Rapidly progressive pneumonia caused by Cryptococcus neoformans in the patient of granulomatosis with polyangiitis.

A 57-year-old male who had been treated for granulomatosis with polyangiitis (GPA) presented with cough and back pain that had persisted for three days. Mild infiltration shadows and nodules were found on computed tomography images at that time. Increase of GPA lesions and/or bacterial pneumonia was initially suspected. However, serum Cryptococcus neoformans antigen was positive and the chest X-ray findings had worsened by the following day despite of appropriate antibiotic treatment. Thus, pneumonia due to C. neoformans was diagnosed because C. neoformans was also isolated blood and lung tissues, and he was treated with antifungal agents: L-AMB and 5-FC, and followed up by chest radiography on a daily basis.

Introduction

Cryptococcus neoformans (C. neoformans) is an encapsulated fungus found in soil that is associated with bird droppings, especially pigeons [1-3].

Cell-mediated immunity is essential in controlling cryptococcal infections, and it is considered an opportunistic pathogen because infections occur primarily in patients with profoundly impaired cell-mediated immunity although C. neoformans sometimes infects immunocompetent hosts [2].

Here, we describe rapidly progressive and lobar pneumonia caused by C. neoformans that could be followed up as changes in chest X-ray findings.

Case report

A 57-year-old man who was administered with oral methyl prednisolone 20 mg/day and methotrexate to treat granulomatosis with polyangiitis (GPA) visited at our emergency department on December 2013 with acute back pain around the left shoulder and mild fever accompanied by fatigue that had persisted for three days. The GPA seemed to be controlled because the level of PR3-ANCA, a common biomarker of GPA, was increased to 6.3 IU/mL (<3.5 IU/mL) for a few months, but not significantly increased at that time.

A physical examination indicated the following: temperature, 37.9 °C; blood pressure, 132/82 mmHg; respiratory rate, 24 breaths/min (O2 2 L), but it did not reveal crackles and opacity was not found on chest radiographs on Day 1 (Fig. 1A). However, chest computed tomography (CT) indicated a mild infiltration shadow in the left dorsal lobe (Fig. 2). His initial WBC count was 11,550/μL and the C-reactive protein (CRP) level was 5.67 mg/dL. Bacterial pneumonia was initially suspected, and then sputum, urine and blood samples were collected to detect the pathogens, and tosufloxacin 450 mg/day was administered and he went back.

Fig. 1

Chest radiography images of 57-year-old patient admitted with C. neoformans pneumonia in December 2013. Image on Day 1 shows no specific shadows (A), but infiltration shadows (arrows) on left middle field and dullness of left costophrenic angle appeared on Day 2 (B), and remained rapidly progressive on Day 4 (C). These findings gradually improved on Days 8 (D), 15 (E) and 20 (F).

Fig. 2

Chest computed tomography images at Day 1. Infiltration shadow and nodules are evident (arrows).

However, he presented again on the following day (Day 2) with increased back pain. Chest radiography at this time revealed significant lobar shadows (Fig. 1B). We initially suspected bacterial pneumonia and started antibiotic therapy: meropenem 1 g × 3 times/day on admission. But serum that had been collected on the previous day was positive for Cryptococcus antigen (×512). Binax Now rapid antigen tests for influenza A and B virus, Streptococcus pneumoniae and Legionella species (Binax, Portland, OR, USA) were negative. The QuantiFERON-TB Gold test (Quest Diagnostics, Madison, CT, USA) for tuberculosis was negative. In addition, we could not found any pathogenic bacteria on both gram staining and culture of his sputum. Therefore, we suspected rapidly progressive Cryptococcus pneumonia and administered fos-fluconazole (fos-FLCZ) 400 mg/day. Two days later, C. neoformans was cultured from both sputum and blood samples (Fig. 3A).

Fig. 3

Cryptococcus detected in blood and lung tissues. Unstained yeasts are surrounded by empty space (arrows in blood stained with India ink preparation; magnification ×1000 (A). Yeasts are visualized with Grocott stain in lung tissue samples collected by bronchoscopy; magnification ×400 (B).

Although increase of GPA lesions, which make similar granuloma with Cryptococcus infection, was also suspected, we detected significant numbers of C. neoformans by transbronchial biopsy (TBB) of the left lower lobe by bronchoscopy examination (Fig. 3B), and finally diagnosed his main pathogenicity as acute lobar pneumonia by C. neoformans.

We did not detect C. neoformans in cerebrospinal fluid (CSF), which appeared essentially normal (pressure, 140 mm H2O; cells, 2/μL; protein, 19 mg/dL; glucose, 70 mg/dL) and negative for Cryptococcus antigen, but we changed fos-FLCZ to liposomal-amphotericin B (5 mg/kg/day) plus 5-FC (4 × 25 mg/kg/day) at Day 2, and continued for two weeks followed by fluconazole (200 mg/day) according to severe cryptococcal infection cases. The susceptibility of the isolated C. neoformans to antifungal drugs (minimum inhibitory concentration; MIC) was as follows: AMPH-B (0.5 μg/mL), 5-FC (8 μg/mL), FLCZ (2 μg/mL), VRCZ (0.03 μg/mL), and MCFG (>16 μg/mL), respectively, and blood cultures became negative on Day 11.

Signs on chest radiograms worsened until Day 4 (Fig. 1C), but improved daily until day 20 (Fig. 1E and F).

Discussion

Disease related to C. neoformans or Cryptococcus gattii has become increasingly prevalent in immunocompromised patients, including those with AIDS, although pulmonary cryptococcosis has been isolated sometimes from apparently immunocompetent patients. Infection with C. neoformans first occurs after inhaling fungal basidiospores. A small focal pneumonitis then develops that may or may not be symptomatic [2,4]. The clinical manifestations of pulmonary cryptococcosis include localized nodular lesions with or without cavitations, segmental pneumonic infiltrates, patchy interstitial or alveolar infiltrates, pleural effusions, hilar masses and thoracic lymphadenopathy [1,4].

Our patient had progressive, localized disease with a mild to moderate systemic inflammatory response and an initial indolent presentation. Chest radiography showed mild nodules and infiltrate on Day 1 that rapidly worsened on Days 2 and 4. These findings suggested acute or its on chronic C. neoformans infection in this patient. He was HIV-negative, but was under corticosteroid therapy for GPA, which is pathologically similar to granulomata and appears as radiographic nodules. His CD4 cell counts decreased to 116/uL because methotrexate had been administered to treat worsening GPA. Thus, he might have been immunocompromised, and susceptible to progressive lobar types of pneumonia. Macrophages and lymphocytes might be inactivated, and levels of immunoglobulin G (IgG), IgA, and IgM in the blood have been decreased [5]. Our patient had low IgG levels (585 mg/dL) which required occasional supplementation, and this factor also might accelerate the progress of C. neoformans pneumonia in this patient. In addition, corticosteroid had increased the level of HbA1c, an indicator of diabetes mellitus, to 8.0% (NGSP), which supported the notion that he was in fact immunocompromised. Symptoms and radiographic signs also worsened in our patient within a few days. Such changes might be the most rapid among all reports of C. neoformans pneumonia [3,4,6,7] although it can progress over days instead of weeks in hosts with extreme immunosuppression such as those with AIDS or under medication with high-dose corticosteroid and/or cyclophosphamide [2].

In this case, we detected C. neoformans in sputum, blood and in TBB specimens of infiltrated lesions. These findings together with laboratory data support the notion that the pathogenicity and radiographic changes were mainly due to C. neoformans infection rather than GPA exacerbation. In addition, PR3-ANCA did not change, but levels of cryptococcal antigen, which has >90% sensitivity and specificity, was increased [2]. The presence of C. neoformans antigen should be always assessed when patients present with the immunocompromised conditions, although worsening GPA and related pulmonary lesions might be suspected.

Patients with symptomatic cryptococcal pneumonia can present with cough, chest pain, increased sputum production, fever, weight loss and hemoptysis. In contrast, the ratio of patients with asymptomatic pulmonary cryptococcosis is about 30% and infection is incidentally discovered in such patients [2,4]. Biopsy specimens from symptomatic patients with chest radiographic findings indicating malignancy occasionally reveal cryptococcosis. Global ecological studies have found C. neoformans in soil samples from around the world in areas frequented by birds, especially pigeons and chickens. Our patient lived close to a park that was populated by flocks of pigeons.

Fluconazole is active against C. neoformans, easily administered, and has safe profiles. Candidates for treatment are those with persistent and/or disabling symptoms, multiple nodules or extensive infiltrates on chest X-rays, and/or positive serum cryptococcal antigen findings. However, we administered liposomal AMPH-B and 5-FC according to the severe cryptococcal condition cases. Additional studies are needed to more precisely determine the role of AMPH-B and 5-FC followed by fluconazole in treating severe or rapidly progressive pulmonary cryptococcosis in immunocompromised patients as well as the optimal dosage and duration of therapy. The optimal fluconazole dosage has not been defined. A daily dose of 200–400 mg, and induction with 600 mg for four weeks, followed by 200 mg for 10–12 weeks have been administered [8]. Our patient was treated with oral fluconazole 200 mg/day after two weeks AMPH-B and 5-FC. At the four-month follow up, the general condition of our patient was obviously improved and chest X-rays have repeatedly shown that the mass in the lower lobe lung continues to decrease.

In conclusion, we described rapidly progressive cryptococcal pneumonia that was clinically and radiologically improved by treatment with liposomal L-AMPB and 5-FC. The time course was followed up by chest X-rays to detect radiographic changes. Symptoms appeared only three days before admission and chest X-ray findings became abnormal within a few days thereafter. We detected C. neoformans from blood and lung samples, which finally distinguished the infection from GPA exacerbation. However, further studies, including accurate diagnosis of C. neoformans and the mechanism of rapid progression under various immunological and microbiological backgrounds are required.