Next Article in Journal
Lignocellulolytic Enzyme Production from Wood Rot Fungi Collected in Chiapas, Mexico, and Their Growth on Lignocellulosic Material
Next Article in Special Issue
Histoplasmosis Diagnosed in Europe and Israel: A Case Report and Systematic Review of the Literature from 2005 to 2020
Previous Article in Journal
Potential of Antifungal Proteins (AFPs) to Control Penicillium Postharvest Fruit Decay
Previous Article in Special Issue
Treatment and Prevention of Histoplasmosis in Adults Living with HIV
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JoF
Volume 7
Issue 6
10.3390/jof7060448
jof-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases

by
Rebecca MacInnes
1 and
Adilia Warris
1,2,*
1
Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
2
MRC Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter 4EX 4QD, UK
*
Author to whom correspondence should be addressed.
J. Fungi 2021, 7(6), 448; https://doi.org/10.3390/jof7060448
Submission received: 14 May 2021 / Revised: 31 May 2021 / Accepted: 1 June 2021 / Published: 4 June 2021
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
Browse Figures
Review Reports Versions Notes

Abstract

:
Histoplasmosis is an endemic fungal infection that is confined to specific geographical regions. Histoplasma spp. are primary pathogens that cause disease in both immunocompetent and immunocompromised patients, ranging from a single-organ (mostly affecting the lungs) infection to life-threatening disseminated disease. Knowledge about the clinical epidemiology relies on data from adult populations; little is known about the patient and disease characteristics in the paediatric population. Therefore, a structured review of published cases of paediatric histoplasmosis between 2000 and 2019 was performed. A literature search of PubMed was conducted and the epidemiological and clinical data from 83 cases were analysed. The mean age at presentation was 9.5 ± 5.5 years, and 51% were girls. Two-thirds of the children were immunocompromised. The majority of children presented with disseminated disease. The most frequently observed clinical symptoms were respiratory symptoms, alongside non-specific systemic features, including fever, myalgia, fatigue and weight loss. The mortality rate was 11%. Histoplasmosis affects children of any age. Being immunocompromised is a risk factor for severe and disseminated disease. The lack of specific presenting features leads to underreporting and delay in diagnosis. To improve the recognition and outcome of histoplasmosis in childhood, increased awareness and surveillance systems are warranted.

1. Introduction

Histoplasmosis was first described in a paediatric patient in 1934, almost 30 years after the first adult patient with fatal disseminated histoplasmosis was described by Samuel Darling in 1906 [1,2]. Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum, which can be divided into two varieties: H. capsulatum var. capsulatum and H. capsulatum var. duboisii [3]. H. capsulatum var. duboisii is found in Africa, whereas H. capsulatum var. capsulatum is most prevalent in the other endemic regions [4]. In addition to the traditional endemic regions, including the Ohio and Mississippi River Valleys in the United States, Central and South America and Africa, the true global distribution of histoplasmosis has recently been reported to be much more widespread [5]. Seroprevalence data and epidemiological studies from South-East Asia (in particular Thailand), Queensland and New South Wales in Australia, the Po Valley area in Italy, Quebec and Ontaria in Canada and an increased number of states in the United States show that histoplasmosis is endemic across the world [5]. Histoplasma conidia are found in these geographic areas in soil contaminated with bird and bat guano. Activities disturbing the soil lead to the release of the infectious conidia into the air, with infection acquired by inhaling contaminated air.
Every year, thousands of people in North and Central America and Africa are infected with Histoplasma spp.; however, most healthy individuals remain asymptomatic, as shown by an outbreak that occurred in Iowa in 1964 [6]. Six thousand people had asymptomatic infections whilst only 87 had pulmonary disease and 1 had disseminated disease. Immunocompromised patients are at risk of developing more severe primary infections, as well as reactivation of latent histoplasmosis and progression to disseminated disease, especially in patients with HIV [7].
Histoplasmosis in children can be asymptomatic or present as acute pulmonary histoplasmosis or disseminated histoplasmosis. Isolated single-organ infections are rarely reported [3,4]. Acute pulmonary histoplasmosis tends to be self-limiting and presents with fever, headache, malaise, chest pain and cough [8]. Presenting signs and symptoms of disseminated histoplasmosis are fever, malaise, anorexia and weight loss, hepatosplenomegaly, lymphadenopathy, mucous membrane ulceration and skin lesions [9,10,11]. Clinical features of histoplasmosis are non-specific and can mimic malignancies or tuberculosis [12,13].
In children living in endemic areas, asymptomatic histoplasmosis is common [14]. However, infants and immunocompromised paediatric patients are at higher risk of developing more severe disease [4,15]. Most knowledge of paediatric histoplasmosis is derived from outbreaks and case reports, and clinical management is based on adult data and experience [16]. This gap in knowledge increases the risk of late diagnosis or initial misdiagnosis, which can lead to more severe disease, and therefore, significant morbidity and mortality for children living in endemic areas. The aim of this study was to review all reported unique paediatric cases of histoplasmosis from 2000 to 2019 and extract data regarding the patient demographics, clinical features, diagnostic modalities, treatment and outcome to provide a comprehensive overview of childhood histoplasmosis.

2. Materials and Methods

A systematic literature search was conducted using PubMed. The following search terms: (histoplasmosis) OR (Histoplasma) were used. The following limits were applied to the search: “humans”, “age: 0–18 years” and “published between 1 January 2000–1 January 2019”. Cases were included in accordance with the inclusion and exclusion criteria (Table 1). This was done first through title analyses, then abstract analyses. Lastly, full-text analyses of the remaining results were conducted to produce a final set of studies included for final review. Diagnosis of histoplasmosis was defined as: identification of Histoplasma spp. via histopathological examination of tissue samples or culture or molecular methods and/or positive Histoplasma antigen and/or positive Histoplasma antibody detection. If the diagnostic modality was not specified, cases were included only if a definitive diagnosis was disclosed. Cases that did not disclose diagnostic information and specified the diagnosis as “probable” were excluded. Additionally, cases in which the age was not specified were excluded. In order to prevent selection bias, the entire search and selection process was repeated by another independent assessor (A.W.). Any inconsistencies were discussed until there was an agreement as to what studies should be included.
For each case, the following data were recorded: age, gender, disease type (single organ vs. disseminated disease), sites of infection, comorbidities, clinical features, diagnostic test results, treatment and patient outcome. When data on the infection sites were not explicitly provided, clinical features, radiographic findings or specimens used to identify the presence of Histoplasma spp. were used to define this. Data were managed in Microsoft Excel® and descriptive statistics were used to present the data. Statistically significant results were defined as p < 0.05. As the sample sizes were small, when assessing the clinical significance of two nominal variables, Fisher’s exact test was used.

3. Results

Our search strategy yielded a total of 309 papers for histoplasmosis, of which 244 papers were excluded and 65 studies were included in this review. The process of inclusion and exclusion is outlined in Figure 1. Out of the 65 papers included in the case analysis, 83 cases were identified [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81]. The details of the individual cases included in this review are presented in Supplementary Table S1.

3.1. Patient Characteristics

The mean age (±standard deviation) at presentation was 9.5 ± 5.5 years, with a median age of 11 years; range: 1 month–17 years (Table 2). Of the 83 patients, 13 (15.6%) were infants (≤2 years). Gender was reported in 82 cases, of which 42 were female (51.2%). Most cases were reported from North America (63.9%), followed by Asia (16.9%), South America (12%) and Africa (6%). Of the 53 cases presented in North America, one young infant was diagnosed in a non-endemic area of the United States. Infection was most likely acquired via vertical transmission, with the mother being previously infected in Guatemala. The one child reported in Europe was thought to have acquired the infection in the Democratic Republic of Congo.
The patient’s health status was specified in 70 cases, and 49 (72.5%) had an underlying condition reported, resulting in some form of immunosuppression (Table 2). Primary immunodeficiencies, including the hyper-IgE syndrome (n = 4), STAT-1 mutation (n = 2), T-cell deficiency (n = 1), interferon-gamma-receptor-1 deficiency (n = 1), common variable immunodeficiency (n = 1) and hemophagocytic lymphohistiocytosis (n = 1), as well as HIV, were the most common cause of immunosuppression (20.4% and 18.4%, respectively), followed by a history of renal transplantation (16.3%).

3.2. Disease Characteristics

Disease characteristics could be retrieved from 78 out of 83 cases (94%) (Table 3). Of these, 62 presented with a disseminated form of histoplasmosis, 12 had isolated pulmonary histoplasmosis, 2 had an isolated central nervous system infection, 1 suffered from laryngeal histoplasmosis and 1 had an isolated bone infection. The most commonly infected sites were the lungs (55.8%), followed by the lymphatic system (39%) and bone marrow (31.2%) (Table 3). No differences in the infection sites or types of diseases were observed when comparing immunocompromised to immunocompetent patients (p > 0.05, Fisher’s exact test).

3.3. Clinical Disease Presentation

Data on the presented clinical signs and symptoms was available for 78 out of 83 cases (94%). Fever was the most commonly presented feature, occurring in 53 cases (67.9%), followed by cough (29.5%) and weight loss (28.2%) (Figure 2). Less frequent signs and symptoms included (≤10%): nausea/vomiting (n = 8), diarrhoea (n = 7), bone/joint pain (n = 7), anorexia (n = 6), chest pain (n = 5), night sweats (n = 5), bone/joint swelling (n = 4), myalgia (n = 4), dysphagia/odynophagia (n = 4), seizures (n = 3) and slurred speech (n = 2). In one case, the diagnosis of histoplasmosis was an accidental finding.

3.4. Diagnosis

Details of the diagnostic modalities used were available for 94% of the paediatric patients. Histopathology or direct demonstration of Histoplasma spp. confirmed the diagnosis in 44 (56.4%) children, whilst a positive culture was obtained in 15 (19.2%) children. The identification of specific antibodies was performed in 37 cases, either via immunodiffusion (n = 7), complement fixation (n = 8) or a combination of both (n = 10). In 12 patients, the method of antibody detection was not mentioned. Histoplasma antigen detection was performed in 35 cases. Molecular methods were used to confirm the presence of Histoplasma spp. in two cases. Table 4 provides a detailed overview of which samples were used for the diagnosis.

3.5. Treatment and Outcome

Treatment details were retrieved for 69 (83%) patients (Table 5). Seven children did not receive antifungal treatment, and for six children, treatment was not specified. The most common antifungal regimen was an initial treatment with amphotericin B, followed by itraconazole, followed by an itraconazole treatment, especially in those with isolated pulmonary infection (50%). Alternative azoles used included ketoconazole, fluconazole, voriconazole and posaconazole. The mean (± standard deviation) duration of the antifungal treatment was 9.0 ± 7.4 months. Outcome data were available for 73 children (Table 3 and Table 5). The majority of patients were successfully treated (n = 56, 76.7%). The mortality rate was 11.0% (n = 8). No differences in mortality were observed between the immunocompromised and immunocompetent paediatric patients (p > 0.05 using Fisher’s exact test).

4. Discussion

Our systematic and extensive review of the literature produced over a period of 20 years resulted in the identification of 83 unique cases of paediatric histoplasmosis fulfilling the criteria to be included in this review. Our review complements the few data available that were derived from single-centre or single-country clinical studies in the United States and Latin America [15,82,83,84].
The age range and gender distribution were comparable to the previously published data and show that children of all ages are susceptible to developing symptomatic histoplasmosis [82,83,84,85,86]. Infants are considered to be at a higher risk of developing a more severe and disseminated form of the disease [15]. All the 13 infants included in our study presented with disseminated disease, except one; however, the outcomes were comparable between infants and children aged >1 year in our study (10% vs. 11%).
The majority of the children included in this review were living in North America (63.9%). Histoplasmosis is the most common endemic mycosis in North and Central America and was initially believed to be geographically restricted to these areas. More recently, the presence of Histoplasma spp. in other geographic areas, including regions in Africa, Asia and South America, is appreciated and clinical disease is increasingly being recognised [18,87,88,89,90,91,92,93,94]. Our review seems to indicate that there is an underreporting of paediatric histoplasmosis from Africa (only 6% of the cases). Two recent reviews focusing on African histoplasmosis reported that 25% and 30% of the 57 and 94 cases, respectively, were children [95,96]. Lack of awareness and clinical recognition, as well as a lack of management resources, might well explain this observation. Histoplasma antigen testing is not available in many endemic areas [97], resulting in under-diagnosis and -reporting. Cases that presented outside the endemic areas are considered as “import diseases”, as illustrated by two paediatric patients included in our study [55,67]. Histoplasmosis was reported in Europe as a consequence of international travel and migration [3].
Disseminated disease was the most common presentation of histoplasmosis in our study (79.5%), followed by isolated pulmonary histoplasmosis (15.3%). The high number of paediatric patients that presented with disseminated disease is most likely not a reflection of the actual clinical epidemiology of histoplasmosis in infants and children. Publication bias and the high number of children being immunocompromised that were included in this review may have resulted in this remarkable observation. Other studies have reported lower rates of disseminated disease in non-selected paediatric patient cohorts, ranging between 29% and 64% [82,84]. Although a higher number of immunocompromised children included in our review suffered from disseminated disease (87.8% vs. 69.6%), this was not a statistically significant difference.
A high percentage (66.7%) of the children in our study suffered from an underlying condition that resulted in them being immunocompromised. HIV/AIDS, primary immunodeficiency and the receipt of a renal transplant were the most commonly reported co-morbidities. HIV/AIDS is a well-known risk factor for developing histoplasmosis [98,99] and was one of the main underlying conditions reported in our study. All children infected with HIV (n = 9, 12.9%) presented with disseminated disease. Histoplasmosis in kidney transplant patients carries high morbidity and mortality [100,101]. Of the nine children who developed histoplasmosis after kidney transplantation, all but one presented with disseminated disease and one child died. Unfortunately, this diagnosis was only made at the autopsy [60].
An underlying primary immunodeficiency was present in 10 children, rendering them susceptible to developing severe and disseminated histoplasmosis [23,25,29,38,41,44,59,71]. The importance of the IL-12/IFN-γ pathway and Th17-mediated responses in antifungal immune defenses is well acknowledged [102]. An increasing number of both paediatric and adult patients with inborn errors in those pathways have been reported, including patients with CD40L deficiency, IL12 or IFN-γ receptor deficiency and defects in STAT1 or STAT3 [103]. It is remarkable that the presentation of gastro-intestinal histoplasmosis mimics Crohn’s disease in patients with hyper IgE syndrome [103,104,105]. As an invasive fungal disease can be a presenting symptom of primary immunodeficiency, an immunological workup, including an HIV test, should be performed in a child diagnosed with severe and/or disseminated histoplasmosis.
Fever, cough and weight loss were the most frequently reported symptoms, with lymphadenopathy and/or hepatosplenomegaly being common findings on physical examination. The non-specific signs and symptoms of histoplasmosis are well known, and therefore, the differential diagnosis can cover a wide range from common childhood pneumonia, to tuberculosis, to systemic diseases, including malignancies. Knowledge of the geographic distribution of Histoplasma spp. and recognising host factors that expose the patient to increased risk of developing histoplasmosis will be of value for enabling a timely diagnosis and management.
Isolated CNS infection occurred in two immunocompetent children [34,46]; however, 10.4% had some form of CNS involvement. This is in contrast with the observations done in 48 Colombian children with histoplasmosis in which CNS involvement was observed in 48% of those with disseminated histoplasmosis [82]. Delay in diagnosis and/or routine screening for CNS involvement might explain the observed differences. Involvement of the CNS in adult patients with histoplasmosis is a rare finding [106,107].
Proving a diagnosis of histoplasmosis includes demonstrating the presence of the fungus via histopathology or direct microscopy in a tissue sample from an affected site or recovery of the fungus via a culture in a specimen from a normally sterile site [108]. A proven diagnosis, as defined by the EORTC-MSG consensus definitions, was obtained in 75.6% of the paediatric patients presented in this review. Histoplasma antibody testing and antigen testing were performed to make a diagnosis in 47.4% and 44.9% of children, respectively. For the antibody testing, standard assays employing either complement fixation or immunodiffusion are available, with a reported sensitivity as high as 90% [109]. Paediatric-specific data about the performance of these assays are scarce, but two paediatric single-centre studies do suggest that a high percentage of children with histoplasmosis test antibody positive [82,84]. The same holds true for antigen testing, which has been used most commonly on urine samples with reported sensitivities between 76 and 90%. Sensitivity is lower when serum samples are used, with some good experiences reported using CSF and bronchoalveolar lavage samples aiding in the diagnostic process [109].
To treat paediatric histoplasmosis, the Infectious Disease Society of America (IDSA) guideline recommends following the treatment indications and regimens as used in adults [16]. Itraconazole can be used for mild-to-moderate disease, with amphotericin B (2–4 weeks) as the initial treatment for more severe and disseminated disease, followed by itraconazole for a total duration of 3 months. A longer duration of treatment is recommended depending on the severity of the histoplasmosis, concomitant use of immunosuppressive drugs or primary immunodeficiency. In our study, the majority of the patients (59%) received either itraconazole or a combination of amphotericin B followed by itraconazole. In addition, 11 (13%) patients received only amphotericin B, or amphotericin B followed by another azole (n = 9, 10.8%). The duration of treatment was remarkably long, with a mean of 9 months (+/−7.4 months). The high percentage of disseminated infections and the underlying immunocompromised conditions certainly influenced these prolonged treatment courses. No differences were noted in outcomes between immunocompromised and non-immunocompromised conditions and between the treatment regimens used. The mortality rate was 11% and comparable to observations amongst 40 infants with histoplasmosis [15], but higher than the 2.7% of 73 children with histoplasmosis reported by Quelletta et al. [84]. A study of 57 paediatric oncology patients with histoplasmosis showed no case fatalities [83], while a Colombian paediatric study could not report on mortality due to the retrospective nature of the study [82]. The higher mortality in our study is most likely explained by the higher number of children with immunosuppressive conditions, but a publication bias cannot be excluded.
To summarise, our literature review of 83 cases of paediatric histoplasmosis shows that especially children with underlying immunocompromised disorders are at risk for disseminated disease and present with aspecific signs and symptoms. Our review indicates that there is an underreporting of paediatric histoplasmosis in Africa, with a lack of awareness and clinical recognition, as well as a lack of management resources being the most likely explanations. In addition, the real clinical epidemiology of paediatric histoplasmosis is unknown, as mild disease and pulmonary histoplasmosis might go unnoticed and/or undiagnosed. Paediatric histoplasmosis is characterised by significant morbidity, with a fatal outcome in 11% of cases. Improved surveillance and awareness are warranted to obtain a better insight into the clinical epidemiology and to enable a timely diagnosis and treatment.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/jof7060448/s1, Table S1: Details of 83 paediatric histoplasmosis cases included in this review.

Funding

A.W. is supported by the MRC Centre for Medical Mycology (grant MR/N006364/2) at the University of Exeter.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Darling, S. A protozoan general infection producing pseudo tubercles in the lungs and focal necroses in the liver, spleen and lymph nodes. J. Am. Med. Assoc. 1906, 46, 1283–1285. [Google Scholar] [CrossRef] [Green Version]
  2. Dodd, K.; Tompkins, E.H. A Case of Histoplasmosis of Darling in an Infant. Am. J. Trop. Med. Hyg. 1934, 14, 127–137. [Google Scholar] [CrossRef]
  3. Manfredi, R.; Mazzoni, A.; Nanetti, A.; Chiodo, F. Histoplasmosis capsulati and duboisii in Europe: The impact of the HIV pandemic, travel and immigration. Eur. J. Epidemiol. 1994, 10, 675–681. [Google Scholar] [CrossRef] [PubMed]
  4. Kauffman, C.A. Histoplasmosis: A Clinical and Laboratory Update. Clin. Microbiol. Rev. 2007, 20, 115–132. [Google Scholar] [CrossRef] [Green Version]
  5. Ashraf, N.; Kubat, R.C.; Poplin, V.; Adenis, A.; Denning, D.W.; Wright, L.; McCotter, O.; Schwartz, I.S.; Jackson, B.R.; Chiller, T.; et al. Re-drawing the Maps for Endemic Mycoses. Mycopathologia 2020, 185, 843–865. [Google Scholar] [PubMed]
  6. Medeiros, A.; Marty, S.; Tosh, F.; Chin, T. Erythema nodosum and erythema multiforme as clinical manifestations of histo-plasmosis in a community outbreak. N. Engl. J. Med. 1966, 274, 415–420. [Google Scholar] [CrossRef] [PubMed]
  7. Cunha, V.S.; Zampese, M.S.; Aquino, V.R.; Cestari, T.F.; Goldani, L.Z. Mucocutaneous manifestations of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome: Particular aspects in a Latin-American population. Clin. Exp. Dermatol. 2007, 32, 250–255. [Google Scholar] [CrossRef] [PubMed]
  8. Goodwin, R.A.; Loyd, J.E.; Prez, R.M.D. Histoplasmosis in Normal Hosts. Medicine 1981, 60, 231–266. [Google Scholar] [CrossRef]
  9. Goodwin, R.A.; Shapiro, J.L.; Thurman, G.H.; Thurman, S.S.; Prez, R.M.D. Disseminated Histoplasmosis. Medicine 1980, 59, 1–33. [Google Scholar] [CrossRef]
  10. Reddy, P.; Gorelick, D.F.; Brasher, C.A.; Larsh, H. Progressive disseminated histoplasmosis as seen in adults. Am. J. Med. 1970, 48, 629–636. [Google Scholar] [CrossRef]
  11. Smith, J.W.; Utz, J.P. Progressive Disseminated Histoplasmosis. Ann. Intern. Med. 1972, 76, 557–565. [Google Scholar] [CrossRef]
  12. Liu, B.; Qu, L.; Zhu, J.; Yang, Z.; Yan, S. Histoplasmosis mimicking metastatic spinal tumour. J. Int. Med. Res. 2017, 45, 1440–1446. [Google Scholar] [CrossRef]
  13. Kabangila, R.; Semvua, K.; Rambau, P.; Jackson, K.; Mshana, S.; Jaka, H.; Peck, R. Pulmonary histoplasmosis presenting as chronic productive cough, fever and massive unilateral consolidation in a 15-year-old immune-competent boy: A case re-port. J. Med. Case Rep. 2011, 5, 374. [Google Scholar] [CrossRef] [PubMed]
  14. Hage, C.A.; Wheat, L.J.; Loyd, J.; Allen, S.D.; Blue, D.; Knox, K.S. Pulmonary Histoplasmosis. Semin. Respir. Crit. Care Med. 2008, 29, 151–165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Odio, C.M.; Navarrete, M.; Carrillo, J.M.; Mora, L.; Carranza, A. Disseminated histoplasmosis in infants. Pediatr. Infect. Dis. J. 1999, 18, 1065–1068. [Google Scholar] [CrossRef] [PubMed]
  16. Wheat, L.; Freifeld, A.; Kleiman, M.; Baddley, J.; McKinsey, D.; Loyd, J.; Kauffman, C. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2007, 45, 807–825. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Li, W.; Sharma, M. Unusual cause of infant pancytopenia: Granulomatous bone marrow lesion with disseminated histo-plasmosis. Blood 2018, 131, 1154. [Google Scholar] [CrossRef] [Green Version]
  18. Gupta, A.; Ghosh, A.; Singh, G.; Xess, I. A twenty-first-century perspective of disseminated histoplasmosis in India: Litera-ture review and retrospective analysis of published and unpublished cases at a tertiary care hospital in North India. Mycopathologia 2017, 182, 1077–1093. [Google Scholar] [CrossRef]
  19. Ferguson-Paul, K.; Park, C.; Childress, S.; Arnold, S.; Ault, B.; Bagga, B. Disseminated histoplasmosis in pediatric kidney transplant recipients—A report of six cases and review of the literature. Pediatr. Transpl. 2018, 22, 13274. [Google Scholar] [CrossRef]
  20. Sethi, S.K.; Wadhwani, N.; Jha, P.; Duggal, R.; Sharma, R.; Bansal, S.; Kher, V. Uncommon cause of fever in a pediatric kidney transplant recipient: Answers. Pediatr. Nephrol. 2017, 32, 1527–1529. [Google Scholar] [CrossRef]
  21. Leitão, T.M.J.S.; Jorge, I.F.; Freitas, A.E.H.A. Enlarged hilar lymph node due to Histoplasma. Rev. Soc. Bras. Med. Trop. 2016, 49, 663. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Mathews, D.M.; John, R.; Verghese, V.; Parmar, H.; Chaudhary, N.; Mishra, S.; Mathew, L. Histoplasma capsulatum Infection with Extensive Lytic Bone Lesions Mimicking LCH. J. Trop. Pediatr. 2016, 62, 496–499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Ferguson-Paul, K.; Mangum, S.; Porter, A.; Leventaki, V.; Campbell, P.; Wolf, J. Hemophagocytic Lymphohistiocytosis and Progressive Disseminated Histoplasmosis. Emerg. Infect. Dis. 2016, 22, 1119–1121. [Google Scholar] [CrossRef] [PubMed]
  24. Thapa, S.; Jha, S.C.; Trotter, A.B. Persistent Fever and Skin Lesions Due to Histoplasmosis in a Boy from Rural Nepal. Am. J. Trop. Med. Hyg. 2016, 94, 249–250. [Google Scholar] [CrossRef] [Green Version]
  25. Odio, C.; Lee Milligan, K.; McGowan, K.; Rudman Spergel, A.; Bishop, R.; Boris, L.; Urban, A.; Welch, P.; Heller, T.; Kleiner, D.; et al. Endemic mycoses in patients with STAT3-mutated hyper-IgE (Job) syndrome. J. Allergy Clin. Immunol. 2015, 136, 1411–1413. [Google Scholar] [CrossRef] [Green Version]
  26. Agarwal, P.; Capoor, M.; Singh, M.; Gupta, A.; Chhakchhuak, A.; Debatta, P. An unusual presentation of disseminated histo-plasmosis: Case report and review of pediatric immunocompetent patients from India. Mycopathologia 2015, 180, 359–364. [Google Scholar] [CrossRef]
  27. Vergidis, P.; Avery, R.K.; Wheat, L.J.; Dotson, J.L.; Assi, M.A.; Antoun, S.A.; Hamoud, K.A.; Burdette, S.D.; Freifeld, A.G.; McKinsey, D.S.; et al. Histoplasmosis Complicating Tumor Necrosis Factor–α Blocker Therapy: A Retrospective Analysis of 98 Cases. Clin. Infect. Dis. 2015, 61, 409–417. [Google Scholar] [CrossRef]
  28. Robayo Moriones, C.; Ortiz Guerra, C. Histoplasmosis laryngeal: Report first case in Colombia. Colomb. Med. (Cali.) 2014, 45, 186–189. [Google Scholar] [CrossRef]
  29. Shukla, A.; Shah, C.; Hardik, P.; Gupte, P. A probable case of histoplasmosis presenting as portal hypertension and bone lesion in a case of common variable immunodeficiency syndrome. J. Postgrad. Med. 2015, 61, 49–50. [Google Scholar] [CrossRef]
  30. Listernick, R. A 6-Year-Old Male with Daily Fever Accompanied by Nausea and Abdominal Pain. Pediatr. Ann. 2014, 43, 210–213. [Google Scholar] [CrossRef] [Green Version]
  31. Haselow, D.T.; Safi, H.; Holcomb, D.; Smith, N.; Wagner, K.D.; Bolden, B.B.; Harik, N.S. Histoplasmosis Associated with a Bamboo Bonfire—Arkansas, October 2011. MMWR. Morb. Mortal. Wkly. Rep. 2014, 63, 165–168. [Google Scholar]
  32. Ubesie, A.; Okafo, O.; Ibeziako, N.; Onukwuli, V.; Mbanefo, N.; Uzoigwe, J.; Bede, C.; Ibe, B. Disseminated Histoplasmosis in a 13-year-old girl: A case report. Afr. Heal. Sci. 2013, 13, 518–521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Centre for Disease Control and Prevention (CDC). Histoplasmosis in a state where it is not known to be endemic-Montana, 2012–2013. Am. J. Transpl. 2014, 14, 229–232. [Google Scholar] [CrossRef]
  34. Schuster, J.E.; Wushensky, C.A.; Di Pentima, M.C. Chronic Primary Central Nervous System Histoplasmosis in a Healthy Child With Intermittent Neurological Manifestations. Pediatr. Infect. Dis. J. 2013, 32, 794–796. [Google Scholar] [CrossRef] [PubMed]
  35. Ecka, R.S.; Bhatia, P.; Varma, N.; Marwaha, R.K. Disseminated Histoplasmosis with Peripheral Blood Spill Over. Indian J. Pediatr. 2013, 81, 313–314. [Google Scholar] [CrossRef]
  36. Richmond, B.W.; Worrell, J.A.; Bastarache, J.A.; Gervich, D.H.; Slattery, W.R.; Loyd, J.E. Histoplasmomas of Uncommon Size. Chest 2013, 143, 1795–1798. [Google Scholar] [CrossRef] [PubMed]
  37. Hata, J.; Johnson, M.; Booth, G. Neonatal alloimmunization: A rare case of multiple alloantibody formation in a patient with disseminated histoplasmosis. Transfusion 2013, 53, 1140–1141. [Google Scholar] [CrossRef]
  38. Sampaio, E.P.; Hsu, A.P.; Pechacek, J.; Bax, H.I.; Dias, D.L.; Paulson, M.L.; Chandrasekaran, P.; Rosen, L.B.; Carvalho, D.S.; Ding, L.; et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J. Allergy Clin. Immunol. 2013, 131, 1624–1634. [Google Scholar] [CrossRef]
  39. Dall Bello, A.; Severo, C.; Guazzelli, L.; Oliveira, F.; Hochhegger, B.; Severo, L. Histoplasmose simulando neoplasia primária de pulmão ou metástases pulmonares. J. Bras. Pneumol. 2013, 39, 63–68. [Google Scholar] [CrossRef] [Green Version]
  40. Huang, L.; Wu, Y.; Miao, X. Localized Histoplasma capsulatum osteomyelitis of the fibula in an immunocompetent teenage boy: A case report. BMC Infect. Dis. 2013, 13, 132. [Google Scholar] [CrossRef] [Green Version]
  41. Johansen, M.; Hoyer, M.; Kleiman, M. Transcatheter treatment of SVC syndrome from histoplasmosis-related mediastinal fibrosis in a 9-year old male. Catheter. Cardiovasc. Interv. 2013, 82, 708–711. [Google Scholar] [CrossRef]
  42. França, C.M.P.; Cavalcante, E.G.; Ribeiro, A.S.M.; Oliveira, G.T.; Litvinov, N.; Silva, C.A. Disseminated histoplasmosis in a juvenile lupus erythematosus patient. Acta Reum. Port. 2013, 37, 276–279. [Google Scholar]
  43. Gonçalves, D.; Ferraz, C.; Vaz, L. Posaconazole as rescue therapy in African histoplasmosis. Braz. J. Infect. Dis. 2013, 17, 102–105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Rana, C.; Krishnani, N.; Kumari, N.; Shastri, C.; Poddar, U. Rectal histoplasmosis in Job’s syndrome. Indian J. Gastroenterol 2012, 32, 64–65. [Google Scholar] [CrossRef] [PubMed]
  45. Quilter, L.A.S.; Kleiman, M.B.; Kirsch, E.; Wheat, L.J. Disseminated Histoplasmosis of Infancy in one of the Twins. Pediatr. Infect. Dis. J. 2012, 31, 990–991. [Google Scholar] [CrossRef] [PubMed]
  46. Threlkeld, Z.; Broughton, R.; Khan, G.; Berger, J. Isolated Histoplasma capsulatum meningoencephalitis in an immunocompe-tent child. J. Child. Neurol. 2012, 27, 532–535. [Google Scholar] [CrossRef] [PubMed]
  47. Roby, B.B.; Drehner, D.; Sidman, J.D. Pediatric Tracheal and Endobronchial Tumors: An Institutional Experience. Arch. Otolaryngol. Head Neck Surg. 2012, 137, 925–929. [Google Scholar] [CrossRef] [Green Version]
  48. Lim, L.T.; Ruzmetova, N.; Ballinger, S.H.; Moorthy, R.S. Acute pulmonary histoplasmosis in a patient with uveitis after infliximab therapy. Int. Ophthalmol. 2011, 31, 349–351. [Google Scholar] [CrossRef]
  49. Zahn, M.; Hesson, M.; Morton, R.; Wheat, L.J. Granulomatous pleuritis caused by histoplasmosis in a healthy child. Pediatr. Pulmonol. 2011, 46, 729–731. [Google Scholar] [CrossRef]
  50. Zöllner, M.; Rezende, K.; Birman, S.; Elias, C.; Arisawa, E.; Santos, M. Clinical and evolutionary characteristics of four pa-tients with pulmonary histoplasmosis reported in the Paraíba Paulista Valley region. Rev. Soc. Bras. Med. Trop. 2010, 43, 599–601. [Google Scholar] [CrossRef] [Green Version]
  51. Dhawan, J.; Verma, P.; Sharma, A.; Ramam, M.; Kabra, S.; Gupta, S. Disseminated cutaneous histoplasmosis in an immuno-competent child, relapsed with Itraconazole, successfully treated with Voriconazole. Pediatr. Dermatol. 2010, 27, 549–551. [Google Scholar] [CrossRef] [PubMed]
  52. Dotson, J.; Crandall, W.; Mousa, H.; Honegger, J.; Denson, L.; Samson, C.; Cunningham, D.; Balint, J.; Dienhart, M.; Jaggi, P.; et al. Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with an-titumor necrosis factor alpha therapy: A case series. Inflamm. Bowel Dis. 2011, 17, 56–61. [Google Scholar] [CrossRef] [PubMed]
  53. Updesh, M.; Sachdeva, S.; Das, R. Peripheral smear discloses histoplasmosis. Blood 2010, 115, 3653. [Google Scholar] [CrossRef] [Green Version]
  54. Tschudy, J.; Michail, S. Disseminated Histoplasmosis and Pneumocystis Pneumonia in a Child with Crohn Disease Receiving Infliximab. J. Pediatr. Gastroenterol. Nutr. 2010, 51, 221–222. [Google Scholar] [CrossRef]
  55. Alverson, B.; Alexander, N.; LeGolvan, M.P.; Dunlap, W.; Levy, C. A human immunodeficiency virus-positive infant with probable congenital histoplasmosis in a nonendemic area. Pediatr. Infect. Dis. J. 2010, 29, 1055–1057. [Google Scholar] [CrossRef] [PubMed]
  56. Perko, R.; Messinger, Y.; Moertel, C. Pseudometastasis secondary to histoplasmosis infection: False-positive PET/CT findings. Pediatr. Blood Cancer 2009, 54, 621–623. [Google Scholar] [CrossRef] [PubMed]
  57. Hage, C.; Bowyer, S.; Tarvin, S.; Helper, D.; Kleiman, M.; Wheat, L.J. Recognition, diagnosis and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin. Infect. Dis. 2010, 50, 85–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Pamnani, R.; Rajab, J.; Githang’a, J.; Kasmani, R. Disseminated histoplasmosis diagnosed on bone marrow aspirate cytology: Report of four cases. East. Afr. Med. J. 2010, 86, 102–105. [Google Scholar] [CrossRef] [Green Version]
  59. Steiner, S.; Kleiman, M.; Corkins, M.; Christenson, J.; Wheat, L. Ileocecal histoplasmosis simulating Crohn disease in a patient with hyperimmunoglobulin E syndrome. Pediatr. Infect. Dis. J. 2009, 28, 744–746. [Google Scholar] [CrossRef]
  60. Vargas, F.; Gedalia, A.; Craver, R.D.; Vehaskari, V.M. Recurrence of granulomatous interstitial nephritis in transplanted kidney. Pediatr. Transplant. 2009, 14, 54–57. [Google Scholar] [CrossRef]
  61. Srinivasan, A.; Kleiman, M.B.; Debelenko, L.; Stokes, D.; De Vincenzo, J.; Wheat, J.L. False-negative histoplasma antigen in acute pulmonary histoplasmosis. Pediatr. Infect. Dis. J. 2009, 28, 447–449. [Google Scholar] [CrossRef] [Green Version]
  62. Pereira, G.; Pádua, S.; Park, M.; Muller, R.; Passos, R.; Menezes, Y. Chronic meningitis by histoplasmosis: Report of a child with acute myeloid leukemia. Braz. J. Infect. Dis. 2008, 12, 555–557. [Google Scholar] [CrossRef] [Green Version]
  63. Freifeld, A.; Proia, L.; Andes, D.; Baddour, L.M.; Blair, J.; Spellberg, B.; Arnold, S.; Lentnek, A.; Wheat, L.J. Voriconazole Use for Endemic Fungal Infections. Antimicrob. Agents Chemother. 2009, 53, 1648–1651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Garcia-Guiñon, A.; Torres-Rodríguez, J.; Ndidongarte, D.; Cortadellas, F.; Labrín, L. Disseminated histoplasmosis by Histo-plasma capsulatum var. duboisii in a paediatric patient from the Chad Republic, Africa. Eur. J. Clin. Microbiol. Infect. Dis. 2008, 28, 697–699. [Google Scholar] [CrossRef]
  65. Qureshi, A. A case of histoplasmosis mimicking tuberculosis. J. Pak. Med. Assoc. 2008, 58, 457–458. [Google Scholar]
  66. Rafee, Y.; Xavier, A.; Antoine, M.; Borkin, M.; Rongkavilit, C. An Infant with Fever, Hepatosplenomegaly and Pancytopenia. Pediatr. Infect. Dis. J. 2008, 27, 571. [Google Scholar] [CrossRef]
  67. Loulergue, P.; Bastides, F.; Baudouin, V.; Chandenier, J.; Mariani-Kurkdjian, P.; Dupont, B.; Viard, J.; Dromer, F.; Lortholary, O. Literature review and case histories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients. Emerg. Infect. Dis. 2007, 13, 1647–1652. [Google Scholar] [CrossRef]
  68. Hunstad, D.; French, A. Histoplasmosis in a child with JRA on low-dose methotrexate. Rheumatology 2007, 46, 177–178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Mosam, A.; Moodley, V.; Ramdial, P.K. Persistent pyrexia and plaques: A perplexing puzzle. Lancet 2006, 368, 551. [Google Scholar] [CrossRef]
  70. Garrido, L.; Mata-Essayag, S.; Hartung, D.C.; Eugenia, L.M.; Pacheco, I.; Fuentes, Z. Pulmonary histoplas-mosis: Unusual histopathologic findings. Pathol. Res. Pract. 2006, 202, 373–378. [Google Scholar] [CrossRef] [PubMed]
  71. Zerbe, C.S.; Holland, S.M. Disseminated Histoplasmosis in Persons with Interferon-Receptor 1 Deficiency. Clin. Infect. Dis. 2005, 41, 38–41. [Google Scholar] [CrossRef]
  72. N’Golet, A.; N’Gouoni, B.G.; Moukassa, D.; Nkoua-Mbon, J.B. Maxillary African histoplasmosis: Unusual diagnostic problems of an unusual presentation. Pathol. Res. Pract. 2005, 200, 841–844. [Google Scholar] [CrossRef] [PubMed]
  73. Steiner, S.; Cox, E.; Gupta, S.; Kleiman, M.; Fitzgerald, J. Esophageal diverticulum: A complication of histoplasmosis in chil-dren. J. Pediatr. 2005, 146, 426–428. [Google Scholar] [CrossRef] [PubMed]
  74. Wood, K.; Hage, C.; Knox, K.; Kleiman, M.; Sannuti, A.; Day, R.; Wheat, L.; Twigg, H. Histoplasmosis after Treatment with Anti–Tumor Necrosis Factor-α Therapy. Am. J. Respir. Crit. Care Med. 2003, 167, 1279–1282. [Google Scholar] [CrossRef] [PubMed]
  75. Kane, J.M.; Schmidt, K.; Conway, J.H. Fever, hepatosplenomegaly and pancytopenia in a 5-month-old infant. Arch. Pediatr. Adolesc. Med. 2003, 157, 201–205. [Google Scholar] [CrossRef] [Green Version]
  76. McGraw, E.P.; Kane, J.M.; Kleiman, M.B.; Scherer, L. Cervical abscess and mediastinal adenopathy: An unusual presentation of childhood histoplasmosis. Pediatr. Radiol. 2002, 32, 862–864. [Google Scholar] [CrossRef]
  77. Verhaert, K.; Rodriguez, M.; Mendoza, G.; Delgadillo, J.-L.; Casaer, P. Polyarthritis and humeral epiphysial separation in an infant with acute disseminated histoplasmosis. Pediatr. Infect. Dis. J. 2002, 21, 352–353. [Google Scholar] [CrossRef] [PubMed]
  78. Ramdial, P.; Mosam, A.; Dlova, N.; Satar, N.B.; Aboobaker, J.; Singh, S. Disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus. J. Cut Pathol. 2002, 29, 215–225. [Google Scholar] [CrossRef]
  79. Sáez-Llorens, X. Starry, starry night. Pediatr. Infect. Dis. J. 2002, 21, 254. [Google Scholar] [CrossRef]
  80. Ormerod, L.D.; Qamar, T.U.; Toller, K.; Cooperstock, M.S.; Caldwell, C.W.; Giangiacomo, J. Acute disseminated histoplasmosis with multifocal choroiditis in a child. Pediatr. Infect. Dis. J. 2000, 19, 479–481. [Google Scholar] [CrossRef]
  81. Tutor, J.D.; Schoumacher, R.A.; Chesney, J.P. Chylothorax associated with histoplasmosis in a child. Pediatr. Infect. Dis. J. 2000, 19, 262–263. [Google Scholar] [CrossRef] [PubMed]
  82. López, L.F.; Valencia, Y.; Tobón, Á.M.; Velásquez, O.; Santa, C.D.; Cáceres, D.H.; Restrepo, Á.; Cano, L.E. Childhood Histoplasmosis in Colombia: Clinical and Laboratory Observations of 45 Patients. Med. Mycol. 2016, 54, 677–683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Adderson, E.E. Histoplasmosis in a pediatric oncology center. J. Pediatr. 2004, 144, 100–106. [Google Scholar] [CrossRef] [PubMed]
  84. Quellette, C.P.; Stanek, J.R.; Leber, A.; Ardura, M.L. Pediatric histoplasmosis in an area of endemicity: A contemporary anal-ysis. J. Pediatr. Infect. Dis. Soc. 2019, 8, 400–407. [Google Scholar] [CrossRef] [PubMed]
  85. Vega, W.; Almeida, R.; Miño, G.; Gené, J.; Guarro, J. A quick and cost-effective method for diagnosing disseminated histo-plasmosis in children. Diagn. Microbiol. Infect. Dis. 2007, 57, 405–408. [Google Scholar] [CrossRef] [PubMed]
  86. Chu, J.H.; Feudtner, C.; Heydon, K.; Walsh, T.J.; Zaoutis, T.E. Hospitalizations for Endemic Mycoses: A Population-Based National Study. Clin. Infect. Dis. 2006, 42, 822–825. [Google Scholar] [CrossRef] [Green Version]
  87. Faiolla, R.C.L.; Coelho, M.C.; Santana, R.D.C.; Martinez, R. Histoplasmosis in immunocompetent individuals living in an endemic area in the Brazilian Southeast. Rev. Soc. Bras. Med. Trop. 2013, 46, 461–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Bahr, N.C.; Antinori, S.; Wheat, L.J.; Sarosi, G.A. Histoplasmosis Infections Worldwide: Thinking Outside of the Ohio River Valley. Curr. Trop. Med. Rep. 2015, 2, 70–80. [Google Scholar] [CrossRef] [Green Version]
  89. Zurita, J.; Denning, D.W.; Paz-Y-Miño, A.; Solís, M.B.; Arias, L.M. Serious fungal infections in Ecuador. Eur. J. Clin. Microbiol. Infect. Dis. 2017, 36, 975–981. [Google Scholar] [CrossRef] [Green Version]
  90. Norkaew, T.; Ohno, H.; Sriburee, P.; Tanabe, K.; Tharavichitkul, P.; Takarn, P.; Puengchan, T.; Bumrungsri, S.; Miyazaki, Y. Detection of Environmental Sources of Histoplasma capsulatum in Chiang Mai, Thailand, by Nested PCR. Mycopathologia 2013, 176, 395–402. [Google Scholar] [CrossRef]
  91. Goswami, R.; Pramanik, N.; Banerjee, D.; Raza, M.; Guha, S.; Maiti, P. Histoplasmosis in eastern India: The tip of the iceberg? Trans. R. Soc. Trop. Med. Hyg. 1999, 93, 540–542. [Google Scholar] [CrossRef]
  92. Gugnani, H.C.; Muotoe-Okafor, F. African histoplasmosis: A review. Rev. Iberoam. Micol. 1997, 14, 155–159. [Google Scholar]
  93. Oladele, R.; Ayanlowo, O.; Richardson, M.; Denning, D. Histoplasmosis in Africa: An emerging or a neglected disease? PLoS Negl. Trop. Dis. 2018, 12, 0006046. [Google Scholar] [CrossRef]
  94. Antinori, S. Histoplasma capsulatum: More Widespread than Previously Thought. Am. J. Trop. Med. Hyg. 2014, 90, 982–983. [Google Scholar] [CrossRef] [Green Version]
  95. Develoux, M.; Amona, F.M.; Hennequin, C. Histoplasmosis Caused by Histoplasma capsulatum var. duboisii: A Comprehensive Review of Cases From 1993 to 2019. Clin. Infect. Dis. 2020. [Google Scholar] [CrossRef] [PubMed]
  96. Amona, F.M.; Denning, D.W.; Moukassa, D.; Develoux, M.; Hennequin, C. Histoplasmosis in the Republic of Congo dominated by African histoplasmosis, Histoplasma capsulatum var. duboisii. PLoS Negl. Trop. Dis. 2021, 15, 0009318. [Google Scholar] [CrossRef] [PubMed]
  97. Couppié, P.; Aznar, C.; Carme, B.; Nacher, M. American histoplasmosis in developing countries with a special focus on pa-tients with HIV: Diagnosis, treatment and prognosis. Curr. Opin. Infec.t Dis. 2006, 19, 443–449. [Google Scholar] [CrossRef] [PubMed]
  98. Wheat, J.; Hafner, R.; Korzun, A.; Limj, M.; Spencer, P.; Larsen, R.; Hecht, F.; Powderly, W. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am. J. Med. 1995, 98, 336–342. [Google Scholar] [CrossRef]
  99. McKinsey, D.S.; Spiegel, R.A.; Hutwagner, L.; Stanford, J.; Driks, M.R.; Brewer, J.; Gupta, M.R.; Smith, D.L.; O’Connor, M.C.; Dall, L. Prospective Study of Histoplasmosis in Patients Infected with Human Immunodeficiency Virus: Incidence, Risk Factors and Pathophysiology. Clin. Infect. Dis. 1997, 24, 1195–1203. [Google Scholar] [CrossRef] [Green Version]
  100. Nieto-Ríos, J.; Serna-Higuita, L.; Guzman-Luna, C.; Ocampo-Kohn, C.; Aristizabal-Alzate, A.; Ramírez, I.; Velez-Echeverri, C.; Vanegas-Ruiz, J.; Zuleta, J.; Zuluaga-Valencia, G. Histoplasmosis in renal transplant patients in an endemic area at a ref-erence hospital in Medellin, Colombia. Transpl. Proc. 2014, 46, 3004–3009. [Google Scholar] [CrossRef]
  101. Cuellar-Rodriguez, J.; Avery, R.K.; Lard, M.; Budev, M.; Gordon, S.M.; Shrestha, N.K.; Duin, D.V.; Oethinger, M.; Mawhorter, S.D. Histoplasmosis in Solid Organ Transplant Recipients: 10 Years of Experience at a Large Transplant Center in an Endemic Area. Clin. Infect. Dis. 2009, 49, 710–716. [Google Scholar] [CrossRef] [Green Version]
  102. Lee, P.P.-W.; Lau, Y.-L. Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses. Front. Immunol. 2017, 8, 735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Lovell, J.P.; Foruraghi, L.F.; Freeman, A.F.; Uzel, G.; Zerbe, C.S.; Su, H.; Hsu, A.P.; Holland, S.M. Persisten nodal histoplasmosis in NF-B essential modulator (NEMO) deficiency: Report of a case and review of infection in primary immunodeficiencies. J. Allergy Clin. Immunol. 2016, 138, 903–905. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Alberti-Flor, J.; Granda, A. Ileocecal histoplasmosis mimicking Crohn’s disease in a patient with Job’s syndrome. Digestion 1986, 33, 76–180. [Google Scholar] [CrossRef] [PubMed]
  105. Robinson, W.; Arnold, S.; Michael, C.; Vickery, J.; Schoumacher, R.; Pivnick, E.; Ward, J.; Nagabhushanam, V.; Lew, D. Case report of a young child with disseminated histoplasmosis and review of hyperimmunoglobulin E syndrome (HIES). Clin. Mol. All. 2011, 9, 1–7. [Google Scholar]
  106. Wheat, L.J.; Batteiger, B.E.; Sathapatayavongs, B. Histoplasma capsulatum Infections of the Central Nervous System. Medicine 1990, 69, 244–260. [Google Scholar] [CrossRef]
  107. Epelboin, L.; Dione, A.; Serris, A.; Blanchet, D.; Bidaud, B.; Walter, G.; Abboud, P.; Mosnier, E.; Gaillet, M.; Michaud, C.; et al. Histoplasmosis of the central nervous system: A case series between 1990 and 2019 in French Guiana. Am. J. Trop. Med. Hyg. 2021. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
  108. Donnelly, J.P.; Chen, S.C.; Kauffman, C.A.; Steinbach, W.J.; Baddley, J.W.; Verweij, P.E.; Clancy, C.J.; Wingard, J.R.; Lockhart, S.R.; Groll, A.H.; et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin. Infect. Dis. 2019, 71, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
  109. Linder, K.A.; Kauffman, C.A. Current and New Perspectives in the Diagnosis of Blastomycosis and Histoplasmosis. J. Fungi 2020, 7, 12. [Google Scholar] [CrossRef]
Jof 07 00448 g001 550
Figure 1. PRISMA flow chart demonstrating the process of inclusion/exclusion of histoplasmosis studies for analysis. The initial literature search found 309 papers related to histoplasmosis. Of these, 81 were excluded via title analysis, 24 were excluded via abstract analysis and 34 had no access to the full text. This left 170 studies, of which, 105 were excluded via full-text analysis; a total of 65 studies were included in the final analysis. Diagram adapted from Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., The PRISMA Group. (2009).
Figure 1. PRISMA flow chart demonstrating the process of inclusion/exclusion of histoplasmosis studies for analysis. The initial literature search found 309 papers related to histoplasmosis. Of these, 81 were excluded via title analysis, 24 were excluded via abstract analysis and 34 had no access to the full text. This left 170 studies, of which, 105 were excluded via full-text analysis; a total of 65 studies were included in the final analysis. Diagram adapted from Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., The PRISMA Group. (2009).
Jof 07 00448 g001
Jof 07 00448 g002 550
Figure 2. The most commonly presented features of the 78 children with histoplasmosis.
Figure 2. The most commonly presented features of the 78 children with histoplasmosis.
Jof 07 00448 g002
Table
Table 1. Inclusion and exclusion criteria that were used in the literature search.
Table 1. Inclusion and exclusion criteria that were used in the literature search.
Inclusion CriteriaExclusion Criteria
Patient characteristics<18 yearsExclusively ≥18 years
Diagnosis of
histoplasmosis		No diagnosis of
histoplasmosis
StudyPublished 1 January 2000–
1 January 2019		Published before 1 January 2000
Full textNo full text
English languageNot in the English language
Paediatric data distinguishable from adult dataPaediatric data indistinguishable from adult data
Original case reports of histoplasmosisNo original case reports of
histoplasmosis
Population study in which the characteristics of individual cases were not described
Systematic/literature reviews
Outcome measures ≥5 of the following outcomes described: age, gender, infection type, underlying conditions, presenting signs and symptoms, method(s) of diagnosis, treatment and patient outcome<5 of the following outcomes described: age, gender, infection type, underlying conditions, presenting signs and symptoms, method(s) of diagnosis, treatment and patient outcome
Table
Table 2. Patient demographics and characteristics of 83 children with histoplasmosis.
Table 2. Patient demographics and characteristics of 83 children with histoplasmosis.
Age (n = 83)
Mean ± SD9.5 ± 5.5 years
Median (range)11 years (1 month–17 years)
Gender (n = 82)
Female/male42 (51.2%)/40 (48.8%)
Underlying condition (n = 70)
None21 (30.0%)
Primary immunodeficiency *10 (14.3%)
HIV/AIDS9 (12.9%)
Renal transplant8 (11.4%)
Crohn’s disease6 (8.6%)
Juvenile rheumatoid arthritis6 (8.6%)
Haematological malignancy &4 (5.7%)
Other #5 (7.2%)
Disease Type (n = 78)
Disseminated62 (79.5%)
Pulmonary12 (15.4%)
Central nervous system2 (2.6%)
Other $2 (2.6%)
Geographic Area (n = 83)
North America53 (63.9%)
Asia14 (16.9%)
Europe1 (1.2%)
Africa5 (6.0%)
South America10 (12.0%)
* Hyper-IgE syndrome (n = 4), STAT1 mutation (n = 2), T-cell deficiency (n = 1), interferon-gamma-receptor-1 deficiency (n = 1), common variable immunodeficiency (n = 1), hemophagocytic lympho-histiocytosis (n = 1). & Acute lymphoblastic leukaemia (n = 2), acute myeloid leukaemia (n = 1), Hodgkin’s lymphoma (n = 1). # Idiopathic chronic anterior uveitis (n = 2) and juvenile systemic lupus erythematosus (n = 1) treated with immunosuppression; gastrointestinal stromal tumor (n = 1) and Wilms tumor (n = 1) treated with chemotherapy; EBV infection (n = 2); tuberculosis (n = 1). $ Osseous (n = 1) and laryngeal (n = 1) infections.
Table
Table 3. Disease characteristics and outcome compared between immunocompetent and immunocompromised children with histoplasmosis.
Table 3. Disease characteristics and outcome compared between immunocompetent and immunocompromised children with histoplasmosis.
TotalImmunocompromisedImmunocompetent
Infection siten = 78n = 40n = 23
Lungs43 (55.8%)26 (65%)10 (43.5%)
Lymph nodes30 (39%)16 (40%)7 (30.4%)
Bone marrow24 (31.2%)16 (40%)6 (26.1%)
Skin12 (15.6%)7 (17.5%)4 (17.4%)
Central nervous system8 (10.4%)2 (5%)3 (13%)
Bone6 (7.8%)2 (5%)2 (8.7%)
Other *13 (16.9%)12 (3%)1 (4.3%)
Disease typen = 78n = 41n = 23
Disseminated62 (79.5%)36 (87.8%)16 (69.6%)
Single organ16 (20.5%)5 (12.2%)7 (30.4%)
Lungs12 (15.4%)4 (9.8%)4 (17.4%)
Central nervous system2 (2.6%)-2 (8.7%)
Other2 (2.6%)1 (2.4%), larynx1 (4.3%), bone
Outcomen = 73n = 43n = 19
Cure35 (47.9%)20 (46.5%)10 (52.6%)
Clinical improvement21 (28.8%)11 (25.6%)7 (36.8%)
Recurrence6 (8.2%)4 (9.3%)1 (5.3%)
Death8 (11%)5 (11.6%)1 (5.3%)
Lost to follow-up3 (4.1%)3 (7%)-
* Other infection sites included: pericardium (n = 1), gastrointestinal tract (n = 4), larynx (n = 1), soft tissue (n = 2), liver (n = 2), spleen (n = 1), pancreas (n = 1), eye (n = 1).
Table
Table 4. Tissue and body fluids that were used to diagnose histoplasmosis in 83 paediatric patients.
Table 4. Tissue and body fluids that were used to diagnose histoplasmosis in 83 paediatric patients.
Number of SamplesAntibodyAntigenCultureHistopathologyMicroscopy
Urine24-24---
Blood/serum5137134-
Bone marrow #16--514-
Lymph node15--513-
Bronchoalveolar lavage fluid6--1-5
Skin #7--35-
Lung tissue6---6-
Cerebrospinal fluid5-42-1
Bone5--15-
Gastrointestinal tissue4--23-
Other *5-2-3-
Not specified11-10-1-
* Larynx exsudate (n = 1), joint tissue (n = 2), pericardial fluid (n = 1), pleural fluid (n = 1), soft tissue (n = 1); # molecular methods were used on one bone marrow sample and one skin sample.
Table
Table 5. Treatment and outcome of 83 children with histoplasmosis.
Table 5. Treatment and outcome of 83 children with histoplasmosis.
Antifungal TherapyNumber of PatientsCured or Clinical ImprovementRecurrenceDeathLost to Follow-Up/Not Specified
Antifungal Therapy
AmB → Itra3123 (74.2%)2-6
Itra only1815 (83.3%)1-2
AmB only116 (72.7%)-5-
AmB → other azoles65 (83.3%)1--
Other azoles32 (66.7%)1--
None74 (57.1%)-3-
Not specified61 (16.7%)1-4
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

MacInnes, R.; Warris, A. Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases. J. Fungi 2021, 7, 448. https://doi.org/10.3390/jof7060448

AMA Style

MacInnes R, Warris A. Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases. Journal of Fungi. 2021; 7(6):448. https://doi.org/10.3390/jof7060448

Chicago/Turabian Style

MacInnes, Rebecca, and Adilia Warris. 2021. "Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases" Journal of Fungi 7, no. 6: 448. https://doi.org/10.3390/jof7060448

APA Style

MacInnes, R., & Warris, A. (2021). Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases. Journal of Fungi, 7(6), 448. https://doi.org/10.3390/jof7060448

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop