Type of article: Case Report
Title of the article: HISTOPLASMA STOMATITIS UNVEILED: Not all
opportunistic infections get better after initiation of antiretroviral
therapy
Running title: Histoplasma stomatitis in HIV patient
Contributors
1. Bansal, Saurabh MDa
2. Singhania, Namrata MDb
3. Nukala, Chandra Mouli MDc
4. Singh, Anil Kumar MDd
5. Al-Rabadi, Laith MDe
Department(s) and institution(s)
aDepartment of Internal Medicine, University of
Illinois College of Medicine at Peoria, Peoria IL USA 61637
bDepartment of Hospital Medicine, Mount Carmel East
Hospital, Columbus OH USA 43213
cDepartment of Hospital Medicine, CHI St Vincent
Infirmary, Little Rock AR USA 72205
dDepartment of Internal Medicine, Geisinger Community
Medical Center, Scranton, PA USA 18510
eDivision of Nephrology, University of Utah, Salt Lake
City, Utah USA 84132
Corresponding Author:
Full name: Laith Al-Rabadi
Department/University: University of Utah
Street Name & Number: 30 N Medical Drive, Rm 4R312
City, State, Country, Postal code: Salt Lake City, Utah, USA, 84132
Tel: +1-319-855-8439; Fax: +1-801-581-4343; E-mail:
laithalrabadi3@gmail.com
Total number of photographs: 1
Word counts
for abstract: 50 words
for the text: 996 words
Funding source(s) of support: None to report
Conflict of Interest: There are no conflict of interest to disclose
Title of the article: HISTOPLASMA STOMATITIS UNVEILED: Not all
opportunistic infections get better after initiation of antiretroviral
therapy
Abstract:
Histoplasmosis occurs primarily in the lungs but can disseminate in
immunocompromised patients. Serology can be negative in patients with
local infection, making the diagnosis challenging. Definite diagnosis is
by microscopic examination of the tissue sample. We report a rare case
of Histoplasma stomatitis whose lesions manifested after initiating
antiretroviral therapy.
Keywords: Histoplasma , HIV, stomatitis, IRIS, antiretroviral
therapy
Key Message:
Immune reconstitution syndrome in AIDS patients can lead to initial
worsening of underlying diseases due to body’s ability to mount a strong
immune response after recovery of CD4 counts.
Introduction:
Histoplasma Capsulatum is a dimorphic, round, budding yeast that
is found primarily along the Mississippi and Ohio River valleys in the
United States but can be seen in other areas also.1Infection occurs by inhalation of conidia, which primarily manifests
initially as pulmonary infection, but via hematogenous route,
dissemination can occur, especially in high-risk immunocompromised
patients. Dissemination occurs in extra-pulmonary organs causing
gastrointestinal infection, stomatitis, mucositis, central nervous
system, or bone marrow infection.2 Immune
reconstitution inflammatory syndrome (IRIS) is a phenomenon in which
there is paradoxical worsening of pre-existing disease or unmasking of
subclinical disease after starting antiretroviral therapy (ART) due to
improvement in immune response of the body.3,4Muco-cutaneous lesions due to H. capsulatum have been rarely associated
with IRIS.5–7 We herein report a case of H.
capsulatum stomatitis in a HIV infected patient after resumption of his
ART.
Case History:
A 34-year-old African American male with a past medical history of
hemophilia A requiring twice-weekly recombinant Factor-VIII infusions,
HIV-1, and Hepatitis C infection presented with 3-month history of
intermittent fever, significant weight loss, and worsening lip swelling
and ulceration. He became compliant with ART 6 months ago as evident by
improvement in CD4 count from 94 cells/mm3 to 160
cells/mm3. His muco-cutaneous lesions appeared two
months after improvement in CD4 count. He received multiple antibiotics
and steroids in the past with no relief. He was on acyclovir and dapsone
for Herpes Simplex virus (HSV) and Pneumocystis jiroveci prophylaxis,
respectively. Physical examination revealed significantly swollen lips
and multiple superficial ulcers with heaped-up margins (Figure 1). No
obvious hepatomegaly or splenomegaly was noted. Differential diagnosis
included herpetic ulcers, bacterial infections, fungal infections or
angioedema. He was initially started on valacyclovir for presumed HSV
infection. HSV polymerase chain reaction taken from the base of lip
ulcer was negative. HIV & Hepatitis-C viral loads were undetectable.
Complement C1-esterase inhibitor level was negative. Gram stain,
acid-fast stain, mucicarmine stain, fungal blood cultures, urine and
serum Histoplasma antigen, were negative. Complement fixation
test was positive for H. capsulatum mycelial and yeast forms
(titer>1:256). Serum immunodiffusion assay was strongly
positive for H. capsulatum ‘H’ and ‘M’ bands but negative for
Aspergillus fumigatus, Blastomyces dermatiditis andCoccidiodes immitis . Biopsy of the lips revealed granulomatous
and mixed inflammatory infiltrate predominantly with lymphocytes with
areas of necrosis and presence of small budding yeast forms. Patient was
diagnosed with H. capsulatum associated stomatitis and was started on
itraconazole for total twelve months. He demonstrated dramatic
regression of oral edema and ulcerations at six-month follow up visit.
Discussion:
Histoplasmosis is the most common endemic mycosis in AIDS patients,
frequently observed in Mississippi and Ohio River
valley.1 Incidence is reportedly 3.4 cases per 100,000
person-years in the United States. It usually manifests as primary
pulmonary infection from inhalation of microconidia but can disseminate
hematogenously in immunocompromised patients - leading to skin,
neurological, bone marrow or gastrointestinal
abnormalities.2 The most common symptoms of pulmonary
histoplasmosis are fever, chills, weakness and cough with chest
radiograph commonly revealing interstitial or reticulo-nodular
infiltrates. Other findings seen on chest imaging are pneumonia-like
consolidation with or without hilar lymphadenopathy, and/or cavitary
lung lesion. Disseminated histoplasmosis patients often have progressive
weight loss and fever with other clinical symptoms depending on the
organ system involved.8
Diagnosing histoplasmosis in mild to moderate local infection can be
challenging. Serum and urine antigen testing and tissue cultures may
remain negative. Definite diagnosis is achieved by microscopic
examination of tissue sample which can reveal immature
forms.9 Both the immunodiffusion test and the
complement fixation test should be used for workup. Antibody detection
of ‘H’ & ‘M’ bands through immunodiffusion has higher sensitivity than
complement fixation. Titers > 1:32 or increasing titers
when checked at an interval of 1-2 weeks is highly suggestive of H.
capsulatum infection.9,10 Antibody testing can have
low sensitivity in immunocompromised patients.10 New
emerging tests such as microbial cell-free DNA testing can have quick
turnaround time and help in diagnosing the disease
sooner.11
Unveiling of manifestations of histoplasmosis as a result of Immune
reconstitution inflammatory syndrome (IRIS) has been rarely reported in
literature.5–7 Patients with active HIV infection who
are not taking ART, have low CD4 count, high viral load and poor immune
response.12 Rapid improvement in immune function and
suppression of viral load after initiation of ART can lead to systemic
or local inflammatory response at sites of preexisting infection which
were not clinically apparent before initiation of ART. Increases in T
lymphocytes after initiation of ART activates suppressed immune response
leading to inflammation and granuloma formation. This can happen in 1 to
3 months after initiation of ART.13 This phenomenon is
more commonly reported in patients with tuberculosis; therefore,
tuberculosis remains main differential in suspected IRIS patients.
Our patient developed his lesions two months after he started taking ART
as evident from his improvement in CD4 counts and suppression of HIV
viral load. Strong immune response to localized H. capsulatum infection
as evidenced by both immunodiffusion and complement fixation assays is
also compelling. Treatment of histoplasmosis depends on clinical form
and severity and involves various antifungals like azole drugs in mild
to moderate disease or amphotericin B in moderate to severe
cases.14 Also, immunocompromised patients with severe
disease at presentation are frequently treated with amphotericin B. In
patients with severe disease, after initial induction phase of one to
two weeks with amphotericin B, treatment can be switched to oral azole
drugs like itraconazole. The preferred duration for mild to moderate
infection is 12 months and longer for severe disease, keeping in mind,
lifelong therapy may be needed in selected
individuals.15 Monitoring of drug levels is
recommended to ascertain compliance and adequate levels.Histoplasma antigen levels are frequently used to monitor
treatment response. For treatment of IRIS, use of glucocorticoids, which
may seem counter-intuitive in an immunocompromised patient with
disseminated infection, may be needed in selected individuals.
In summary, H. capsulatum associated stomatitis can be diagnosed by
microscopic examination of tissue sample along with immunodiffusion and
complement fixation tests. Antigen test can be negative in localized
infection. It can be associated with IRIS with paradoxical worsening of
mucocutaneous lesions after initiation of ART.
Acknowledgement: None
Author contributions: SB and NS contributed equally in preparing the
manuscript and reviewed the literature. CMN, AKS and LA critically
revised the manuscript.
Ethical Approval: Ethic committee was not consulted for approval as it
is a case report and all possible efforts were made to maintain complete
anonymity.
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Figure legend:
Figure 1. Histoplasma associated stomatitis showing swollen lips
and superficial ulcers with heaped up margins.