis is sufficiently rare
ing indications by the U.S. Food and Drug Administration in term and preterm infants that any cases within a unit
(FDA), TMP-SMX currently is recommended as the drug of should prompt a careful consideration of possible sources of
choice in children with HIV infection. This recommenda- environmental contamination as a means to avoid larger
tion is based on the known safety profile of TMP-SMX and outbreaks.
its efficacy in adults with HIV infection and in children with
malignancies. Alternative regimens recommended for HIV- THE ORGANISM
infected children who cannot tolerate TMP-SMX include
aerosolized pentamidine in children older than 5 years of The genus Aspergillus is within the family Moniliaceae and
age, oral dapsone, and oral atovaquone. One study suggests is classified as an ascomycetous, saprophytic mold. The
that TMP-SMX use is associated with a decreased incidence species that cause disease most commonly are Aspergillus
of P. jirovecii pneumonitis and an increased incidence of fumigatus, which causes at least 90% of all disease, followed
HIV encephalopathy, both as initial AIDS-defining condi- by Aspergillus flavus, Aspergillus niger, and Aspergillus ter-
tions in infants and children.205 Most likely this was related reus.206 However, as the number of people living with pro-
to an “unmasking” of progressive encephalopathy among found immunosuppression has increased, the number of
infants who otherwise would have died earlier because of Aspergillus spp. that have been reported to cause invasive
P. jirovecii pneumonia. disease has increased; the list contains at least 20 differ-
ent species. Almost all cases of neonatal aspergillosis have
been caused by A. fumigatus.208 A distinguishing feature of
Aspergillosis pathogenic species is their ability to grow at human body
temperature (37° C); A. fumigatus, for example, can grow
Aspergillosis is the most common cause of human mold at temperatures as high as 50° C, and this characteristic
infections, and the most common species isolated from can be used to identify this specific species. Microscopically,
patients is Aspergillus fumigatus. Invasive infections are Aspergillus is a hyaline, septate, monomorphic mold that
extremely rare in preterm and term infants and are much shows dichotomous branching. The species are differenti-
less common than in older patients with compromised ated using a variety of distinguishing morphologic, myco-
immunity.206 Immunocompromised older children and logic, and biochemical characteristics. It is important to
adults typically present with pulmonary aspergillosis and, note that it can be difficult to differentiate Aspergillus spp.
from other types of molds during the initial evaluation of that lead to decreased growth at 37° C are attenuated for
clinical samples. virulence in animal models of aspergillosis. Other genes
that have been associated with decreased virulence in ani-
mal models include amino acid metabolism and iron acqui-
sition, as well as others.215 Once the fungus has breached
Aspergillosis is a rare infection in neonates and infants, and the pulmonary epithelium or epidermis, it is well known
the literature of such infections is limited to case reports and to invade tissue and blood vessels. Consistent with its sap-
case series. Consequently, it is not possible to estimate an rophytic nature, it is well adapted to growth along envi-
incidence rate. In general, the two primary modes of trans- ronmental gradients, which is thought to contribute to its
mission are inhalation of airborne conidia or through direct, characteristic angiotropism. Invasion of blood vessels has
localized inoculation of damaged or compromised tissues. two consequences. First, it leads to additional tissue damage
Person-to-person transmission has not been documented, and necrosis by destroying the blood vessel and depriving
whereas the clustering of multiple cases has been linked the local tissue of oxygen and nutrients. Second, angioinva-
to exposure to a common environmental source, such as sion facilitates dissemination to other organ systems within
humidifying units.210 Thus isolating affected patients is the host. The latter characteristic is particularly relevant
unlikely to prevent additional cases within a closed unit. to neonatal aspergillosis because many cases of PCA ulti-
The identification and control of possible sources of envi- mately lead to disseminated disease accompanied by sepsis
ronmental contamination is more likely to lead to the pre- and multiorgan system involvement.208,211 A commonly
vention of additional cases. encountered target organ of Aspergillus is the central ner-
For preterm infants in the NICU setting, PCA is the most vous system (CNS), and its angiotropism appears to also
common manifestation of aspergillosis, as illustrated by allow it to readily penetrate the blood-brain barrier.216 As
the large case series reported by Groll and associates.208 one might expect, CNS involvement is a complication of
As discussed in depth by Walsh,211 it is likely that the well- aspergillosis that is associated with a very poor prognosis.
characterized fragility of the skin of preterm infants is the
primary reason for the disproportionate rate of PCA relative PATHOLOGY
to pulmonary aspergillosis. A large multicenter retrospec-
tive analysis of 139 cases of invasive aspergillosis in chil- Because PCA is one of the primary manifestations of asper-
dren of all ages found that cutaneous aspergillosis was more gillosis in neonates, the histopathologic analysis of biopsy
common in children than adults; however, this study did specimens of infected tissue and skin is an important mode
not correlate age with incidence of PCA.212 In other popu- of diagnosis.208 Aspergillus is readily demonstrated in tissue
lations, a primary risk factor acquiring invasive aspergillo- using standard GMS or PAS stains. The hyphae are septate
sis is decreased levels or function of peripheral neutrophils. and hyaline and, classically, display dichotomous branches
Although neutropenia is not generally a complication of that emerge at an acute angle to the primary filament (<90
prematurity, there are numerous studies indicating that degrees). Although these features can allow one to distin-
premature infants have defects in specific neutrophil func- guish Aspergillus from Zygomycetes (aseptate, right-angle
tions, including migration, phagocytosis, and microbial branching), the histopathologic characteristics of Aspergil-
killing.213 No specific studies have examined the ability of lus are similar to a wide range of other pathogenic molds,
neutrophils from premature infants to respond to Aspergil- including Fusarium and Scedosporium. However, because
lus, but it is certainly possible that an inability of prema- these molds are exceedingly rare in infants and are gen-
ture neutrophils to make an effective response to microbial erally treated with the same agents, this ambiguity rarely
pathogens contributes to their risk for aspergillosis. The has clinical significance. Because of its angiotropic nature
study of Groll and associates208 underscores this possibil- and destructive effect on blood vessels, hemorrhagic necro-
ity in that it found that a significant portion of term infants sis is typical of infected tissue and is consistent with the
who developed pulmonary aspergillosis also had chronic necrotic skin lesions that are part and parcel of PCA in
granulomatous disease. Chronic granulomatous disease is neonates.207-210
genetic disease caused by mutation of the phox gene, lead-
ing to decreased respiratory burst in phagocytes, and is CLINICAL MANIFESTATIONS
characterized by increased susceptibility to aspergillosis as
well as other pathogens.214 The findings of Groll suggest The most distinctive manifestation of aspergillosis in neo-
that infants who develop pulmonary aspergillosis be evalu- nates and infants is the high percentage of PCA. The char-
ated for defects in neutrophil function, including chronic acteristic clinical feature of PCA is the appearance of skin
granulomatous disease.208 lesions. Initially, these lesions can be nonspecific raised
erythematous plaques and pustules.207-210 However, they
generally progress to macerated, ulcerated lesions with a
PATHOGENESIS
punched out appearance. In almost all cases, the lesions
Consistent with their opportunistic nature, Aspergillus spp. form necrotic eschars. Although these lesions are almost
do not display virulence factors in the traditional micro- characteristic of PCA, it is important to note that their
biologic sense (e.g., cholera toxin). To replicate and cause appearance is not pathognomonic of PCA, and they cannot
disease, the fungus must be able to withstand the host envi- be distinguished from skin lesions resulting from the sys-
ronment, and the thermotolerant nature of Aspergillus spp. temic dissemination of other microbial pathogens such as
that cause disease is an important trait required for viru- Pseudomonas aeruginosa or Staphylococcus aureus. Similarly,
lence. For example, mutants of specific genes (e.g., crgA215) as a number of authors have noted, pulmonary aspergillosis
does not have distinctive clinical characteristics that allow studies have evaluated its use in neonates and infants, and
it to be readily identified.207-210 thus its value for this patient population remains unknown
Regardless of the initial site of infection, many neonates and may be complicated by false-positive results. Other tests
develop disseminated disease with a sepsis-like syndrome that have been developed for aspergillosis, including serum
and multiorgan system involvement. Symptoms accompa- 1,3-β-glucan and PCR-based methods, remain experimen-
nying dissemination include hypotension, coagulopathy, tal or have not been sufficiently studied in this population to
and hepatosplenomegaly. Although almost any organ can warrant routine use.
be involved after dissemination, CNS disease is a frequent
complication. Because aspergillosis is difficult to diagnose, it THERAPY
is not surprising that CNS symptoms or findings may be the
initial clue to the diagnosis, as for the patient described by All three classes of antifungal agents used as monotherapy
Fuchs and coworkers.216 In the series of children younger (polyenes, azoles, and echinocandins) have specific agents
than 3 months reported by Groll and coworkers,208 four with activity against Aspergillus. Of these, amphotericin
patients with CNS disease as the only manifestation were B, either as the deoxycholate or as a lipid-based formula-
identified. tion, is the recommended therapy for neonatal aspergillosis.
The recommended dose of amphotericin B deoxycholate is
1 mg/kg day for infants and neonates.219 Three lipid formu-
DIAGNOSIS/DIFFERENTIAL DIAGNOSIS
lations of amphotericin B are available: L-amB (AmBisome),
The diagnosis of aspergillosis in the neonate and infant is amphotericin B lipid complex (ABLC, or Abelcet), and ABCD
extremely difficult for a wide variety of reasons, including (Amphotec). The pharmacokinetics and pharmacodynam-
its rarity and the fact that its clinical manifestations overlap ics of the lipid-based amphotericin B preparations have not
with other, much more commonly encountered pathogens. been studied extensively in neonates or infants, but doses
The most important method of diagnosing invasive infec- of 3 to 5 mg/kg/day are typically used.219 Amphotericin
tions in any patient population is the blood culture. Unfor- B deoxycholate appears to be tolerated better in neonates
tunately, blood cultures are almost invariably negative in than in older patients,220 and a small study comparing
the setting of invasive aspergillosis, a fact that is somewhat amphotericin B with liposomal amphotericin and ampho-
counterintuitive, given its angiotropism.206,212 In older tericin B colloidal dispersion found no difference in efficacy
patients, radiographic characteristics of pulmonary asper- or adverse events.221 In adult patients, liposomal prepara-
gillosis, such as the halo sign, can be suggestive of the diag- tions generally are associated with less renal toxicity and
nosis in an at-risk patient population.212 However, no such would be reasonable to use for a neonate with decreased
characteristics have been identified in neonates or infants. renal function. However, it is important to note that the
The skin lesions characteristic of PCA provide the most direct lipid preparations do not penetrate renal tissue well.
opportunity for diagnosis through biopsy, stains, and cul- In adult patients with aspergillosis, voriconazole, an azole
ture. In contrast to blood cultures, tissue culture yields rea- antifungal, was found to be superior to amphotericin B.222
sonable results; however, histologic identification of hyphal Two case reports have been published describing the use of
elements in a biopsy specimen in the absence of culture voriconazole, either alone or in combination with ampho-
results should prompt immediate treatment and is certainly tericin B and micafungin, to treat infants with PCA.223,224
sufficient for a presumptive diagnosis. It is also important to In both case reports, the infants had not responded to treat-
consider other potential diagnoses that are associated with ment with amphotericin B–based agents. Although Santos
a critically ill infant displaying ulcerative or necrotic skin and coworkers224 measured a variety of pharmacokinetic
lesions; these include other fungal infections such as inva- data for voriconazole, the routine use of voriconazole in
sive candidiasis, bacterial infections such as P. aeruginosa, infants and neonates awaits studies designed to establish
and disseminated viral infections such as congenital herpes effective dosing in this age group. This is particularly impor-
or enterovirus. tant for voriconazole because studies in older children have
Non–culture-based methods for the diagnosis of aspergil- revealed significant age-based variations in pharmacoki-
losis have been the subject of intensive interest.206,212 The netics and pharmacodynamics. Of the other azole agents
most widely used and best characterized of these tests is the available, itraconazole and posaconazole also have activity
serum galactomannan assay. The assay uses an enzyme- against Aspergillus. However, neither agent has been stud-
linked immunosorbent assay (ELISA)–based technology ied in neonates and, in general, should not be considered
to detect the presence of galactomannan in serum and, as a first-line treatment option. It is extremely important to
less commonly, other fluids such as BAL samples. Galacto- note that fluconazole, the most widely used antifungal in
mannan is a component of the Aspergillus cell wall but is NICUs, has no activity toward Aspergillus. If the diagnosis
absent from Candida spp. The assay has been widely adopted of aspergillosis is being considered and the patient is being
to monitor for and diagnose aspergillosis in adult patients. treated empirically with fluconazole, then the antifungal
Initial, small studies of the assay in children found that neo- agent should be changed to a mold-active drug.
nates had a significantly higher rate of false-positive tests. The echinocandins have been approved for salvage treat-
Subsequent studies indicate that this high false-positive rate ment of aspergillosis in adults. In contrast to voriconazole,
may be due to the high levels of Bifidobacterium in the gut of a reasonable amount of data is available to guide dosing of
neonates217; the lipoteichoic acid from this organism cross- this class of agents in neonates and infants.219 Currently,
reacts with the galactomannan ELISA. The galactomannan three echinocandins are available: caspofungin, micafungin,
assay has been studied in older children and seems to per- and anidulafungin. The recommended doses for these agents
form similarly to adult patients.218 However, no prospective vary with age and agent: caspofungin (25 mg/m2/day for
neonates younger than 30 days, 50 mg/m2/day for infants described in the literature.227-229 Of importance, transpla-
31 days-2 years of age), micafungin (10 mg/kg/day for cental transmission to the fetus appears to occur only rarely.
infants and neonates up to 2 years of age), and anidulafun- For example, Lemos and coworkers228 reviewed the litera-
gin (3 mg/kg/loading dose, followed by 1.5 mg/kg/day for ture reports of pregnancies complicated by blastomycosis and
infants and neonates up to 2 years of age). The echinocan- found that the fetus was infected in 2 of 20 cases (10%). Both
dins are only available as intravenous preparations. In addi- of the infected infants, however, died of blastomycosis.228,229
tion, they have an excellent safety profile and few drug-drug
interactions. Echinocandins are primarily used in the NICU THE ORGANISM
to treat invasive candidiasis caused by Candida spp. with
reduced susceptibility to fluconazole, for instance, Candida B. dermatitidis is a dimorphic fungus that grows naturally
glabrata and Candida krusei. Thus it seems reasonable to con- in the environment. At ambient temperature in the soil, it
sider the echinocandins as a logical choice as second-line or exists as a mycelial form. The conidia are the infectious form
salvage therapy for aspergillosis in a neonate or infant who of the organism, which, upon entrance into a mammalian
is either intolerant of, or not a candidate for, amphotericin host, rapidly germinate into the yeast form; a process that
B–based treatment. can be triggered in vitro by cultivation at 37° C. The yeast
form has a thick cell wall and forms a characteristically
wide bud-neck with daughter cells.
PROGNOSIS
In general, invasive aspergillosis carries a very poor prog- EPIDEMIOLOGY AND TRANSMISSION
nosis, regardless of underlying conditions. Because most of
the information regarding neonatal and infant aspergillosis B. dermatitidis is endemic to specific regions of North Amer-
is based on relatively small case series and case reports, it ica.225 Most cases occur in states that are located along the
is subject to significant ascertainment bias as well as other Mississippi and Ohio Rivers of the Midwest. In addition,
confounding factors. The large case series by Groll and cases have been reported in states and Canadian provinces
coworkers208 suggests that neonates and infants with PCA that border the Great Lakes and the St. Lawrence River.
that does not disseminate respond to therapy much more Within these regions are areas of hyperendemicity as well
frequently than those with secondary dissemination. In as isolated epidemics. Although sporadic cases of blastomy-
that study, 73% of patients with limited PCA were cured cosis have been reported outside of the traditional range,
with either medical or a combination of medical surgical many appear to be due to exposures within an endemic
therapy, whereas all patients with disseminated disease region, followed by travel.
died. However, because a significant number of cases of B. dermatitidis infects a mammalian host when the spores
PCA are complicated by dissemination, the serious nature are inhaled.225 Once inside the host, the organism germi-
of this infection cannot be underestimated and, as with nates to the yeast form, which replicates. The organism is
other fungal infection, early recognition and institution of not generally considered as being transmitted from person
appropriate therapy is crucial. to person, although there are reports of transmission via the
bite of an infected dog.230
PREVENTION
PATHOGENESIS
Outbreaks of aspergillosis in the health care setting have
been linked to environmental contamination related to Once the conidial form enters the pulmonary system, it rap-
construction at the health care sites as well as to contami- idly germinates to the yeast form. This transition appears to
nated equipment within NICUs per se.209,210 Therefore be required for pathogenesis. The conidia are more suscepti-
adherence to standard maintenance and practices with ble to killing by phagocytes, such as alveolar macrophages,
respect to humidifiers and other equipment that could har- than the yeast form.231 The surviving yeast forms are then
bor extensive contamination of mold is important. Because thought to replicate within the lung and spread to other
this is a rare disease, it would seem prudent to strongly con- body sites via the bloodstream. Infected tissues are subject
sider investigating any case of aspergillosis within a NICU to an acute inflammatory response involving both neutro-
for a potential environmental source. phils and macrophages; ultimately, cellular immunity to
Blastomyces develops.232
Blastomycosis PATHOLOGY
Blastomycosis is an endemic mycosis caused by Blastomyces Infected tissues are characterized by a pyogranulomatous
dermatitides, a dimorphic environmental fungus. In general, it response involving neutrophils, followed by macrophages.
is thought that the majority of B. dermatitides infections lead to The granulomas are generally not caseating, in distinction
a subclinical or nonspecific illness that is followed by resolu- from mycobacterial infections.
tion and the development of protective immunity.225 Outside
of epidemic outbreaks, children rarely present with clinically CLINICAL MANIFESTATIONS
apparent disease.226 In addition, immunocompromise does
not appear to predispose a patient to blastomycosis, but such The most common symptoms associated with blastomy-
patients may develop more severe disease.225 A number of cosis are nonspecific, including fever, malaise, and weight
cases of pregnant women with blastomycosis have been loss.225 Pulmonary symptoms include cough and pleuritic
chest pain. Disseminated disease can involve skin, bones, yeast form upon infection of a mammalian host or incuba-
CNS, and deep organs. Skin is the most common extrapul- tion at 37° C. The conidia of H. capsulatum are of two types:
monary site of infection. There have not been sufficient macroconidia with thick walls that contain projections
cases in neonates or infants to formulate a typical set of pre- and microconidia with smooth walls. The budding yeast
senting findings. forms are frequently seen with macrophages in histologic
samples.
DIAGNOSIS
As with the clinical manifestations, radiographic findings
associated with blastomycosis are not specific. The diagnosis H. capsulatum is distributed worldwide but has a well-
is most commonly made by microscopic or histologic identi- characterized endemic region within the United States
fication within infected tissue or fluid samples. It is cultiva- that includes the Mississippi and Ohio River Valleys of the
ble in the laboratory and can be isolated from blood, lavage Midwest and Southeastern regions of the country.233 The
fluid, and tissue. Non–culture-based methods, such as sero- microconidia of H. capsulatum in its mycelial phase are
logic and skin testing, are not helpful clinically, and none small (2-4 μm), readily aerosolized, and pass into the alveoli
have been studied in the setting of neonates and/or infants. when inhaled. The vast majority of histoplasmosis is sub-
clinical or results in a self-limited nonspecific illness.225,233
Almost all cases are due to sporadic, local exposure, but
THERAPY
two large outbreaks have been associated with urban con-
Because there are very few cases of blastomycosis in neonates struction projects in Indianapolis.237 Before the advent of
and because amphotericin B–based therapy has been used in highly active antiretroviral therapy for HIV/AIDS, attack
adults for serious infections, it would seem most prudent to use rates were much higher for persons living with HIV/AIDS
this agent.225 Fluconazole has been used in mild-to-moderate in Histoplasma-endemic areas.238
disease in older children and adults and could be regarded as
an alternative. Again, there is almost no experience available, PATHOGENESIS
and any treatment plan must be devised on a case-by-case
basis by analogy to those used in adults and older children. The inhaled conidia undergo morphogenesis to the yeast
form. Alveolar macrophages phagocytose both conidia and
yeast cells, but the yeast cells are able to survive within the
PROGNOSIS
phagolysosome and replicate. Within the macrophages,
All reported cases of blastomycosis in neonates have been the organisms traffic to hilar and mediastinal lymph nodes
fatal. On a more encouraging note, very few infants appear from which they disseminate to other sites of the reticuloen-
to be born to pregnant women with disseminated disease. dothelial system. The crucial factor for containment of the
infection is the development of T-cell immunity.233 The sen-
sitized T cells activate macrophages which, in turn, are able
PREVENTION
to kill the organism and clear the infection. As discussed by
Because many of the pregnant women with blastomycosis Kauffman,233 the severity of disease is also dependent on
were treated, it is possible that treatment could play a role in the size of the infecting inoculum. An immunocompetent
preventing transmission to the fetus. person, for example, can develop severe disease if they are
exposed to a large amount of conidia. Thus the nature of the
clinical outcome of histoplasmosis is a function of both the
Histoplasmosis nature of the patient’s exposure and the immune response
that the patient mounts to the pathogen. With that said, the
Histoplasmosis is an endemic mycosis caused by the dimor- majority of patients who develop severe disease also have
phic fungus, Histoplasma capsulatum. Histoplasmosis is the deficiencies in cell-mediated immunity.
most common endemic mycosis in the United States.233
However, like blastomycosis, very few cases of histoplasmo- PATHOLOGY
sis have been reported in neonates and young infants. A rela-
tively large case series of histoplasmosis in older infants has Tissue biopsy, from lymph nodes most commonly, will dem-
been reported, with the youngest patient being 6 weeks of onstrate yeast cells either within macrophages or free in
age.234 There have been two cases of congenital transmission the tissue upon staining with GMS or periodic acid–Schiff.
of histoplasmosis in the literature, including one patient with BAL samples rarely are positive unless there is a very large
congenital HIV infection.235,236 In contrast to the neonates organism burden; in such cases, it can also be possible to
who contracted blastomycosis, both infants with histoplas- identify organisms within neutrophils from smears of
mosis responded well to antifungal therapy and survived. peripheral blood. Infected lymph nodes also typically dem-
onstrate caseating granulomas.
THE ORGANISM
CLINICAL MANIFESTATIONS
H. capsulatum is a dimorphic, environmental fungus that
appears to thrive in soil containing the droppings of birds Histoplasmosis is generally asymptomatic or leads to
or bats.233 In its environmental niche, H. capsulatum exists an illness that is nonspecific, mild, and self-limited.
in a mycelial form and, like B. dermatitidis, transitions to the The most common clinically apparent manifestation of
histoplasmosis is acute pulmonary disease; most of these The child with relapse was cured after a second treatment
cases resolve without the need for antifungal therapy, course.234
whereas severe and chronic cases require antifungal ther-
apy.233 As noted earlier, dissemination of histoplasmosis
throughout the reticular-endothelial system occurs in Coccidiodomycosis
almost all cases. However, clinical disease accompanies
this dissemination only in immunosuppressed patients. Coccidioides immitis is a dimorphic fungus that is found in
Based on the case series reported by Odio and cowork- the soil of the Western Hemisphere. C. immitis is geographi-
ers,234 dissemination also occurs in otherwise normal cally restricted to area between 40°N and 40°S and, in the
infants.234 Of interest, many of these infants have T-cell United States, is found in the southwestern states, includ-
abnormalities at the time of infection that resolve with ing California, Nevada, Utah, Arizona, New Mexico, and
treatment of the histoplasmosis. Both children who were Texas.239 C. immitis is the etiologic agent of so-called valley
reported to have contracted histoplasmosis congenitally fever, which refers to its endemicity within the San Joaquin
presented with disseminated disease235,236 and, for one Valley in central California. Like other endemic fungi, C.
case, yeast forms were demonstrated within placental immitis is a mold in the soil that then undergoes morpho-
villi.235 The CNS can also be infected either as part of dis- genesis to a spherule form within the host. Also similar to
seminated histoplasmosis or in isolation. In accordance, other endemic dimorphs, the majority of C. immitis infec-
cultures of the cerebrospinal fluid (CSF) of both infants tions are asymptomatic, and most symptomatic infections
with congenital histoplasmosis were positive, indicating are self-limited. Severe pulmonary disease and dissemina-
CNS involvement.235,236 tion occur in a minority of cases, and people with deficits in
cell-mediated immunity are at higher risk for these compli-
cations. Pregnant women are at increased risk for severe
DIAGNOSIS
primary and disseminated coccidioidomycosis during the
H. capsulatum is cultivatable from tissue, blood, bone mar- second and third trimester.240,241 Based on the fact that
row, BAL, as well as other patient samples. In addition, there have been many cases of coccidioidomycosis in preg-
it is readily identified in biopsy samples by standard his- nant women and relatively few cases of neonatal infec-
topathologic techniques. An antigen assay that detects tions, it appears that vertical transmission of C. immitis is
a polysaccharide in serum or urine is also available. It is relatively rare. However, there have been 15 cases of neo-
most sensitive in the setting of disseminated disease and natal coccidioidomycosis described in the literature.242,243
severe pulmonary disease (75%-90%) but is much less so The majority of neonates infected with C. immitis have
in the setting of mild or chronic disease (10%-20%). The developed disseminated disease, with many resulting in the
urine antigen assay was positive in one of the congenitally death of the infant.
infected infants. A complement fixation test is also avail-
able and can be used to aid diagnosis, particularly in the THE ORGANISM
setting of disseminated or chronic pulmonary disease. Like
many serologic tests, it can be falsely negative in immuno- C. immitis is classified as an ascomycete, and ribosomal
compromised patients who are unable to generate a nor- DNA analysis indicates that C. immitis is related to the
mal humoral response. However, Odio and coworkers234 endemic dimorphic fungi H. capsulatum and B. dermatiti-
found that 93% of infants with disseminated histoplas- dis.241 In the soil, C. immitis forms septate hyphae that frag-
mosis were positive by complement fixation at the time of ment into barrel-shaped arthroconidia that are thought to
diagnosis, indicating that the test should be useful in this be the infectious particle. Within the host, the organism
age group. undergoes morphogenesis to a large (120 μm) compart-
mented, multinucleate structure called a spherule. The
internal structures within the spherule are referred to as
TREATMENT
endospores.241
The recommended treatment of histoplasmosis is depen-
dent on the severity of disease233; mild-to-moderate infec- EPIDEMIOLOGY AND TRANSMISSION
tions are treated with itraconazole, and severe infections
are treated with amphotericin B–based drugs. In the two Within endemic regions, seropositivity of residents has been
reported congenital infections,235,236 the children were reported to be quite high, particularly based on older studies.
treated with amphotericin B and a combination of ampho- A seroprevalence study performed in Arizona in 1985 indi-
tericin B and itraconazole. The infants described in the cated that 30% of those tested were seropositive.244 A study
series reported by Odio and coworkers234 were treated with comparing the incidence from 1937 to 1939 to that in 1995
amphotericin B for 40 days, followed by ketoconazole for a within the San Joaquin Valley indicated that it had decreased
total of 3 months. from 10% per year to 2% per year, respectively.245 Outbreaks
of coccidioidomycosis have been associated with strong wind
storms or earthquakes that generated large dust clouds.246
PROGNOSIS
Transmission is primarily through inhalation of dust con-
Both congenitally infected infants responded to treatment taining aerosolized arthroconidia. However, direct inocu-
and were cured.235,236 The cure rate for the series of infants lation of skin through traumatic wounds contaminated
with disseminated disease was similarly good, with 88% with soil has also been reported.247 Direct person-to-person
of patients cured; four died and one had recurrent disease. transmission of pulmonary coccidioidomycosis has not been
reported. Contact with infected fomites in the health care set- and requires special precautions in the laboratory. There-
ting has been documented.239 Some controversy exists in the fore the laboratory should be notified when samples from a
literature as to whether neonatal cases result from intrauter- patient suspected of being infected with C. immitis are sub-
ine transmission or from contact with infected body fluids mitted for processing. The diagnosis of coccidioidomycosis
within the birth canal.241 can also be established by histopathologic identification of
the characteristic spherules within biopsy or other clinical
samples. The organisms are readily stained with GMS and
PATHOGENESIS
PAS procedures. Finally, serologic assays are available. The
The inhaled arthrocondia of C. immitis undergo germina- IgM and IgG responses can both be determined using a vari-
tion, followed by isotropic growth that ultimately results ety of methods. Neonates infected with C. immitis appear to
in the formation of large spherules.239 The cycle of patho- generate antibodies reactive in these assays.242,243
genesis has been characterized as a parasitic life cycle. In
this model, the initial arthroconidia lead to spherule forma- TREATMENT
tion that contains a large number of small endospores. The
spherule then releases the endospores, which undergo dis- Similar to the approaches used for other pathogenic dimor-
persion and additional rounds of growth, spherule forma- phic fungi, amphotericin B is the drug of choice for severe
tion, and endospore release. The spherules are too large to or disseminated disease. Azoles (fluconazole, itraconazole,
be effectively phagocytosed by macrophages, whereas there and ketoconazole) also have activity against C. immitis and
is also evidence that the endospores are relatively resis- have been used as well. Sequential treatment with an ini-
tant to phagocyte-mediated killing. Ultimately, an effective tial course of amphotericin B, followed by oral fluconazole,
cell-mediated immune response appears to be required to has also been used. For example, the neonate described
contain the infection. For example, people who have mild, in the report by Charlton and coworkers243 was success-
self-limited infections develop delayed-type hypersensitivity fully treated with a three-week course of amphotericin B,
to C. immitis, whereas failure to mount this response is asso- followed by oral fluconazole. In adult patients, the relapse
ciated with more severe or disseminated disease.248 rate is between 15% and 30% after discontinuation of azole
therapy.
PATHOLOGY
PROGNOSIS
Pathologic specimens of tissue infected with C. immitis
show necrotizing granulomas, classically. In addition, the The outcome of disseminated disease in neonates and
spherules can be seen by histopathology and are diagnos- infants based on the available case reports is grim, with the
tic of coccidioidomycosis. Histopathology studies of the majority of patients succumbing to infection. The infant
placenta from pregnant women with disseminated disease described by Charlton and coworkers243 responded to ther-
have shown the presence of C. immitis spherules.249 apy and was well after a 6-month follow-up.
CLINICAL MANIFESTATIONS Cryptococcosis

Many infections with C. immitis are asymptomatic or lead
to mild, nonspecific symptoms, such as fever, cough, and Cryptococcosis is caused by Cryptococcus species and pri-
headache.239 Primary pulmonary disease is characterized marily manifests as meningoencephalitis and pneumonia
by an atypical pneumonia with radiographic findings that in immunocompromised persons.250 It is a global health
are indistinguishable from other types of pneumonia. Coc- problem primarily because people living with HIV/AIDS
cidiodomycosis is associated with a pruritic skin rash as are at increased risk, and it is one of the most common life-
well as the development of erythema nodosum or erythema threatening, opportunistic infections within that patient
multiforme in up to 25% of patients. Symptoms generally population.251 Otherwise healthy pregnant women also
manifest 1 to 4 weeks after infection and resolve without appear to be at increased risk of cryptococcosis.252 However,
treatment over weeks to months. Disseminated disease is even in the setting of infants born to HIV-positive mothers
associated with a poor cellular immune response248 and with cryptococcosis, vertical transmission of Cryptococcus
has been estimated to occur in less than 1% of patients. seems to be a rare event.253 With that said, a dozen cases of
Dissemination frequently involves the skin, bones, and congenital and presumed congenital infection in neonates
joints. Meningitis can also develop. The majority of neona- have been reported. The majority of these involved CNS and
tal coccidioidomycosis reported in the literature have been pulmonary manifestations.253
cases of disseminated disease involving CNS as well as deep
organs.242,243 THE ORGANISM
Cryptococcosis is caused by three varieties of the Cryptococcus
DIAGNOSIS
neoformans: var. neoformans; var. grubii; and var. gattii.250
C. immitis can be cultured in the laboratory from infected tis- C. neoformans is a basidiomycetous budding yeast that has a
sues.239 The yields are highest in respiratory secretions; for polysaccharide capsule. Five serotypes (A, B, C, D, and A/D)
example, C. immitis was cultured from deep tracheal aspi- have been identified based on the antigenic properties of the
rate from two of the neonatal cases.242,243 It is important capsule. The capsule plays an important role in pathogen-
to note that C. immitis presents a risk to laboratory workers esis. C. neoformans is an environmental organism associated
with bird droppings, particularly pigeon, as well as eucalyp- hematoxylin and eosin–stained samples. C. neoformans has
tus trees. The organism can undergo mating, which results been identified within placental tissue by histopathology
in the formation of mycelia and basidiospores. However, and involved both villi and intravillous space.
mating has not been observed outside of the laboratory.
CLINICAL MANIFESTATIONS
The pulmonary disease caused by C. neoformans in older
Park and coworkers251 have estimated that approximately children and adults does not have a specific presentation.250
1 million new cases of cryptococcosis occur each year world- Immunocompetent people are generally asymptomatic or
wide. The majority of these cases occur in regions with high have very mild disease, and constitutional symptoms are
rates of HIV; in sub-Saharan Africa, more people die each uncommon even in the setting of confirmed pulmonary
year from cryptococcal meningitis than from tuberculosis. infection. Pulmonary disease in an immunocompromised
The majority of these cases are caused by C. neoformans var. patient, however, is frequently accompanied by extrapul-
grubii and affect immunocompromised individuals. In the monary disease, including subclinical meningoencephali-
Pacific Northwest region of North America, C. neoformans tis258; therefore such patients require a full evaluation for
var. gattii is causing an ongoing outbreak that has mainly CNS and extrapulmonary disease. The meningoencepha-
involved people without apparent deficits in immunity.254 litis caused by C. neoformans is notable for its general lack
Transmission is thought to occur via inhalation of the organ- of meningismus and wide range of severity, from asymp-
ism; however, it is unclear as to whether the yeast form or tomatic disease to fulminant symptoms.250 Cranial nerve
the basidiospore is the infectious form.250 There are rare deficits are common, as is evidence of elevated intracranial
reports of local inoculation leading to skin infection. Person- pressure. Seizures can occur and are frequently related
to-person transmission through an aerosol route has not to cryptococcomas within the brain parenchyma. Skin
been reported. Vertical transmission to newborns has been lesions occur frequently (≈15%) and also range widely in
documented.253 The mechanism of vertical transmission appearance from pustules and papules to frank ulcers and
appears to involve both intrauterine and extrauterine expo- abscesses. It is also important to note that disseminated dis-
sure, with the latter thought to be more common. A study ease can involve almost any organ. The majority of cases in
of the seroprevalence of response to C. neoformans antigens neonates have had evidence of CNS involvement, and many
indicates that exposure before the age of 2 years is rare, but cases involved sepsis-like presentations. Finally, a number
common in children older than 2 years.255 of cases of cryptococcosis in pregnant mothers without ver-
tical transmission have been reported, including cases in
PATHOGENESIS which placental infection was documented.259
The pathogenesis of C. neoformans has been the subject of

DIAGNOSIS
intensive study.250,254,256 The inhaled organism enters into
the bronchioles, where it establishes an initial infection. The The clinical symptoms of cryptococcosis are not sufficiently
alveolar macrophage appears to be the first line of host defense specific to directly suggest the diagnosis, but in the context
and is involved in containing the infection; however, the inter- of high-risk patients with pulmonary or CNS symptoms,
action between macrophages and C. neoformans is complex. cryptococcosis should be part of the differential diagno-
The polysaccharide capsule of C. neoformans is an important sis.250 The diagnosis of cryptococcosis is most readily estab-
virulence factor and is antiphagocytic as well as immuno- lished in the setting of CNS disease. Lumbar puncture will
modulatory.256 Once inside the macrophage, C. neoformans is generally show elevated opening pressure, lymphocytic
also able to replicate within the phagolysosome and lyse mac- pleocytosis, decreased glucose, and increased protein. How-
rophages.256,257 The ability of C. neoformans to survive within ever, the CSF parameters can also be near normal, particu-
the hostile environment of the phagolysosome is partly depen- larly in HIV-positive patients. Culture of CSF is positive in
dent upon its ability to produce the antioxidant melanin. Ulti- 89% to 95% of patients with cryptococcal meningitis, and
mately, a cell-mediated immune response is required to clear blood cultures are positive in 55% of patients.260 Crypto-
the infection; although it is clear that cell-mediated immunity coccal polysaccharide antigen is readily detectable in CSF,
is critical, there are also data to suggest that humoral immu- serum, and urine by using a latex-agglutination test. The
nity contributes to the host response to C. neoformans.256 In sensitivity is highest for meningitis in HIV-infected patients
the absence of this response, C. neoformans disseminates to (90%-95%) and much lower for pulmonary disease in HIV-
the CNS and causes a meningoencephalitis.250 The mecha- uninfected patients. Classically, India ink preparations can
nistic details of dissemination are not understood completely. be used to demonstrate the presence of C. neoformans in clin-
In addition to hematogenous spread and direct transmigra- ical samples, but testing for the presence of antigen is more
tion across the blood-brain barrier, a “Trojan horse–type” widely used. Culture and antigen testing have been positive
mechanism, where C. neoformans enters the CNS within mac- in cases of neonatal cryptococcosis.253
rophages, may also play a role.257 Once CNS infection is estab-
lished, it is generally fatal in the absence of effective treatment.
TREATMENT
PATHOLOGY The gold standard therapy for cryptocococcal meningoen-
cephalitis is amphotericin B combined with 5-flucytosine.
C. neoformans is detectable in infected tissue using standard A randomized clinical trial demonstrated the superiority
GMS and PAS stains but is generally hard to identify in of the combination relative to amphotericin B alone for
cryptococcal meningitis.261 Fluconazole and other azoles PATHOGENESIS

have activity against C. neoformans but are less effective
compared with amphotericin B–based therapy because The pathogenesis of diseases caused by Malassezia is poorly
of the fact that azoles are fungistatic, and early fungi- understood at the microbiologic and molecular level.270 With
cidal activity is correlated with better outcome.262 Cur- respect to invasive disease associated with intravascular cath-
rent recommendations for treatment of adults are to treat eters and intralipid infusions, it appears most plausible that the
with an amphotericin B–based preparation in combina- skin is first colonized as part of the normal establishment of the
tion with 5-flucytosine for at least 2 weeks, followed by human microbiome. The high concentration of lipid within
a maintenance treatment of oral fluconazole for at least the catheter could then allow the lipid-dependent organism to
10 weeks.263 establish colonization, leading to systemic infection.
PROGNOSIS CLINICAL MANIFESTATIONS

The outcome of treatment varies significantly, based on the Malassezia have been linked to a variety of skin diseases, such
immune status of the patient, access to amphotericin B, and as neonatal pustulosis, tinea versicolor, seborrheic dermati-
geoeconomic factors. As summarized by Patel and cowork- tis, and eczema.265 A prospective study of newborns, how-
ers,253 the mortality rate for neonatal cases reported in the ever, showed that infants without pustulosis were as likely
literature has been quite high (60%). to be colonized with Malassezia as children without pustulo-
sis.266 The symptoms associated with Malassezia fungemia
are nonspecific and similar to those associated with other
Malassezia infections, including poor feeding, temperature instability,
lethargy, and respiratory distress.
Malassezia spp. are among the most commonly isolated
organisms colonizing human skin.264 In older children and DIAGNOSIS
adults, these organisms are associated with tinea versi-
color, seborrheic dermatitis, and dandruff; in neonates and Malassezia spp. infection is diagnosed by culture of the
infants, Malassezia spp. cause catheter-related bloodstream organism, and because the optimal growth of the organism
infections in patients receiving intralipid infusions and requires special media (supplementation with oil), it is cru-
have been associated with neonatal cephalic pustulosis.263 cial to notify the clinical microbiology laboratory when the
The causal nature of the latter association has, however, diagnosis is suspected.267
not been established.265
TREATMENT
THE ORGANISM
The treatment of Malessezia fungemia is prompt removal of
Malassezia spp. are dimorphic fungi and thus are isolated as the infected catheter, which eliminates the colonization site
both yeast and filamentous forms. Fourteen species of Mal- from the bloodstream and the source of highly concentrated
assezia are recognized, with M. furfur being the most widely lipid. Although dissemination is rare, systemic therapy with
reported in the setting of invasive infections in preterm amphotericin B has also been administered after removal of
infants.266 Sequencing studies of organisms isolated from the catheter to ensure clearance. No treatment is required for
skin of adult humans have shown that Malessezia spp. are neonatal pustulosis.
the predominant microorganism (fungi or bacteria) inhab-
iting this medically important niche.264 With the exception PROGNOSIS
of M. pachydermatis, Malassezia spp. are characterized as
obligate lipophilic organisms.265 Consequently, the recom- In general, the outcome for invasive disease in neonates is
mended culture conditions for the isolation of Malassezia spp. excellent, although some deaths in extremely-low-birth-
include incubation on Sabouraud medium supplemented weight infants have been reported.
with olive oil.267 This feature of their biology provides a rea-
sonable explanation for the association of bloodstream infec- PREVENTION
tions with the administration of concentrated lipid.
The prevention of Malassezia infections in neonates has
not been studied. The judicious use of intralipids may
significantly limit the risk. In patients in whom intralipid
Malassezia spp. have been shown to rapidly colonize the skin therapy cannot be avoided, this fungal infection should be
of newborn infants and remain an important component of suspected if the central venous catheter malfunctions or if
the human microbiome throughout life.264,268 This fungus mild, nonspecific signs of infection are noted.
is associated with a variety of dermatoses and invasive dis-
ease in a small set of immunocompromised patients. The
latter infections are associated with colonization of intravas- Zygomycosis
cular catheters and the administration of lipid-containing
parenteral nutrition.265,269 Given the near-universal colo- Zygomycosis refers to mold infections caused by organisms
nization of health care workers and patients, it is important of the class Zygomycetes and order Mucorales.271,272 In
to recognize that the rate of invasive disease is quite low. previous editions of this book, these infections were termed
phycomycosis, which was the name of this class of organ- those treated with steroids or with diabetes develop dissemi-
isms. This name is no longer used, and to maintain consis- nated infection.275 The alveolar macrophages harvested
tency with other references, we will use zygomycosis to refer from immunocompetent mice ingest the spores and prevent
to infections caused by molds of the genera Mucor, Rhizopus, germination, whereas those from immunocompromised
and Rhizomucor.272 Zygomycosis is a rare infection within mice are unable to prevent germination.275 Iron levels and
neonates and infants, with approximately fewer than 80 receipt of iron chelation therapy appear to contribute to
cases reported in the literature.273 Zygomycosis is increas- susceptibility of patients to zygomycosis.274 It is thought
ing in incidence among older children and adults with that the iron chelators may act as siderophores, providing
compromised immunity.271 Classically, major risk factors essential iron to the organism.
for zygomycosis are diabetic ketoacidosis, iron chelation
therapy, malignancy, steroids, and other immunosuppres- PATHOLOGY
sive factors or conditions.271,272 A review of the published
cases of neonatal zygomycosis reported before, and includ- Histopathologic evidence of tissue damage, along with the
ing, 2007 found that most occurred in premature infants presence of hyphal elements of the characteristic morphol-
independent of other risk factors, with the gastrointestinal ogy, is part and parcel of the diagnosis of zygomycosis.
tract and skin being the most commonly affected organs.273
Consistent with other uncommon invasive mold infections CLINICAL MANIFESTATIONS
in premature infants, the fatality rate in this case series was
very high (64%). It is difficult to ascertain whether the inci- In neonates, the most common sites of infection are the
dence of zygomycosis is increasing in neonates and infants gastrointestinal tract and skin.273,276 Of interest, pulmo-
because no prospective data are available, but the number nary and rhinocerebral disease has been reported in only
of reported cases has increased since 1990.273 10% of cases. Of importance, a number of neonates have
presented with signs and symptoms similar to necrotizing
enterocolitis, albeit without pneumatosis intestinalis.273 In
THE ORGANISM
these cases, the diagnosis was made based on cultures or
Zygomycetes is a class of molds that includes the orders histopathologic analysis of surgical specimens. Approxi-
Mucorales and Entomophthorales.272 The majority of inva- mately half of the cases of neonatal zygomycosis progressed
sive infections are due to genera within Mucorales, includ- to disseminated disease, whereas dissemination was much
ing Rhizopus, Mucor, and Rhizomucor.271 Classically, the less common in infants older than 1 month.273
morphology of these molds includes ribbon-like aseptate
hyphae that display right-angle branching. Zygomycetes TREATMENT
can be difficult to distinguish from other molds, such as
Aspergillus spp., on biopsy, but the latter organisms typi- The treatment of zygomycosis should involve a consideration
cally have acute-angle branching and visible septa.272 The of both surgical and medical approaches. Amphotericin B is
Zygomycetes are ubiquitous environmental organisms the drug of choice for neonatal zygomycosis. Echinocandins
found within the soil and in association with decaying mat- have no activity against Zygomycetes. Itraconazole and
ter. They are spore forming, and the airborne spores are posaconazole are the two azoles with in vitro activity against
likely to play a role in pathogenesis. Based on the review of Zygomycetes. Posaconazole has been used to treat zygomy-
reported cases published by Roilides and coworkers,273 the cosis in adult patients, but this agent is limited to an oral
most common species affecting neonates are Rhizopus spp. formulation, and no dosing data are available for neonates.
(72% of reported cases). According to the review by Roilides and coworkers,273 neo-
nates who were treated with a combination of surgery and
amphotericin B had better outcomes than patients treated
with amphotericin B alone.
The incidence of zygomycosis appears to be increasing in
populations of immunocompromised adult patients.271 Part PROGNOSIS
of that increase may be due to the fact that the agents used
for prophylaxis against candidiasis and aspergillosis are not Neonatal zygomycosis is associated with high mortality
active against Zygomycetes.271 As noted above, the number (64%) and high rates of disseminated disease.
of neonatal cases reported in the literature has increased in
recent years; however, it is not possible to firmly determine
if this represents a true increase in incidence. The two pri- Dermatophytoses
mary modes of transmission of zygomycosis are inhalation
of spores and direct inoculation of damaged skin. The dermatophytoses are caused by three genera of fungi
that infect the keratinized regions of the skin: Microspo-
rum, Trichophyton, and Epidermophyton.277,278 Collectively,
PATHOGENESIS
these organisms cause tinea, which is then further modi-
The pathogenesis of zygomycosis has not been as exten- fied by a description of the affected region of the body, that
sively studied as other organisms.274 Animal models is, tinea capitis.278 Despite the fact that young children are
have confirmed the importance of phagocytes in the host frequently affected by the various tineas, neonates and
response. For example, immunocompetent mice do not young infants only rarely develop dermatophytoses.279
develop zygomycosis after inhalation of spores, whereas Because these dermatophytoses are thought to result from
contact with persons or animals harboring the causative DIAGNOSIS

organisms, the low incidence in neonates and young
infants is most likely due to the fact that the pathogenic Classically, the diagnosis of dermatophytes is made by
cycle of exposure, establishment of infection, and develop- microscopic examination of potassium hydroxide prepara-
ment of symptoms are rarely completed within the first few tions of skin scrapings.277,278 Potassium hydroxide digests
weeks of life. However, as with other less common fungal the epithelial cells and leaves the fungal elements intact.
infections of this age group, a number of cases of neona- Culture of the specimens will then confirm the diagnosis
tal dermatophytosis have been reported over the years.279 and identify the organism. Typically, selective medium
Consistent with tinea in other age groups, the most com- supplemented with antibiotics is used to suppress the
mon organisms isolated from neonatal cases have been growth of bacteria, and cycloheximide is used to prevent
Trichophyton rubrum and Microsporum canis. Nosocomial the growth of other molds. No molecular or serologic tests
outbreaks of M. canis have been reported in a number of are available.
newborn nurseries.280,281
TREATMENT
THE ORGANISM
The majority of neonates were treated with topical agents,
Dermatophytoses are caused by organisms of the genera such as clotrimazole, econazole, ketoconazole, or micon-
Microsporum, Trichophyton, and Epidermophyton. All form azole.279-281,284 For older children, griseofulvin has been
septate hyphae as well as a wide range of morphologic types the gold standard therapy for years and has been used as
of macroconidia, microconidia, and arthoconidia.277,278 systemic therapy as has itraconazole.
EPIDEMIOLOGY AND TRANSMISSION PROGNOSIS

The etiologic organisms for the dermatophytoses vary All cases of neonatal dermatophytoses have responded well
according to the affected body site and the geographic loca- to topical, systemic, or combination therapy.
tion of the patient. The most common cause of tinea corpis
is T. rubrum, whereas M. canis is the typical agent respon- PREVENTION
sible for tinea capitis.277,278 Of the neonatal dermatophyto-
sis cases reported in the literature, M. canis and T. rubrum Because a number of outbreaks of nosocomial dermato-
have been the organisms most commonly isolated.279 phytoses have occurred within nurseries, it seems prudent
Transmission is person to person or through contact with that health care workers with symptoms of dermatophyte
infected animals. The nosocomial outbreaks of neonatal infection identify themselves to their i nstitution’s infection
dermatophytosis reported in the literature have been due control group, to institute effective precautions to prevent
to M. canis.280,281 transmission to neonates in the unit.
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Less Common Fungal Infections: Pneumocystis and Other

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34 Pneumocystis and Other

Less Common Fungal

CHAPTER OUTLINE Pneumocystis jirovecii (Formerly Known as Epidemiology and Transmission

have been based exclusively on morphologic observations

of rodents with Pneumocystis was discovered in patients’

CLINICAL MANIFESTATIONS Cryptococcosis

The pathogenesis of C. neoformans has been the subject of

cryptococcal meningitis.261 Fluconazole and other azoles PATHOGENESIS

PROGNOSIS CLINICAL MANIFESTATIONS

contact with persons or animals harboring the causative DIAGNOSIS

EPIDEMIOLOGY AND TRANSMISSION PROGNOSIS

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