|Year : 2018 | Volume
| Issue : 1 | Page : 72-77
Disseminated histoplasmosis with Hypergammaglobulinemia in rare subtype of severe combined immunodeficiency: A case report of a 7-year-old child
Sheetal Arora1, Deepshikha Rana1, Leelawathi Dawson2, Anand Kumar Verma3
1 Department of Pathology, ESIC Medical College and Hospital, NIT Faridabad, Faridabad, Haryana, India
2 Department of Pathology, Safdarjung Hospital and Vardhman Mahavir Medical College, New Delhi, India
3 Department of Pathology, National Institute of Pathology (ICMR), New Delhi, India
|Date of Submission||15-Nov-2016|
|Date of Acceptance||22-May-2017|
|Date of Web Publication||23-Apr-2018|
Dr. Sheetal Arora
Department of Pathology, ESIC Medical College and Hospital, NIT Faridabad, Faridabad, Haryana
Source of Support: None, Conflict of Interest: None
Background: Histoplasmosis is a progressive disease caused by dimorphic intracellular fungi. When infection is present, it is usually in immunocompromised individuals. We report an unusual presentation of progressive disseminated histoplasmosis in patient with raised Ig levels as but low CD4 and CD8 levels, in a rare case of severe combined immunodefiency.
Case Report: A 7-year-old female with history of intermittent fever for 8 months, multiple joint pain and weight loss for 2 months. On examination, she had pallor, erythematous plaque on face and hepatosplenomegaly. The patient had high levels of immunoglobulins and reduced CD4, CD8 count. Disseminated histoplasmosis (DH) was diagnosed on microscopic examination of bone marrow and skin biopsy and was confirmed by fungal culture of bone marrow & blood.
Discussion: SCID is characterized by abnormalities in T-cell, B-cell, and NK-cell functions. In our case, CD-4, CD-8 count was reduced but B-cell defect was not present, leading to the wrong perception of immune status of patient. Our patient might be suffering from the type of SCID which has T-cell defect without the loss of B-cell function.
Conclusion: Our case represents a unique paradox in which the impaired cellular immunity resulted in immune deficient status causing disseminated histoplasmosis in an individual with intact humoral immunity, posing a diagnostic challenge.
The following core competencies are addressed in this article: Medical Knowledge, Patient care.
Keywords: CD4 count, CD8 count, immunocompetent, severe combined immunodeficiency
|How to cite this article:|
Arora S, Rana D, Dawson L, Verma AK. Disseminated histoplasmosis with Hypergammaglobulinemia in rare subtype of severe combined immunodeficiency: A case report of a 7-year-old child. Int J Acad Med 2018;4:72-7
|How to cite this URL:|
Arora S, Rana D, Dawson L, Verma AK. Disseminated histoplasmosis with Hypergammaglobulinemia in rare subtype of severe combined immunodeficiency: A case report of a 7-year-old child. Int J Acad Med [serial online] 2018 [cited 2019 Jul 23];4:72-7. Available from: http://www.ijam-web.org/text.asp?2018/4/1/72/230856
| Introduction|| |
Histoplasmosis was first described in 1906 by Darling among the workers of the Panama Canal. Histoplasmosis is currently the most common cause of fungal respiratory disease with almost 500,000 individuals acquiring the fungus each year. The etiologic agent responsible for histoplasmosis is Histoplasma capsulatum, a thermally dimorphic fungus with worldwide distribution. The fungus is primarily found in soil, where it exists in a mycelia form.
The entry portal of H. capsulatum is through inhalation of aerosolized 2–4 μm diameter microconidia. Morphogenesis is initiated after infection with the conidia developing into a 2–4 μm oval yeast form. The organism exists in the mold (mycelial) form at soil temperatures and switches to the yeast form at normal human body temperatures (37°C) and resides within macrophages. The fungus is rapidly ingested by macrophages and neutrophils but manages to avoid intracellular destruction. It resists killing by macrophages by production of secreted defenses against fungicidal reactive oxygen species (ROS) and modulation of the phagosomal environment to prevent activation of lysosomal hydrolases. Production of external factors to specifically eliminate phagocyte-derived ROS is a common characteristic of pathogens that are able to infect and survive within phagocytes.,,,, Intracellular yeast can be transported diffusely through the lymphatics and into the bloodstream.
The infected macrophages induce cytokines to enlist more macrophages and monocytes to fight the organism and these coalesce together to form granulomas. This activation of the T-cell-mediated immune response is usually complete within 2 weeks and failure of this result in the progressive spread of infection to other organs; nevertheless, initial infection is typically contained by innate and adaptive host responses. This activation of the T-cell-mediated immune response is usually complete within 2 weeks and failure of this result in the progressive spread of infection to other organs. Histoplasmosis may present clinically in different forms – Asymptomatic infection, an acute or chronic pulmonary infection, mediastinal fibrosis or granulomas, and disseminated histoplasmosis (DH). The development of progressive DH indicates impaired cell-mediated immune responses. The acute form of DH is seen mostly in the immunocompromised host and is characterized by an abrupt onset of symptoms (fever, malaise, hepatosplenomegaly, lymphadenopathy, anemia, leukopenia, and thrombocytopenia); lack of granulomatous inflammatory response; and high case-fatality rates. The chronic form of DH is characterized by an indolent course, focal lesions, and an effective cell-mediated immune response. The subacute DH pursues a subacute but relentless course and focal lesions in various visceral organs. We present the case of acute DH in a 7-year-old child with impaired cellular immunity and hyperglobulinemia. DH has been reported in X-linked hyperimmunoglobulin M syndrome. There is a report of successful immune control of pulmonary histoplasmosis in an individual with hypogammaglobulinemia, indicating the superfluity of antibody production to Histoplasma containment and elimination. To the best of our knowledge, there are no reported cases of histoplasmosis in persons with hyperglobulinemia. Therefore, the occurrence of a relatively rare disseminated infection in individuals with rare genetic disorders suggests a causal link.
| Clinical History|| |
A 7-year-old female admitted in pediatrics ward of our hospital with a history of intermittent fever for 8 months, with multiple joint pain and weight loss for 2 months. She had a history of fever of unknown origin for which she received broad-spectrum antibiotics followed by antitubercular treatment for 1½ month from a private practitioner, but she did not have any records for the investigations of tuberculosis.
On examination, she had marked pallor and erythematous plaque on the face. Abdominal examination showed enlargement of the liver (6 cm below the costal margin) and spleen (10 cm below the costal margin), which was confirmed on ultrasonography. Radiological examination of the chest was normal. Differential diagnosis of leukemia or parasitic infection was considered.
Laboratory investigations revealed pancytopenia (hemoglobin = 8.6 g/dl, total leukocyte count = 2800 cells/mm 3, and platelets = 88,000/mm 3). Serological tests for malaria antigen and typhoid were negative. Antibodies for HIV1 and HIV2 were also negative. Bone marrow aspirate showed intracellular and extracellular globose yeast-like organisms measuring approximately 3–4 mm × 2–3 μm in size giving the suspicion of histoplasmosis [Figure 1] and [Figure 2].
|Figure 1: Bone marrow aspirate (×20) (Giemsa stained) showing intracellular and extracellular globose yeast-like cells|
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|Figure 2: Bone marrow aspirate (Giemsa stained, ×40) showing intracellular yeast-like globose bodies|
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Liver function test showed elevated liver enzymes (aspartate aminotransferase = 80 U/L, alanine aminotransferase = 20 U/L, alkaline phosphatase = 192 U/L, lactate dehydrogenase = 62 IU/L, and total bilirubin = 0.5 mg/dl). Renal function parameters were within normal limits. The biopsy was taken from erythematous plaque present on face.
| Materials and Methods|| |
Enzyme-linked immunosorbent assay was performed for the quantitative measurement of immunoglobulins (IgM, IgG, IgE, and IgA) and flow cytometry was done for cell counts. Hematoxylin and eosin (H and E) stain along with periodic acid–Schiff (PAS) stain was done on biopsy obtained from skin lesion [Figure 3] and [Figure 4].
|Figure 3: Skin biopsy (hematoxylin and eosin stained, ×4) showing yeast-like cells with halo around them, suggestive of Histoplasma|
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|Figure 4: Skin biopsy (periodic acid–Schiff-stained, ×4) showing bright eosinophilic structures of Histoplasma|
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| Results|| |
H and E stained sections from skin biopsy showed granulomatous inflammation with tiny globular organisms, which were confirmed on PAS, stain (seen as bright eosinophilic globular structures with clear halo around them) to be fungal in origin. Based on bone marrow and skin biopsy histopathological examination, a diagnosis of H. capsulatum was formulated which was confirmed on blood and bone marrow culture.
As H. capsulatum is common in immunocompromised individuals, the patient was also investigated for HIV status and Ig profile. The patient was negative for HIV antibodies. Ig profile showed IgG = 1799.9 mg/dl (570–1410 mg/dl), IgA = 424.6 mg/dl (65–260 mg/dl), IgM = 208.8 mg/dl (60–175 mg/dl), and IgE = 1092 IU/L (<100 IU/ml) which led to the consideration of immunocompetent status.
Flow cytometry was done much later as an ancillary test with peripheral blood for lymphocyte count, which showed low CD counts, that is, 3% of CD3-positive lymphocytes (normal range 50%–73%), 0.8% of CD4-positive lymphocytes (normal range 26%–44%), and 0.8% of CD8 count (14%–30%).
| Discussion|| |
After being exposed to Histoplasma, the host relies on both innate and adaptive immune response mechanisms to neutralize the pathogen and withstand infection. Macrophages and dendritic cells have major roles in the activation of cellular pathways, and the numerous cytokines, especially interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), significantly impact host responses.
Macrophages have a central role in the interaction between the fungus and the host, although their contribution has a dual nature. They represent the first line of defense during infection with H. capsulatum, as they rapidly phagocytose the inhaled conidia and transforming yeast cells, and the infected macrophage subsequently activates effector T-cells and enhance the release of Th1-associated proinflammatory cytokines (interleukin [IL-12], IFN-γ, and TNF-α)., Deprivation of zinc and iron is among the means used by macrophages to neutralize the intruding pathogen, along with production of superoxide, nitric oxide, and lysosomal hydrolysis. However, the fungus displays various mechanisms to elude destruction after phagocytosis. For example, H. capsulatum yeast cells are able to regulate the pH of the phagolysosomes at a neutral pH (approximately pH 6.5), where lysosomal hydrolases have decreased activity. Hence, the H. capsulatum yeast cells manage to survive and even replicate inside macrophages.
Dendritic cells are also an important effector of the innate immunity. They are able to phagocytose and degrade the fungal cells with higher efficacy than macrophages, which might be due to recognition of the pathogen through a different type of receptor (fibronectin receptor on dendritic cells vs. CD18 on macrophages). Dendritic cells also are extremely efficient at processing and presenting antigens to specific CD8 T-cells, either following ingestion of the yeast, or through “cross-presentation” of fungal antigens engulfed from infected apoptotic macrophages. In a recent study, the addition of antigen-presenting dendritic cells was found to suppress excessive production of IL-4 by CD4 T-cells in lungs of CCR2-deficient mice infected with H. capsulatum, demonstrating the importance of these cells in the regulation of immune responses.
Cellular immunity is crucial in the host defense against intracellular pathogens; therefore, T-cells, as the central effectors of the cellular immunity, have a substantial role in neutralizing H. capsulatum yeast cells. Mice depleted of both CD4 and CD8 T-cells have accelerated time to death after challenge with H. capsulatum yeast cells, especially in a primary histoplasmosis model, which underlines the importance of the interaction between the two cell subsets in withstanding Histoplasma infection by eliciting a Th1 response. CD4 cell depletion is associated with survival during primary infection, as a result of impaired IFN-γ production. The elimination of CD8 T-cells results in decreased clearance of yeast cells in primary but not secondary infection.
In our case, on the basis of raised Ig levels, the patient was considered to be immunocompetent and was treated with antifungal therapy. The patient did not respond to the treatment and died.
The CD4 and CD8 cell count which was done later revealed that the patient had low CD4 and CD8 counts, that is, immunocompromised due to low cellular immunity. This clearly indicates that merely on the basis of high Ig levels, patient should not be considered immunocompetent as B-cell work vaguely by producing the Igs to kill the infectious organism. One school of thought says that T-cells activate B-cells which then produce Igs. However, there are various presentations of severe combined immunodeficiency (SCID) syndrome [Table 1]. SCID can be broadly classified into two groups: SCID with B-cells (70% of patients with SCID) and SCID without B-cells. Beyond this basic grouping, SCID may be categorized according to phenotypic lymphocyte profiles that include both B-cell status (B + or B −) and NK-cell status (NK + or NK −) in addition to T-cell status (T −, because there is always a T-cell deficiency in SCID).
|Table 1: Common causes of severe combined immunodeficiency, cellular defects, and inheritance pattern|
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SCID is characterized by abnormalities in T-cell, B-cell, and NK-cell functions. The genetic mutations can be X-linked, autosomal recessive or sporadic, depending on the location of the gene affected. Although the list of gene defects is extensive, the disease can be stratified according to the absence of T-cell function with or without the loss of B- and NK-cell host defenses [Table 1].
In our case, B-cell defect was not present, so the patient had raised Ig level (IgG, IgA, IgM, and IgE) due to the fungal infection leading to the wrong perception of immune status of patient, but T-cell defect was evident with reduced CD4 and CD8 count (CD4 positivity as 0.8% and CD8 as 0.4%). Although the exact genetic defect was not worked on, the patient might be suffering from the type of SCID which has T-cell defect without the loss of B-cell function [Table 1].
The great majority of SCID cases present in patients younger than 3 months (average age at symptom onset, 2 months; mean age at diagnosis, 6.5 months). Patients with adenosine deaminase-deficient SCID seem to have less severe mutations; some are not identified until adulthood. Patients with common γ-chain mutation may reveal less severe mutations and present in the 2nd year of life but this occurs rarely. Although the patient presented to our hospital at 7 years of age, the patient gave the history of infection with the symptoms of fever 4–5 years back and in the developing countries like India, the cause of fever being considered was typhoid or tuberculosis. This infers that the patient might have succumbed to infections at an early age of about 2 years.
Humoral immune response generally has a limited role in the clearance of intracellular pathogens, which explains the immunocompromised status of the patient due to the low cellular immunity. As seen in our case, the levels of antibodies (Igs) were raised but were unable to combat the infection and the patient succumbed to death despite getting treatment for histoplasmosis.
T-cells have substantial role in neutralizing H. capsulatum. It appears that the cell-mediated immunity is crucial for host defense. Lin and Wu-Hsieh  also showed that both CD4 and CD8 are activated and engage in IFN-γ production as a primary immune response in histoplasmosis.
This case study concerns an atypical manifestation of systemic infection in a rare type of SCID patient.
Hostoffer et al. described DH in patient with hyper-IgM immunodeficiency. Other study  described histoplasmosis along with other infections in X-linked hyper-IgM syndrome which is characterized by normal or elevated serum IgM, reduced levels of IgG and IgA along with defective T-cell function. In our case, not only IgM but also IgG, IgA, and IgE were raised with reduced CD4 and CD8 count.
It is to be emphasized that it is the CD4, and CD8 cell count should always be done along with the Ig levels for determining the immune status. The mortality rate associated with invasive histoplasmosis is high even in immunocompetent individuals, despite the use of broad-spectrum antifungal agents. One study of patients who were hospitalized for histoplasmosis in the US estimated the crude mortality rate to be approximately 5% for children and 8% for adults. Another study found a 6-month mortality rate of 4% among patients with symptomatic histoplasmosis. The present case emphasizes the need for finding the root cause of infection by setting the protocols of investigations in developing countries like India, so that such patients are not missed and receive the right treatment and have better prognosis thereafter. In primary immunocompromised individuals, death from infection usually occurs within the first 2 years of life without treatment. Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or bone marrow transplant; such treatment can lead to long-term survival. With bone marrow and other stem cell reconstitution techniques, many patients with SCID are fully reconstituted without complications.
| Conclusion|| |
Our case represents a unique paradox in which the impaired cellular immunity resulted in immune deficient status for an individual with intact humoral immunity.
With a continuously expanding population of immunocompromised patients secondary to ongoing HIV epidemics, increasing use of immunosuppressant therapies, and rising number of transplant recipients a high-risk template for histoplasmosis and other life-threatening infections are present in the population.
Declaration of patient consent
The authors certify that they have obtained appropriate patient consent documentation, wherein the patient(s) has/ have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patient(s) understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors would like to acknowledge the contribution by Dr. Manushree Gupta, assistant professor, Department of Psychiatry, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]