Pulmonary cryptococcosis in childhood systemic lupus erythematosus and Sjögren syndrome overlap: a rare opportunistic infection

Introduction

Infections are one of the main causes of morbidity and mortality in childhood-systemic lupus erythematosus (C-SLE) patients. The majority of infections are caused by viruses and bacteria, and occasionally by opportunistic agents, such as fungi.^1–5 Of note, Cryptococcus sp. infection is usually insidious, is hard to diagnose in immunosuppressed patients, particularly in the C-SLE population, ⁴ and has been rarely reported in adult SLE.^6–8 Importantly, isolated meningitis or disseminated infections are the main manifestations of cryptococcosis in adult SLE, and other organs and systems, such as the lung, are rarely affected in this fungal infection.^6–8 However, to our knowledge, no case of isolated pulmonary cryptococcosis has been described in the pediatric lupus population. Therefore, we report one case of overlap of C-SLE and Sjögren’s syndrome that presented pulmonary cryptococcosis.

Case report

A 14-year-old girl was diagnosed with C-SLE according to the American College of Rheumatology (ACR) classification criteria, ⁹ based on hematological disorder (leukopenia, lymphopenia and thrombocytopenia), cellular casts, antinuclear antibodies (ANA) 1/1280 (speckled pattern) and presence of anti-Sm antibodies. She also presented alopecia, leukocyturia and hematuria. At that time, the SLE Disease Activity Index 2000 (SLEDAI-2K) ¹⁰ was 16 and she was treated with prednisone (0.5 mg/kg/day) and chloroquine.

At the age of 14 years and 7 months, she presented with xerostomia, xerophthalmia, parotid gland involvement in salivary gland scintigraphy, with abnormal Schirmer’s test and Rose Bengal score, and presence of anti-SS-A and anti-SS-B autoantibodies. Therefore, the diagnosis of juvenile Sjögren’s syndrome was established according to the American-European Consensus Group¹¹ and she was treated with topical ocular methylcellulose and artificial saliva.

At 14 years and 11 months, she presented with arthritis in elbows and knees, platelets 80,000/mm³ and elevations of muscle enzymes [creatine kinase (CK) 2142 U/l (normal range 24–204) and aldolase 30.6 U/l (normal range 1–7.5)]. Muscle biopsy of brachial biceps was performed and revealed marked variation in the muscle fiber size with inflammatory infiltration in the region surrounding the normal and degenerated fibers, compatible with inflammatory myopathy and requiring azathioprine (2.0 mg/kg/day).

At 15 years and 2 months, her white blood cell count (WBC) was 3600/mm³ (56% neutrophils, 38% lymphocytes, 1% eosinophils and 5% monocytes), platelets 87,000/mm³, and azathioprine was replaced by mycophenolate mofetil (2.0 g/day), with maintenance of chloroquine and prednisone 10 mg/day.

At 16 years and 5 months, she presented with fever, cough and dyspnea, without headache, vomiting, signs of meningeal irritation and other clinical manifestations. No contact with bird droppings was reported. She was being treated with mycophenolate mofetil (2.0 g/day), hydroxychloroquine and prednisone 10 mg/day. WBC was 3700/mm ³ (69% neutrophils, 25% lymphocytes and 6% monocytes), platelets 61,000/mm³, erythrocyte sedimentation rate was 55 mm/1st hour and C-reactive protein was 22.8 mg/dl. Chest radiography and chest computer tomography showed a single nodule in the left posterior apex without air-fluid levels and three nodular lesions in the left hemithorax respectively. At that time, the SLEDAI-2K was 5, based on platelets 61,000/mm³, presence of anti-DNAds antibodies and C4 14 mg/dl (normal 16–38 mg/dl) and she was treated with ceftriaxone for 14 days without clinical improvement. The tuberculin skin test was 0 mm. Bronchoalveolar lavage and transbronchial biopsy were normal and without isolation of bacteria or fungi. Then, voriconazole (6.0 mg/kg/day) was empirically introduced for 21 days, as our first clinical and radiological diagnosis was invasive aspergillosis.

Fifteen days after the first biopsy, her clinical condition worsened and she underwent open thoracotomy with surgical left lung biopsy and encapsulated Cryptococcus yeast cells were isolated in lung tissue section by Gomori-Grocott and Mayer’s mucicarmine stains. At the time, she was being treated with mycophenolate mofetil (2.0 g/day), hydroxychloroquine and prednisone 10 mg/day. Voriconazole was replaced with oral fluconazole (6.0 mg/kg/day) and this antifungal therapy has been maintained with improvement of clinical manifestations and radiological findings. Currently, she is followed-up in our service and she is asymptomatic, but still under fluconazole.

Discussion

A computer-assisted (Medline, National Library of Medicine) search of the English literature was performed using the following terms: cryptococcosis, pulmonary, lupus and Sjögren’s syndrome, but no results were found. Therefore, to our knowledge, we describe here the first case of overlap of C-SLE and Sjögren’s syndrome associated with non-fatal isolated pulmonary cryptococcal infection.

Cryptococcosis is an opportunistic fungal infection, caused by Cryptococcus sp. acquired from the inhalation of aerosolized particles especially in patients exposed to bird droppings.^4,8,12 It affects mainly immunocompromised hosts, such as patients with diabetes, acquired immunodeficiency syndrome and lupus.^7,13 The infection may be localized or generalized and it is frequently insidious and may affect several organs and tissues, such as central nervous system, liver, skin and lungs. ⁸ Meningoencephalitis is the most common and severe manifestation,^4,12 contrasting with our case who presented only pulmonary involvement.

Of note, the clinical presentation of pulmonary cryptococcosis ranges from asymptomatic infection to severe pneumonia with respiratory failure.^12,13 Fever and cough associated with radiological findings contribute to an earlier diagnosis, ¹³ as evidenced in our case. In addition, better evaluation of pulmonary parenchyma can be obtained by using chest computer tomography instead of chest X-ray in patients with cryptococcosis. ⁶ The thoracic computer tomography may reveal pulmonary masses, consolidations, ground-glass opacity, perihilar lymphadenopathy, pleural effusion, cavitations and nodules. ¹² The presence of pulmonary nodules gave rise to various different diagnoses in our patient, such as malignant tumor, tuberculosis ¹⁴ and aspergillosis.^3,14 Video-assisted thoracoscopic surgery (VATS) is a preferable method to lung nodule biopsy with low morbidity compared with open thoracotomy. However, open thoracotomy has been indicated in patients with small and deeper nodules, as observed herein. ¹⁵

Remarkably, the diagnosis of pulmonary cryptococcosis is usually performed by isolating the agent in pulmonary sputum, bronchoalveolar lavage or pleural effusion.^6,12 Additionally, the identification of serum cryptococcal antigen, as cryptococcal antigen latex agglutination test, may help cryptococcosis diagnosis with sensitivity and specificity of 100%, ¹⁶ especially in localized forms such as pneumonia. ¹⁷ The gold standard for fungal infectious disease diagnosis is direct identification of the microorganism through culture. ³ However, our patient had negative culture and the definitive diagnosis of pulmonary cryptococcosis was established by histopathological identification of fungi in lung biopsy specimens.

This localized or disseminated fungal infection has been rarely reported in lupus,^4,8 especially in the adult population, ¹⁸ and was not described in C-SLE associated with this sicca syndrome. The most important risk factors associated with invasive fungal disease in lupus population are associated with the disease (activity, lymphopenia, leukopenia and neutropenia) and the treatment.^1–3 Importantly, corticosteroids, immunosuppressive drugs and disease activity were most frequently observed in C-SLE compared with adult SLE. ¹⁹ These factors may contribute to opportunist infection in pediatric versus adult lupus population. In addition, severe lymphopenia was reported in Sjögren’s syndrome and cryptococcal infection, ²⁰ as also observed in our case. Further comparative and multicenter study will be required in pediatric and adult populations with SLE and Sjögren’s syndrome.

The first choice therapy for pulmonary cryptococcosis is fluconazole or amphotericin B with or without flucytosine. ²¹ Our patient received empirically voriconazole as our first clinical and radiological diagnosis was invasive aspergillosis. This is the first choice treatment for this severe infection, as described in our lupus patients. ³ Oral fluconazole is suggested as a maintenance therapy and it was started in our patient after improvement with voriconazole. ²¹ Prophylactic therapy with fluconazole should also be recommended after 6–12 months of treatment, ¹⁸ according to the Guidelines for Management of Cryptococcal Disease by the Infectious Disease Society of America. Death from cryptococcosis is generally associated with meningitis and septic shock, as previously evidenced in one of our C-SLE patients. ⁴

In conclusion, we report the first case of pulmonary cryptococcosis in a Sjögren and C-SLE patient with adequate clinical response to antifungal therapy. Fungal infections should be excluded in the presence of lung nodules and etiological identification is required for proper treatment.