Uncommon Invasive Penicillium Species Infection in a Patient with
Advanced HIV: A Rare Case Report
ERIN R. CARR1, TORAL SHASTRI2, DIVYA PANDYA3, AMR ABULABAN4,
DUSHYANTHA JAYAWEERA3, TERESA A. CHUENG3
1University of Miami Miller School of Medicine,
Miami, FL,
USA
2Department of Medicine,
University of Miami Miller School of Medicine,
Miami, FL,
USA
3Division of Infectious Diseases, Department of Medicine,
University of Miami Miller School of Medicine,
Miami, FL,
USA
4Department of Pathology & Laboratory Science,
University of Miami Miller School of Medicine,
Miami, FL,
USA
Abstract: - Penicillium species are ubiquitous worldwide and constitute one of the largest fungal genera.
Typically benign, Penicillium (P.) non-marneffei species can become a serious threat in immunocompromised
hosts with the potential for high mortality. We present a rare care of disseminated P. non-marneffei infection in
a Honduran patient with advanced HIV, initially manifesting as nonspecific symptoms. After a thorough and
unrevealing workup, an inguinal lymph node biopsy resulted in positive fungal staining of tissue. However,
expanded polymerase chain reaction (PCR) amplification of fungal 28S rDNA was necessary to confirm the
diagnosis. Here we describe the first reported case of disseminated infection in a patient with HIV/AIDS
presenting with lymphadenitis and propose treatment recommendations as no standards have been developed
yet.
Key-Words: - Penicillium non-marneffei, HIV/AIDS, fungal lymphadenitis, disseminated infection,
opportunistic infections, PCR, 28S rRNA.
Received: April 7, 2024. Revised: August 11, 2024. Accepted: September 16, 2024. Published: October 29, 2024.
1 Introduction
Penicillium species are ubiquitous fungi found in
human environments, including air and soil, and
represent one of the largest fungal genera, [1], [2].
Notably, all Penicillium species (spp.) within the
subgenus Biverticillium have been recently
reassigned to the genus Talaromyces, [3], [4].
Among these, Penicillium (P.) marneffei has been
officially reclassified as Talaromyces (T.) marneffei,
[1], [2], [4], [5]. This dimorphic fungus is endemic
to Southeast, East, and South Asia and is associated
with the development of an AIDS-defining illness,
[4], [6], [7].
The reclassification of P. marneffei is
particularly significant in the context of the ongoing
HIV pandemic. While the global incidence of HIV
has declined, T. marneffei infections have not,
especially in Southeast Asia, [8]. By the end of
2018, 288,000 cases were reported by 33
countries—excluding the United States (US)—with
an estimated 17,300 cases per year, [8]. Detecting
these infections is challenging due to their
nonspecific clinical presentations. Additionally,
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Erin R. Carr, Toral Shastri, Divya Pandya,
Amr Abulaban, Dushyantha Jayaweera,
Teresa A. Chueng
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Penicillium spp. are not typically included in the
differential diagnosis for people living with HIV
(PLWH) presenting with nonspecific symptoms in
non-endemic countries like the US.
Conversely, P. non-marneffei spp. are generally
non-pathogenic and often identified as laboratory
contaminants [2], [5]. However, in
immunocompromised individuals, these species can
cause severe and potentially fatal fungal infections
globally, [9], [10], [11], [12], [13], [14], [15], [16],
[17], [18], [19]. The clinical presentations of these
infections are diverse, including pneumonia,
bloodstream infections, fungus balls, pericarditis,
rhinosinusitis, intestinal invasion, endocarditis, and
other systemic invasive diseases, [5], [18].
A review of the medical literature found only
one reported case of disseminated P. non-marneffei
infection in an immunocompromised patient without
HIV in Malaysia in 2017, highlighting the rarity of
such infections not only in the US but also
worldwide, [20]. To our knowledge, our case is
likely the first documented instance of disseminated
P. non-marneffei infection in a patient with HIV. In
the US, fungal infections in PLWH typically include
cryptococcosis, histoplasmosis, and pneumocystis
pneumonia, [21]. The advent of antiretroviral
therapy (ART) has significantly reduced the
incidence and mortality of fungal diseases among
people with advanced HIV in the US since the
1980s, [21]. For instance, the incidence of
cryptococcosis in PLWH decreased by
approximately 90% in the 1990s, although fungal
infections remain a significant source of morbidity
and mortality globally, especially in low- and
middle-income countries, [21], [22].
Diagnosis of Penicillium infections typically
involves microscopy, histology, and culture. Rapid
diagnosis can be achieved using antigen detection
and polymerase chain reaction (PCR) methods when
available, [4], [5]. Left untreated, Penicillium spp.
infections can be fatal, [4], [6]. Currently, no
standardized treatment guidelines exist for P. non-
marneffei species. A comparative study on the
antifungal susceptibility of T. marneffei and non-
marneffei Penicillium species found that
itraconazole and voriconazole are the drugs of
choice for managing infections caused by these
species, [20]. However, in the case of disseminated
P. non-marneffei infection in Malaysia, the patient
deteriorated on this initial therapy, and amphotericin
B was subsequently added, leading to clinical
improvement, [20].
This case report describes a Honduran patient
recently diagnosed with HIV/AIDS who developed
an invasive infection caused by a P. non-marneffei
species. This case is novel as it represents the first
reported instance of disseminated P. non-marneffei
infection in a patient with HIV/AIDS. Due to the
vague symptomatology and clinical presentation,
physicians in non-endemic areas may not consider
Penicillium spp. infection in the initial differential
diagnosis, posing delayed identification and
treatment. The fungal organism in this case was
identified only after PCR amplification of fungal
28S rDNA from an inguinal lymph node biopsy.
Prompt diagnosis, timely treatment, and initiation of
ART contributed to the patient's rapid recovery.
This case underscores the need for heightened
clinical awareness and the development of specific
treatment guidelines for P. non-marneffei infections.
2 Case Presentation
A 46-year-old Honduran man, recently diagnosed
with HIV by his primary care physician one week
prior to admission, was referred to the emergency
department due to a hemoglobin level of 5.5 g/dL.
He reported experiencing fatigue and dizziness over
the past seven months, along with two instances of
fever and an unintentional weight loss of thirty
pounds. He also reported not yet starting
antiretroviral therapy (ART) since receiving the
HIV diagnosis. He declined any headaches, chills,
or syncopal episodes. Of note, he reported having
condomless sex with two men in the past six
months. Born in Honduras, he immigrated to Miami
in 2015.
The physical examination revealed palpable
lymphadenopathy in the bilateral inguinal region,
massive splenomegaly, and hyperpigmented
violaceous lesions with indurated nodules in the
right lower extremity (Figure 1). His laboratory
findings were significant for pancytopenia, with a
white blood cell count of 2 x 103/µL, absolute
neutrophil count of 1.2, hemoglobin level of 5.5
g/dL, platelet count at 72 x 103/µL, CD4 count of 36
cells/mm3, and an HIV viral load of 1530
copies/mL. Given a normal value of lactate
dehydrogenase, bilirubin, and haptoglobin,
hemolytic anemia was ruled out. Computed
tomography (CT) with intravenous (IV) contrast of
the abdomen was ordered given his abnormal
physical exam findings and pancytopenia. It
revealed splenomegaly measuring 24.5 cm, along
with mesenteric, retroperitoneal, and inguinal
lymphadenopathy (Figure 2). CT chest with contrast
was also ordered which showed evidence of prior
granulomatous disease and several tiny calcified
lymph nodes. The calcified granulomas varied from
2 to 9 mm in size and were located in the right and
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left lobe. At this point, it was thought that HIV
infection was likely causing an impairment in the
production of hematopoietic lineage and
suppression of bone marrow proinflammatory
cytokines.
The patient was initiated on
bictegravir/emtricitabine/tenofovir alafenamide for
HIV/AIDS treatment, as well as atovaquone for
Pneumocystis jirovecii prophylaxis (trimethoprim-
sulfamethoxazole was avoided due to
thrombocytopenia). The patient also received a
transfusion of 2 units of leukoreduced packed red
blood cells.
Fig. 1: Cutaneous findings involving
hyperpigmented violaceous lesions with indurated
nodules in the right lower extremity
Fig. 2: CT with IV contrast of the abdomen
demonstrating splenomegaly measuring 24.5 cm,
along with mesenteric, retroperitoneal, and inguinal
lymphadenopathy
Given the lack of improvement in the patient’s
symptoms and the persistence of his anemia, an
extensive workup was undertaken in collaboration
with infectious disease and hematology/oncology
specialists. Overall, the patient was found to be
negative for Aspergillus, Blastomyces,
Cryptococcus, Histoplasma, Leishmania,
parvovirus, Toxoplasma, and Coccidioides. Blood
cultures for bacterial, fungal, and anaerobic
infection remained negative as well. The
hematology/oncology team was initially consulted
due to a concern for an underlying malignancy
given the negative infectious disease workup. Two
bone marrow biopsies were conducted, both
yielding no evidence of viral, fungal, or
mycobacterial infiltration, nor possible malignancy.
Bilateral inguinal lymph node biopsies were also
pursued, revealing positive findings for reactive
hyperplasia with atypical megakaryocytes, likely
secondary to HIV infection. The right groin biopsy
specifically showed minute fragments of
fibroadipose tissue with crushed lymphoplasmacytic
infiltrate with negativity for HHV-8, EBV, and
fungal infection. However, the patient's left inguinal
lymph node biopsy indicated fungal lymphadenitis
with atypical paracortical hyperplasia and
plasmacytosis (Figure 3A-B, Figure 4).
In response to the fungal lymphadenitis
findings, the patient was initiated on empiric
treatment with IV liposomal amphotericin B at 3
mg/kg. The left inguinal node biopsy specimen was
sent to the University of Washington for further
evaluation through tissue PCR for additional fungal,
acid-fast bacilli, and leishmaniasis testing. Results
from the University of Washington's comprehensive
fungal PCR workup revealed positivity for a
Penicillium species. Notably, the specific
Penicillium species could not be identified.
However, the laboratory noted that the tissue sample
tested negative on PCR for T. marneffei. Therefore,
the patient’s pancytopenia, lymphadenopathy,
splenomegaly, and overall fatigue in the setting of
advanced HIV were diagnosed as infections from P.
non-marneffei fungi.
The patient’s treatment regimen for P. non-
marneffei infection was developed from guidelines
for the treatment of systemic T. marneffei infection.
The patient received IV liposomal amphotericin B at
a dosage of 3 mg/kg daily totaling four weeks.
However, different from the above-cited guidelines,
we extended the amphotericin B duration from 2
weeks to 4 weeks as a clinical judgment due to the
patient’s slow initial clinical improvement. During
the remainder of his hospitalization, the patient’s
pancytopenia remained unchanged.
However, his splenomegaly and
hyperpigmented violaceous lesions in his lower
extremities showed improvement. After completing
induction therapy with amphotericin B for 4 weeks,
the patient was clinically improved and discharged
home on oral itraconazole at 200 mg twice daily for
a period of ten weeks, with subsequent dose change
to 200 mg once daily until achieving virologic
suppression and a CD4 count greater than 100
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cells/mm3 for at least six months. The patient
maintained regular follow-ups in the infectious
disease outpatient clinic.
During subsequent appointments, the patient
reported improvement in symptoms of fatigue and
dizziness with no new complaints. He demonstrated
compliance with the prescribed medications,
including bictegravir/emtricitabine/tenofovir
alafenamide, itraconazole, and atovaquone. Four
months post-initiation of ART, his CD4 count rose
to 73 cells/mm3 (from an initial value of 36
cells/mm3), and his HIV viral load decreased to 26
copies/mL (initially 1530 copies/mL). Ten months
after his initial diagnosis, his pancytopenia
improved markedly, with hemoglobin of 11.3 g/dL,
white blood cell count 2.6 x 109/L, and platelet
count 56 x 103/µL . His HIV viral load was
undetectable and his CD4 count was maintained at
116 cells/mm3, at which point itraconazole was
discontinued. He reported resolution of his fatigue
and dizziness.
Fig. 3A: Inguinal Lymph Node Biopsy,
Hematoxylin and eosin stain (H&E) 100x
magnification. On low power, aggregates of fungal
hyphae (black arrow) are seen in the background of
lymphoid proliferation (blue arrows)
Fig. 3B: Inguinal Lymph Node Biopsy, H&E 400x
magnification. At higher power, the hyphae can be
better appreciated. They appear to be hyaline (i.e.,
lack pigmentation) and narrow. Septations are seen,
along with occasional branching. This morphology
is typical of the mold form of Penicillium species
Fig. 4: Inguinal Lymph Node Biopsy, Grocott's
methenamine silver (GMS) special stain. The
hyphae stain is diffusely positive for GMS,
confirming fungal origin
3 Discussion
While P. non-marneffei fungi typically pose
minimal health risks to humans, they can cause
severe infections, especially in individuals with
compromised immune systems [2], [4], [5]. Our
patient faced a substantial risk factor due to his
immunocompromised state from uncontrolled HIV
[23], [24]. HIV, being a retrovirus, has the
capability to target and eliminate CD4 T
lymphocytes, leading to profound
immunosuppression in affected individuals. This
heightened vulnerability exposes those with
advanced HIV to a significant risk of infection,
particularly when the CD4 count falls below 200, as
observed in our patient with an initial CD4 count of
36 cells/mm3.
While T. marneffei is a prevalent fungus-
causing disease in the HIV/AIDS population in
Southeast Asia, it is not endemic to North or South
America, the regions where our patient has resided
[4], [6], [7], [25]. Notably, he repeatedly declined to
traveling to Asia. The University of Washington
microbiology laboratory’s expanded PCR
amplification of fungal 28S rDNA of lymph node
tissue resulted in positivity for a Penicillium species.
Although the specific Penicillium species could not
be identified, the tissue PCR testing resulted
negative for T. marneffei species. Given the patient's
lack of exposure to an endemic region for T.
marneffei, we deduced that he likely contracted an
infection from a P. non-marneffei species.
While infrequently associated with human
disease, certain P. non-marneffei species hold
significance in immunocompromised hosts. A study
conducted in the United States analyzed 100
isolated specimens from clinical sources, revealing
that the most frequently encountered Penicillium
species were P. citrinum and P. rubens, [2]. Various
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case studies and literature reviews have identified
common disease-causing species, including P.
citrinum, P. chrysogenum, P. digitatum, and P.
expansum, with P. chrysogenum being highlighted
as one of the most prevalent disease-causing species
overall [2], [5], [26]. Additionally, pathogenic
species such as P. oxalicum have been noted, with
some cases even indicating resistance to
voriconazole [2], [16]. Based on this data, it is
reasonable to consider that one of these frequently
identified species may have been the causative agent
responsible for our patient's illness. In our patient’s
case, even after utilizing an expanded PCR
amplification of fungal 28S rDNA of lymph node
tissue we were unable to identify the species of
Penicillium. This points towards the overall
difficulty of diagnosing Penicillium infections and
identification at the species level; we highlight the
need to expand on fungal and Penicillium rapid PCR
databases [5].
Despite the potentially high mortality rate
associated with Penicillium species infections,
reaching 62% in immunocompromised individuals
according to one study, and 59% according to
another review, our patient's prompt diagnosis and
treatment likely played a crucial role in his swift
recovery [5], [20]. Considering there is no standard
of treatment established for P. non-
marneffei infections, we utilized the Guidelines for
the Prevention and Treatment of Opportunistic
Infections in Adults and Adolescents with HIV for T.
marneffei infection [4]. The treatment protocol
involved induction with liposomal amphotericin B
at 3-5 mg/kg IV daily for two weeks, followed by
oral itraconazole at 200 mg twice daily for ten
weeks, with subsequent de-escalation to a
maintenance regimen of oral itraconazole at 200 mg
daily. This maintenance therapy is intended to
continue until virologic suppression and CD4 count
reaches greater than 100 cells/mm3 for a minimum
of six months. The prompt initiation of ART is
recognized as a significant contributing factor to the
patient's recovery. It is important to acknowledge
that the patient remains at continued risk for the
reactivation of disease until the CD4 count is
consistently maintained above 100 cells/mm3 [10],
[12], [27], [28], [29].
Additionally, given that our patient with severe
disseminated P. non-marneffei infection showed
significant improvement in the treatment regimen of
P. marneffei infection among PLWH, we suggest it
is reasonable to extrapolate treatment within the
same genus, [4]. However, if clinical improvement
is not observed, extending therapy or changing to a
broader antifungal regimen may be required. In our
case, we extended induction with amphotericin B
from 2 weeks to 4 weeks due to initial slow clinical
improvement.
Here, we presented a novel clinical case of
disseminated P. non-marneffei infection in a
severely immunocompromised patient with
advanced HIV. No previous cases of P. non-
marneffei infection in PLWH have been cited in the
literature. This case contributes to the diagnostics of
opportunistic infection and management of PLWH.
We have identified an atypical P. non-marneffei
infection to be considered in the differential
diagnoses of patients with advanced HIV with non-
specific symptoms and lymphadenopathy. Here, we
have documented the first successfully treated case
of P. non-marneffei infection in a patient with
HIV/AIDS.
4 Conclusion
Diagnosing Penicillium infections can be
challenging given its nonspecific presentation [2],
[5]. Unfortunately, due to these factors, many
patients are diagnosed post mortem, with one study
reporting a mortality rate of 62% in the
immunosuppressed population [4], [5]. We strongly
advocate for physicians to maintain a high index of
suspicion regarding this pathogen, particularly in
immunosuppressed patients, especially when
symptoms persist after the administration of
appropriate empiric antimicrobial courses.
The identification of Penicillium remains a
difficult hurdle in the process of diagnosis and
treatment. Shared morphological characteristics
among various species make traditional
identification methods of microscopy, culture, and
histology difficult and often limit phenotypic results
to the genus or family level. This underscores the
growing importance of employing DNA sequencing
for accurate identification. Unfortunately, molecular
methods such as Matrix-assisted laser desorption
ionization time-of-flight mass spectrometry
(MALDI-TOF MS) still present challenges in
species identification for clinical purposes, primarily
due to the need for expanding commercial species
databases in order to make accurate species-level
identification [5], [30], [31]. Additionally, rapid
PCR assays have not yet been validated or
standardized for clinical or commercial use, adding
another layer of complexity [4], [5].
Owing to the infrequency of cases, there is
limited data and a scarcity of studies on an
established standard of treatment for Penicillium
non-marneffei diseases. Additional clinical trials and
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in vitro studies are imperative to address this gap in
knowledge.
Consent: Informed consent was obtained from the
patient to publish case details, test results, and
images.
Declaration of Generative AI and AI-assisted
Technologies in the Writing Process
During the preparation of this work the authors used
Microsoft Word and ChatGPT for language editing
(i.e. spelling, grammar). After using these
tools/services, the authors reviewed and edited the
content as needed and take full responsibility for the
content of the publication.
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Erin R. Carr, Toral Shastri, Divya Pandya,
Amr Abulaban, Dushyantha Jayaweera,
Teresa A. Chueng
E-ISSN: 2224-2902
337
Volume 21, 2024
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Contribution of Individual Authors to the
Creation of a Scientific Article (Ghostwriting
Policy)
- Erin R. Carr: Writing – original draft preparation,
writing – review and editing.
- Toral Shastri: Writing – original draft preparation,
writing – review and editing.
- Divya Pandya: Writing – original draft
preparation, writing – review and editing.
- Amr Abulaban: Investigation, writing – review
and editing.
- Dushyantha Jayaweera: Supervision, writing –
review and editing.
- Teresa A. Chueng: Supervision, writing – review
and editing.
Sources of Funding for Research Presented in a
Scientific Article or Scientific Article Itself
No funding was received for conducting this study.
Conflict of Interest
The authors have no conflicts of interest to declare
that are relevant to the content of this article.
Creative Commons Attribution License 4.0
(Attribution 4.0 International, CC BY 4.0)
This article is published under the terms of the
Creative Commons Attribution License 4.0
https://creativecommons.org/licenses/by/4.0/deed.en
_US
WSEAS TRANSACTIONS on BIOLOGY and BIOMEDICINE
DOI: 10.37394/23208.2024.21.33
Erin R. Carr, Toral Shastri, Divya Pandya,
Amr Abulaban, Dushyantha Jayaweera,
Teresa A. Chueng
E-ISSN: 2224-2902
338
Volume 21, 2024
