Pulmonary cryptococcosis with cryptococcal meningitis in an immunocompetent host.

Cryptococcosis is a systemic fungal infection associated with significant morbidity and mortality. It predominantly affects people with immunosuppresion and human immunodeficiency virus infection. Extrapulmonary dissemination is rare in immunocompetent hosts. We present here a case of disseminated cryptococcosis in an immunocompetent patient who presented with an unusually large pulmonary mass and meningitis and successfully managed with medical therapy.

INTRODUCTION

Cryptococcosis is an invasive systemic mycosis increasingly being recognized world-wide. Although the infection is acquired through inhalation of airborne propagules, most pulmonary infections are clinically silent and the disease usually manifests when it disseminate to extrapulmonary sites, most notably to central nervous system (CNS). Meningoencephalitis remains the most commonly diagnosed form of cryptococcal infection. Extrapulmonary dissemination is uncommon in the immunocompetent host.[12] We report here a case of disseminated cryptococcosis presenting as lung mass in an immunocompetent man that resolved completely with fungicidal therapy and discuss the management issues relating to similar published literatures.

CASE REPORT

In September, 2010, a 36-year-old man was referred to our service for evaluation of a suspected lung cancer. He complained of dull aching pain on left anterior chest, cough with scanty sputum, loss of appetite and weight for 6 weeks. He had no fever, hemoptysis, abdominal, or neurological symptoms at presentation. He denied any preexisting lung disease, diabetes, illicit drug abuse or intake of immunosuppressive agents. He was a mason by profession and had smoked for 10 pack-years. He lives in a village in Tamil Nadu, India and had never traveled away from his native state. General physical examination was unremarkable. Chest examination revealed a dull percussion note with diminished breath sound on left hemithorax. Chest radiograph showed a large mass in the left lung [Figure 1]. He was hospitalized for workup of a possible lung cancer. Leukocyte count was 22,500/mm3 with a predominance of neutrophils. Serum electrolytes, liver and renal functions were normal. Serology for human immunodeficiency virus (HIV) was negative. Serum immunoglobulin levels and CD4 count (618 cells/μL) were normal. Chest computed tomography (CT) scan confirmed a large mass (11.9 cm × 8.2 cm) in left upper lobe (LUL) with central hypoattenuation [Figure 2]. On 3rd day of hospitalization, patient developed mild headache and nausea. He was awake-alert and had no neck rigidity or focal neurological deficit. Considering the possibility of meningitis or cerebral metastasis, immediate contrast enhanced CT brain was performed that showed mild meningeal enhancement with normal ventricles and brain parenchyma. CT guided fine needle aspiration cytology (FNAC) of the lung mass showed numerous budding yeasts resembling Cryptococcus and no evidence of malignancy. Lumbar puncture following neurologist opinion revealed clear cerebrospinal fluid (CSF) under normal pressure with pleocytosis (leukocytes 16 cells/μL, 100% lymphocytes) and stained positive for India ink preparation. Serum and CSF were positive for cryptococcal antigen by latex agglutination test. However, culture for the fungus was negative in CSF and blood. Staining for acid fast bacilli was negative in sputum, CSF and bronchial wash. Flexible bronchoscopy showed a whitish-yellow mass in LUL bronchus. Bronchial washings and endobronchial biopsy were consistent with cryptococcal infection [Figure 3]. He was treated with Inj. amphotericin B 50 mg/day (1 mg/kg/day) and flucytosine 4 g/day orally (in four divided doses) for initial 4 weeks. He had remarkable clinical and radiological improvement after completion of induction therapy. His renal function and leukocyte count remained normal throughout the course of therapy. Therapy was switched to oral fluconazole 400 mg/day for 8 weeks followed by 200 mg/day continued until November 2011. Complete resolution of the mass was ensured in follow-up imaging [Figure 4] and he was well until last contact in March 2012.

Figure 1

Chest radiograph showing a large homogenous opacity in left hemithorax silhouetting the cardiac boarder and sparing the apex and costophrenic angle

Figure 2

Computed tomography chest showing left upper lobe mass with central hypoattenuation

Figure 3

Endobronchial biopsy showing cryptococci with thick capsules (H and E, original ×400)

Figure 4

Computed tomography chest after 4 months of fungicidal therapy showing complete melting of the mass

DISCUSSION

Cryptococcosis is a reemerging global mycosis affecting both immunocompetent and immunocompromised host. Recently, the fungus has been separated into two different species namely Cryptococcus neoformans and Cryptococcus gattii. C. neoformans has worldwide distribution being found in pigeon droppings whereas C. gattii is mostly found in tropical and subtropical climate associated with eucalyptus tree. C. gattii is more neurotropic and affects mostly immunocompetent hosts while C. neformans is a common pathogen in immunosuppressed including those with HIV infection.[12] Meningitis in the immunocompetent patient is indolent in nature, meningeal inflammation is intense, but has a better prognosis than immunocompromised host.[2]

The manifestation of pulmonary cryptococcosis varies from incidental detection in an immunocompetent patient to diffuse pulmonary infiltrates with fulminant respiratory failure in the immunocompromised host. The usual symptoms of pulmonary cryptococcosis, when present, are cough, dyspnea, hemoptysis and fever. Chest pain, as in our case, is uncommon as a presenting symptom. Unlike our patient, extrapulmonary dissemination is rare in immunocompetent hosts.[3] Radiologically, pulmonary cryptococcosis presents as nodules, masses or air space consolidation in the immunocompetent host while interstitial pattern, cavitation or lymphadenopathy are more common in immunosuppressed. Almost 50% of patients presenting with meningitis will have abnormal chest radiograph. Concomitant pulmonary mass and meningitis is more common with C. gattii infection.[4] The diagnosis is usually made by demonstration of the organisms in FNAC, bronchoalveolar lavage fluid and bronchoscopic or open lung biopsy specimens. Mere isolation of organisms in the sputum may not represent infection and can be seen in normal individuals. A positive serum cryptococcal antigen may be a marker for dissemination. High titers of cryptococcal antigen are suggestive of invasive disease in HIV patients, but such a correlation is not established in immunocompetent patients. However, decreasing titers of cryptococcal antigen in serum and CSF could be good surrogates for response to treatment. Most laboratories are not equipped to diagnose Cryptococcus to species level.[135] In our patient, the clinico-radiological presentation closely resembles that of C. gattii infection, however species could not be identified due to negative culture.

The differential diagnosis of concurrent pulmonary and neurological lesions usually include various infections including tuberculosis, malignancy with brain metastasis, neurosarcoidosis and langerhan's cell histiocytosis.[5] In India, tuberculosis takes precedence over other infections considering its high endemicity. Hence, a high index of clinical suspicion is necessary to diagnose cryptococcal meningitis in an immunocompetent host. Nevertheless, our patient presented with a lung mass, work-up for tuberculosis was negative and the initial FNAC came to our rescue in early diagnosis and appropriate treatment.

There is a lack of uniformity in the management of pulmonary cryptococcosis. The Infectious Disease Society of America recently published a guideline for the management of cryptococcosis.[6] The guideline recommends severe pulmonary disease or disseminated disease to be treated like CNS disease. The principles of management and drug regimens remain same for C. neoformans and C. gattii disease. The treatment is divided into induction, consolidation and maintenance phases. The preferred induction regimen for CNS infection in an immunocompetent host is intravenous amphotericin B plus oral flucytosine for 4 weeks followed by suppressive fluconazole therapy for 6-12 months. Our patient was treated with the same regimen as he developed CNS dissemination during the hospital stay.

In an earlier series by Zhu et al., three out of four patients required pulmonary resection either for diagnosis or ineffective regimen or inadequate duration of therapy. Only one patient who received an effective combination of amphotericin B, flucytosine and fluconazole had an uneventful recovery.[7] The efficacy of similar regimens was reiterated recently in two immunocompetent patients with C. gattii infection.[89] Recently, a case of disseminated cryptococcosis presenting as soft-tissue abscess in an immunocompetent man was successfully managed with amphotericin B and fluconazole therapy without any surgical debridement.[10] Naik-Mathuria et al. described a similar case who received fluconazole monotherapy despite having meningitis and required pulmonary resection for persistent cryptococcoma 7 months later. Here, treatment with a regimen effective for CNS disease might have resulted in early resolution of the pulmonary lesion thereby avoiding the surgery.[5] Despite having an unusually large lung mass and CNS dissemination, our patient showed excellent response to fungicidal agents and had no neuro-pulmonary sequel.

In summary, a high index of clinical suspicion is necessary to diagnose cryptococcal infection in immunocompetent patients. Physician need to be aware that all lung masses are not necessarily neoplasm and treatable infection like cryptococcosis should be considered as a possibility. Simple test like FNAC may suffice for its diagnosis and should be done promptly to avoid delay in diagnosis. Majority of cryptococcal infections can be managed medically provided appropriate antifungal regimen is initiated early and occasionally surgery may be required in non-responders. Awareness and adherence to the existing treatment guideline is of paramount importance in the successful management of such uncommon entity.