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Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 26-31

Unusual fungal infection in an immunocompetent host

Department of Pulmonology, Baby Memorial Hospital, Calicut, Kerala, India

Date of Submission28-Oct-2021
Date of Decision19-Nov-2021
Date of Acceptance24-Nov-2021
Date of Web Publication17-Jan-2022

Correspondence Address:
Dr. Ravindran Chetambath
Navaneeth, Sarovaram Biopark Road, Civil Station Post, Calicut - 673 020, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jalh.jalh_23_21

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Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients. However, approximately one-third of cases of cryptococcosis are seen in patients who have no readily identifiable immune defects. Pulmonary cryptococcosis often manifests as isolated or multiple nodules, easily mimicking lung cancer clinically and radiologically. This case report highlights the tumor-like presentation of cryptococcosis in an immunocompetent patient.

Keywords: Cryptococcus, immunocompetent patient, mediastinal mass

How to cite this article:
Kumar P, Nandini V, Sabir M C, Chetambath R. Unusual fungal infection in an immunocompetent host. J Adv Lung Health 2022;2:26-31

How to cite this URL:
Kumar P, Nandini V, Sabir M C, Chetambath R. Unusual fungal infection in an immunocompetent host. J Adv Lung Health [serial online] 2022 [cited 2022 May 16];2:26-31. Available from: http://www.jalh.com/text.asp?2022/2/1/26/335925

  Introduction Top

Pulmonary cryptococcosis is a form of pulmonary fungal infection caused by Cryptococcus neoformans and Cryptococcus gattii. The respiratory tract is the principal route of entry for infection through inhalation of fungal spores. Cryptococcosis predominantly occurs in immunocompromised patients but can also be seen in immunocompetent hosts, particularly those exposed to avian (e.g., pigeon) droppings. The presentation of pulmonary cryptococcosis can range from asymptomatic nodular disease to severe acute respiratory distress syndrome. Most often, it causes several lung nodules or masses with or without cavitation, chiefly in immunocompromised patients. In addition, consolidation, mediastinal lymphadenopathy, and pleural effusion may also be present. In the immunocompetent host, the pulmonary infections normally are asymptomatic. In the immunocompromised patient, cryptococcal infection is most often symptomatic and usually disseminates to the central nervous system (CNS), skin, and bones. Symptoms range from a mild cough and low-grade fever to acute presentation with high fever and severe shortness of breath.

  Case Report Top

A 41-year-old female presented to the pulmonary medicine outpatient with complaints of cough and expectoration of 1 month with mild exertional breathlessness. There was a history of low grade on and off fever for the past 3 days. It was not associated with chills or rigors. There is no history of chest pain, hemoptysis, or wheeze. There is no history of weight loss. She had no history of any major medical or surgical illness or any exposure to a patient of active tuberculosis. She was not a diabetic or hypertensive. There was exposure to passive smoking.

On physical examination, the vital signs and oxygen saturation while breathing room air were normal. Respiratory system examination did not reveal any positive findings. The rest of the systemic examination was unremarkable.

Routine chest X-ray (CXR) PA view showed superior mediastinal widening with a well-defined homogenous opacity in the right paratracheal region and a relatively less dense opacity in contiguity [Figure 1]a. Features were in favor of a superior mediastinal mass. The visible part of lung parenchyma was normal, and there was no pleural effusion.
Figure 1: Initial X-ray of the patient showing superior mediastinal widening (a). X-ray after 2 months of antifungal therapy showing slight reduction in the size of the shadow (b). X-ray taken after 1 year (at the end of treatment showing complete resolution of shadow (c)

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A contrast-enhanced computed tomography (CT) scan of the thorax revealed a solid mass right perihilar region associated with large right paratracheal lymph nodal mass causing mass effect on the distal trachea and carina [Figure 2]a and [Figure 2]b. The right paratracheal mass was occluding the distal confluence of azygos vein and infiltrating the superior vena cava (SVC) [Figure 2]c. The paratracheal mass was measuring 65 mm × 40 mm without any postcontrast enhancement. The mass did not have any cystic component or any areas of calcification or necrosis [Figure 2]d.
Figure 2: Large mediastinal mass toward the right side with partial compression on the lower end of trachea (a and b). Mediastinal mass compresses the distal confluence of azygos vein (c). There is no necrosis or cavity formation (d)

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Her complete blood count, liver, and kidney function tests were normal, and viral serology was negative.

Fiberoptic bronchoscopy was done which showed mucosal bulging from the lower end of trachea and carina was blunt [Figure 3]a. There were multiple intraluminal nodules in the right main bronchus [Figure 3]b and [Figure 3]c. There was no bleeding. Multiple biopsies were taken from the nodules, and bronchial washing was collected for microbiological investigations.
Figure 3: Fiberoptic bronchoscopy showed intraluminal nodule at the distal end of trachea (a), blunt carina (b) and multiple endobronchial nodules (c) from which biopsy was taken

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  Differential Diagnosis Top

This patient is a middle-aged, nonsmoker, and immunocompetent female with a mass in the anterior and middle mediastinal compartment. The differential diagnosis based on the clinico-radiological profile of this patient can be broadly divided into benign and neoplastic etiologies. Neoplastic causes include lymphoma (including Hodgkin's lymphoma and Non-Hodgkin's lymphoma), thymoma/thymic carcinoma, Castleman disease, small-cell lung cancer, and lymph nodal metastasis. Benign causes include retrosternal extension of thyroid, lipomas, lymph node enlargement due to granulomatous diseases such as tuberculosis and sarcoidosis. Certain inflammatory conditions such as granulomatosis with polyangiitis can also rarely present with mediastinal masses. However, the clinicoradiological profile of these disorders does not fit with the current presentation.

Considering the relatively short duration of symptoms of cough and low-grade fever, we would like to review some of the important differential diagnoses of this case.

Bronchogenic carcinoma

Bronchogenic carcinoma predominantly small cell type can present with a central lesion.[1] However, considering the age and the absence of smoking status makes this an unlikely cause.[2]


Hodgkin's lymphoma commonly presents with lymph node enlargement of the neck. Mediastinal lymph node enlargement can be seen in 50%–60% of the cases and can be asymptomatic or associated with symptoms such as retrosternal chest pain, cough, and dyspnea. The patient also had an accompanying fever which constitutes a “B symptom.” This disease usually has a peak age of presentation between 15 and 35 years.[3] Considering the clinicoradiological profile of this patient, this etiology will be high on the list of differential diagnosis.

Thymoma/thymic carcinoma

Thymoma may occur in patients of all age groups, with a peak incidence between 40 and 60 years and an equal gender predilection.[4] Paraneoplastic syndromes, the most common myasthenia gravis presenting with muscle weakness are a frequent accompaniment.[4] Usually, a thymic tumor is found to be located between the sternum and the great vessels. Thymoma usually presents with a smooth or lobulated contour arising from one lobe of the thymus. Furthermore, these tumors may have an associated cystic component and peripherally located calcification.[5] On the other hand, thymic carcinomas are aggressive tumors which occur in the age group of 50–70 years and are characterized by imaging findings of anterior mediastinal mass with areas of necrosis, hemorrhage, calcification with locoregional (pleural or pericardial dissemination), and distal spread.[6] The mediastinal mass described was devoid of any cystic or calcified component (usually seen in thymomas), nor there were any radiological features typically described in thymic carcinomas. Considering this clinical picture, both these etiologies though possible, would be less common in the present case.

Retrosternal extension of thyroid

This disease also should be considered in the differential diagnosis of anterior mediastinal mass. However, these lesions usually show contiguity with the thyroid, which was absent in the present case. Furthermore, these lesions are known to frequently present with breathlessness, dysphonia, difficulty in swallowing, or a SVC obstruction, which were absent in the present case.[7] These masses usually have well-defined borders and are associated with punctate calcification.[8] Due to the absence of these features, the possibility of this etiology is less.

Fibrosing mediastinitis

This is a rare disease which is characterized by dense fibrous tissue proliferation in the mediastinum either as a localized form or as a diffuse infiltration. It can either be a response to various infective (histoplasmosis, tuberculosis, and aspergillosis) or noninfective (IgG4 related) causes or may be idiopathic.[9] The disease can affect any age group with equal predilection for both genders. However, in the case of IgG4-related fibrosing mediastinitis associated with an elevated IgG4 level in the blood and tissue, the median age of affected patients reported is 56 years with a distinct male preponderance. Furthermore, the most common radiological pattern of involvement in this disease is periaortic and paravertebral fibrosis.[10] Clinically, most patients are symptomatic, and the symptoms depend on the mediastinal structure involved. Constitutional symptoms such as fever and weight loss are infrequent. Radiologically, either a focal mass (most common) with calcification commonly in the right paratracheal and subcarinal location or a diffuse pattern which is seen infiltrating multiple mediastinal compartments is seen. Usually, such a diffuse pattern is devoid of calcification and is seen in conjunction with other fibrosing diseases such as retroperitoneal fibrosis. Considering these features, this entity seems to be a possible cause in our patients as well.[11]

Infectious causes of mediastinal mass

Tuberculosis is one of the important conditions which can present with a mediastinal lymph nodal mass.[12] The presence of constitutional symptoms of fever also makes this a likely cause in the present case. Other than tuberculosis, fungal infections such as histoplasmosis, cryptococcosis, or aspergillosis may rarely present with a mediastinal mass.[13]

Granulomatous diseases

Diseases such as sarcoidosis are well-known causes of mediastinal lymph node enlargement. However, in sarcoidosis, the nodes are homogeneous, well defined without any invasion of adjacent structures. The pattern of mediastinal involvement in our patient was not consistent with the above distribution; moreover, the encasement of the azygos vein and SVC by the mass makes sarcoidosis an unlikely cause in the present case.[14]

  Diagnosis Top

Histopathological examination of the bronchoalveolar lavage (BAL) fluid and endobronchial biopsy specimens (Hematoxylin and Eosin stain) showed numerous extracellular organisms having a thick mucoid capsule, giving the appearance of a clear halo around a round nucleus [Figure 4]a and [Figure 4]b.
Figure 4: Histopathological examination of the bronchoalveolar lavage fluid and endobronchial biopsy specimens showed numerous extracellular organisms having a thick mucoid capsule, giving the appearance of a clear halo around a round nucleus (a and b). Gomori methenamine silver and periodic acid-Schiff were done to highlight the cryptococcal organisms. The mucoid capsule stained bright pink with periodic acid-Schiff stain (c and d)

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Special stains, namely Gomori Methanamine Silver (GMS) and periodic acid-Schiff (PAS) were done to highlight the cryptococcal organisms [Figure 4]c. The mucoid capsule stained bright pink with PAS stain [Figure 4]d.

India ink preparation was done on the bronchoalveolar lavage and showed the characteristic negative staining pattern. The particles of ink do not enter the capsule that surround the spherical yeast cell and hence result in a zone of clearance around the cells.

  Discussion Top

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with acquired immunodeficiency syndrome and solid-organ transplant recipients, particularly renal transplant recipients.[15],[16],[17] It is also reported that, approximately in one-third of cryptococcosis, there were no readily identifiable immune defects.[18],[19] The CNS and the lung are the two organs that comprise the main sites of Cryptococcus infection. However, skin, soft tissue, joint, bone, kidney, muscle, liver, kidney, and other organs may also be infected by this fungus. Among non-human immunodeficiency virus (HIV) patients, pulmonary cryptococcosis is the most common non-CNS location.

Pulmonary cryptococcosis is commonly seen in immunocompromised patients, and it has become an emerging disease in immunocompetent patients.[20],[21] A study from Uganda reported that 11% of hospitalized patients with HIV infection had pulmonary cryptococcosis as a secondary infection.[22] Recent research from Thailand noted that 13% of HIV patients with pneumonia had cryptococcal antigen present in their serum, although a third of this population did not have cryptococcal meningitis or a history of it.[23] Most likely, the respiratory infections in these patients were cryptococcal. A retrospective review from China revealed that 60% of pulmonary cryptococcosis cases were diagnosed in immunocompetent non-HIV patients.[24] Pulmonary cryptococcosis may also disseminate and lead to fatal complications.[25],[26],[27] A previous study reported that 67% of pulmonary cryptococcosis in immunocompetent patients disseminated into the CNS causing cryptococcal meningitis.[25] Patients with pulmonary cryptococcosis concomitantly with cryptococcal meningitis showed inadequate treatment response and poor clinical outcomes compare to cryptococcal meningitis alone.[28] The spectrum of fungal diseases seen in critically ill patients and immunocompetent patients is broadening, and the role of pulmonary cryptococcosis may be increasingly important.[29],[30]

Pulmonary cryptococcosis usually presents with nonspecific symptoms such as cough, dyspnea, chest pain, and fever both in adults and children. However, it may be totally asymptomatic or may present with respiratory failure. The nonspecific symptoms of this disease are likely to cause delays in diagnosis and proper treatment resulting in further dissemination of Cryptococcus infection. Physical examination may reveal reduced breath sounds, crackles, and/or dullness to percussion indicated pleural effusion. Cryptococcus infection leads to differing clinical manifestations in immunocompromised and immunocompetent people. Approximately half of the immunocompetent patients with pulmonary cryptococcosis are asymptomatic; the infection is incidentally detected during a routine CXR or follow-up of other diseases. In contrast, it is very rare that immunocompromised patients experience asymptomatic pulmonary cryptococcosis, apart from the rare asymptomatic solitary pulmonary nodules in HIV patients. Acute respiratory failure was the presentation in 33% of pulmonary cryptococcosis cases reported without HIV, most of whom had a solid organ transplant as their underlying condition. In all probability, many other factors affect the clinical appearance of pulmonary cryptococcosis such as geography, virulence of different Cryptococcus strains, and possibly immunogenetic variations among patients.

The methods used to confirm the infection are culture, direct microscopic, histopathology, serology, and molecular detection. Identifying a positive culture of Cryptococcus from BAL or pleural fluid, together with appropriate clinical symptoms and/or radiology findings are the key diagnostic approaches. These findings may be discovered in parallel with or without positive antigen tests or direct microscopy from serum and BAL or pleural fluid. Antigen tests from serum or blood or culture are rarely positive unless there is disseminated cryptococcal infection. The use of lysis centrifugation of the buffy coat from blood may increase detection. Diagnosis is based on isolation of Cryptococcus from, or detection of cryptococcal antigen in, a pulmonary specimen.

  Cryptococcal Antigen Lateral Flow Assay Top

Cryptococcal antigen was detected from respiratory samples by Dynamiker Cryptococcal antigen lateral flow assay. This rapid immunochromatographic test detects capsular polysaccharide antigen of Cryptococcus species complex (C. neoformans and C. gatti). Pulmonary Cryptococcus was confirmed by radiological, histopathological, and serological tests.

  Fiberoptic Bronchoscopy Top

Fiberoptic bronchoscopy may reveal intraluminal nodules or masses from which biopsy can be taken. Bronchial lavage fluid is retrieved during this procedure which can be subjected to microbiology and molecular testing.

  Histopathology Top

A lung biopsy is the best diagnostic option when sputum or bronchoscopy specimens are unavailable or negative. There are several methods of lung biopsy including percutaneous lung biopsy, transbronchial lung biopsy, video-assisted thoracoscopic biopsy, and open lung biopsy. The most appropriate method to use for the biopsy depends on the skills available and the location of the lung lesion.

Histological staining with hematoxylin and eosin (H and E), Grocott or Gomori methenamine silver (GMS), and PAS are used to detect Cryptococcus that appears as narrow-based budding yeast (4–10 μm), usually surrounded by thick capsules in the lung tissue. Tissue sections can be processed with alcian blue or mucicarmine to display the capsule. Mucicarmine can differentiate Cryptococcus from other yeast-like structures such as those of coccidioides, histoplasma, or candida.

  Radiology Top

Chest radiograph

CXR may be normal or presents with nodules, mass, or consolidation. Other presentations include diffuse bronchopneumonic shadows, pleural effusion, or mediastinal mass.

  Computed Tomography Thorax Top

In general, there are several CT patterns that can be seen in cryptococcosis. They include:

  1. Clustered nodular pattern: most prevalent
  2. Solitary pulmonary nodule or mass with or without cavitation
  3. Scattered nodules
  4. Peribronchovascular consolidation.

The most common CT findings in immunocompetent patients with pulmonary cryptococcosis are pulmonary nodules. The nodules are most often multiple, smaller than 10 mm in diameter, and well-defined with smooth margins. The nodules usually involve <10% of the parenchyma and tend to be distributed peripherally (up to 65%) in the middle and upper zones. Where there are multiple nodules, they are usually bilateral. Associated cavitation may be seen in up to 40% of cases. Occasionally, unusual presentations such as large cavities may be seen. Cavitations within nodules/masses tend to be more frequently present in immunocompromised patients than in immunocompetent patients.

  Treatment Top

Antifungal treatment with amphotericin B and/or flucytosine is recommended for severe disease, whereas fluconazole is the treatment of choice for mild and localized infections. The optimal duration of therapy is not known. This patient was treated with itraconazole 200 mg twice daily for 2 months, by which the patient had good clinical improvement and partial radiological resolution [Figure 1]b. Itraconazole was continued at 200 mg once daily for 10 more months and X-ray taken at that time showed good resolution [Figure 1]c.

  Summary Top

The above case highlights the importance of keeping cryptococcosis as a differential diagnosis of mediastinal mass in an immunocompetent person. Timely diagnosis can help in reducing hematogenous dissemination and resultant mortality. This infection responds to common antifungal drugs but requires prolonged treatment to prevent relapse.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form 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 patients 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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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