Bilateral pleural masses in an immunocompromised patient

Abstract

We present a case of persistent pleural masses with mediastinal adenopathy in an immunocompromised patient initially biopsied, diagnosed and treated for Pneumocystis jiroveci pneumonia, ultimately requiring surgical thoracoscopy to diagnose pulmonary histoplasmosis. We discuss the diagnostic approach for pleural masses in immunocompromised patients, the limitations of tissue sampling, interpretation and methodology, and pitfalls of testing in making a pathogen-specific diagnosis.

Background

Pulmonary histoplasmosis is one of the three major North American endemic fungal infections. Outbreaks have been discovered near the Ohio and Mississippi River valleys, South and Central America, and parts of Europe, Africa and Asia. Histoplasma capsulatum is found in soil as moulds with microconidia, and other potential exposure sources include chicken coops, prison grounds, bat caves and ship hatch covers. Infection occurs through exposure to a large fungal inoculum and in immunocompromised patients with T-cell abnormalities. Clinical classification of histoplasmosis includes acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis, progressive disseminated histoplasmosis, mediastinal lymphadenitis, fibrosing mediastinitis and broncholithiasis. Radiographic imaging results are variable.¹

Case presentation

A 71-year-old man with a history of chronic lymphocytic leukaemia (CLL) and membranoproliferative glomerulonephritis (MPGN), and on chronic steroids, was presented to our hospital with generalised fatigue, chronic cough, shortness of breath, fever, night sweats, muscle aches, weight loss and joint pain for 2 months. He denied symptoms of chest pain, hemoptysis, leg swelling, sore throat, rash or blurry vision. He also denied smoking, alcohol and illicit drug use, had no pets and made gunpowder for a construction company. He was not receiving Pneumocystis pneumonia prophylaxis. Vital signs showed the patient to be febrile, tachypneic, tachycardiac and hypoxic. The physical examination was significant for pallor, cachexia and diminished breath sounds bilaterally.

Investigations

Chest radiography showed a mass and a nodule in the right and left costophrenic angles, respectively. Chest CT (figure 1A, B) showed bilateral pleural masses with bilateral ground glass opacities and mediastinal adenopathy; all pleural masses were positron emission tomography (PET) avid. Complete blood count showed leucocytosis with left shift, anaemia and low immunoglobulin levels. Metabolic profile showed hyponatremia, lactic acidosis and elevated uric acid levels with normal electrolytes. The combination of serologies and cultures were negative for tuberculosis, histoplasmosis, coccidioidomycosis and bacterial pneumonia but positive for rhinovirus on PCR. He also had normal antinuclear antibody and rheumatoid factor levels. He underwent bronchoscopy with biopsies of nodules and endobronchial ultrasound-guided transbronchial needle aspiration of lymphadenopathy; these were non-diagnostic. Subsequently, he underwent CT-guided biopsy which showed organising pneumonia with findings of Pneumocystis jiroveci. He completed a 3 month course of trimethoprim–sulfamethoxazole without clinical or radiographic improvement. Surgical thoracoscopy (figure 1C) was performed with wedge resection and pleural biopsy. Pathology was initially misinterpreted as Pneumocystis infection on CT-guided biopsy, but it was later confirmed to be organising fibrinous pleuritis with caseating granuloma due to H. capsulatum on wedge resection (figure 1D).

Figure 1.

Chest CT, axial (A) and coronal views (B). Bilateral pleural masses located in right lower lobe lateral basal segment abutting the pleura, right lower lobe posterior basal segment and left lower lobe lateral basal segment with bilateral ground glass opacities. Microscopy: ×40 magnification, H&E staining (C). Normal lung architecture has been replaced by fibro-necrotic tissue with the formation of multiple caseating granulomata. There are lymphocyte and inflammatory cell infiltrates emphasising the host’s response. Microscopy: ×40 magnification, Grocott’s methenamine silver (GMS) staining (D). Centrally located fungal elements (black dots) are seen clustered within granulomata.

Differential diagnosis

A man in his 70s who is immunocompromised due to CLL and MPGN, and on chronic steroids, presented with flu-like illness with cough, shortness of breath, persistent fever, night sweats and malaise over months, and may have had active tuberculosis, another primary lung malignancy, bacterial or fungal infection or sarcoidosis. Certain details in presentation, radiographic imaging, diagnostic testing and tissue pathology can separate these diagnoses.

We ruled out active tuberculosis through bronchoalveolar lavage, transbronchial needle aspiration of lymphadenopathy and CT imaging, which were inconsistent with active or miliary tuberculosis. The possibility of a primary lung malignancy was entertained given the occupational history; however, pathology from lymph node sampling, CT-guided biopsy, wedge resection and pleural biopsy were all negative for malignancy. Other potential considerations were bacterial or atypical pneumonia given the immunocompromised status and clinical symptoms, but bronchoalveolar lavage sampling was negative in cultures and for atypical pathogens (specifically for Psittacosis, Nocardiosis and Actinomycosis). PCR results for rhinovirus were positive, but this did not explain his persistent fever for months and pleural masses on imaging. Finally, pleural masses are rarely associated with sarcoidosis making this diagnosis less favourable. Even though the tissue diagnosis noted granulomatous disease with a background of diffuse mononuclear cells, which is consistent with sarcoidosis, Grocott’s methenamine silver staining revealed fungal elements in tissue samples. This ruled out sarcoidosis, a diagnosis of exclusion; if our patient was initiated on empiric immunosuppressive agents, it would have been detrimental.

The challenge now was to identify the specific fungal organism, with Blastomycosis, Cryptococcus, Coccidioidomycosis, Pneumocystis or Histoplasma as potential pathogens. We ruled out Blastomyces dermatitidis after not finding broad-based budding but seeing small yeasts on microscopy, Cryptococcus with negative mucicarmine stain and Coccidioides species by not identifying remnants of or an intact spherule. Pneumocystis was excluded by not finding an intracystic body but finding budding on pathology, but pleural masses are not typical radiographic features of Pneumocystis infection anyway.^{2 3}

Treatment

Management requires classification of histoplasmosis, clinical assessment and identification of immunodeficiency. Treatment for mild disease is observation, while moderate and severe disease should be treated with itraconazole or amphotericin B.³

Outcome and follow-up

Our patient received itraconazole; 6 months later, he has made a remarkable recovery with radiographic resolution of the pleural masses.

Discussion

H. capsulatum var. capsulatum, an oval-shaped dimorphic fungus with narrow-based budding, is the most common cause of pulmonary histoplasmosis in the world. It is acquired through inhalation of microconidia into the lower airways with a large inoculum exposure and immunodeficiency. After inhalation, conidia are engulfed by alveolar macrophages where they survive for weeks to months multiplying in yeast form and travelling with macrophages to the reticuloendothelial system until dendritic cells kill the yeast and present the antigen to T-cells, preventing further spread of the pathogen and releasing a cytokine response. Immunodeficient patients are at highest risk for disseminated disease with multi-organ failure.²

From established clinical guidelines, it is known that cultures, serum/urine antigen tests and histopathology are positive in only 63%, 50% and 71.4% of immunocompromised patients, respectively.⁴ While complement fixation and immunodiffusion can establish a diagnosis, antibody production may not occur in immunodeficient patients. The infection can also mimic malignancy and, in the acutely ill, biopsy is warranted for histopathological sampling—as in our case. While bronchoscopy with transbronchial biopsies and bronchoalveolar lavage and CT guided biopsy are minimally invasive procedures, misinterpretation can occur due to the limited amount of tissue obtained during sampling, anatomic distortion and diagnostic errors by pathology. Yeasts in granulomas can make Pneumocystis difficult to differentiate from Histoplasma despite using staining to identify tissue host responses and fungal elements.^{2 5 6} We identified Histoplasma by seeing clusters of fungal elements in granuloma, budding and no intracystic focus on the larger samples from thoracoscopy.^{2 3}

A literature review noted multiple cases of pulmonary histoplasmosis diagnosed by clinical presentation, serology, urine testing and bronchoscopy. However, none of these cases reviewed the diagnostic approach of a misdiagnosis along with pitfalls in tissue sampling method and pathology. It is plausible that our immunocompromised patient had coinfection with Histoplasma andPneumocystis or that he was colonised with Pneumocystis. However, our patient had multiple assessments by a multidisciplinary team for persistent symptoms despite completing treatment for Pneumocystis with unresolved pleural masses, which was a diagnostic dilemma.

Learning points.

• Pulmonary histoplasmosis can present as persistent pleural masses in the immunocompromised.

• Histoplasma is differentiated from Pneumocystis pathologically by identifying clusters of fungal elements in granuloma without intracystic foci and seeing budding of yeasts.

• The yield of transbronchial and CT-guided biopsies in fungal identification is low.

• Clinicians need to be aware of the limitations of histopathological diagnosis and understand the various sampling methods and drawbacks of currently available testing to make pathogen-specific diagnoses.