Jose Orsini, MD1,  Jaswinderpal Sandhu, MD2,  Thomas Aldrich, MD2,  
1. Division of Critical Care Medicine
2. Division of Pulmonary Medicine
Albert Einstein College of Medicine and Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA

[emedpub – International Infectious Diseases :   Vol 1:6]                  [Date of Publication: 05.02.2011]
ISSN 2231-6019

April 30, 2011 at 2:23 PM


Invasive pulmonary fungal infections have become a major cause of morbidity and mortality among people with AIDS. Cryptococcus neoformans is an important cause of pulmonary fungal infection in these patients, representing the 4th most common opportunistic infection in patients with HIV/AIDS and one of the most common systemic mycosis among immunocompromised patients. Pulmonary cryptococcosis includes clinical entities ranging from asymptomatic pneumonia to severe acute respiratory distress syndrome (ARDS). While pulmonary cryptococcosis is not an uncommon infection, pleural involvement in the setting of cryptococcal disease has been infrequently reported. We describe a patient with pulmonary Cryptococcus neoformans infection involving the pleura, presenting with pulmonary cavitation and pleural effusion.

Case Report:

A 48-year-old African male was admitted to the hospital because of 2 months of fever, dry cough, and chest discomfort. He had night sweats and a 20-pounds weight loss over the last 6 months prior to admission. His past medical history was significant for pulmonary tuberculosis (TB) treated several years previously in Mauritania, Africa. He denied recreational drugs use or any recent travel.

Vital signs on admission were: blood pressure of 134/68 mmHg, heart rate of 104 beats/minute, respiratory rate of 20 breaths/minute, and temperature of 38.5ºC. Oxygen saturation by pulse oxymetry was 96% with the patient breathing room air. Physical examination demonstrated a cachectic man in mild distress due to the left-sided chest pain. There was no oral trush, clubbing, or adenopathies. Lung auscultation revealed decreased breath sounds and dullness to percussion on the left side of the chest.

The white blood cell count was 8,200/mm3, the hemoglobin level was 9.5 g/dL, and the platelet count was 451,000/mm3. Creatinine level was 0.9 mg/dl. Lactate dehydrogenase, cardiac enzymes, liver function, and coagulation studies were within normal limits. He tested positive for human immunodeficiency virus (HIV). The CD4+ T-cell count was 33/ μL.

Chest radiography showed left upper lobe cavity with pleural effusion. Computed tomography (CT) of the chest confirmed the cavity surrounded by micronodular opacities as well as pleural effusion and pleural thickening. (figure 1). Empiric intravenous antimicrobial therapy with ceftriaxone (Rocephin®, 1 g Q24h) and azithromycin (Zithromax®, 500 mg Q24h) was initiated. Trimethoprim-sulfamethozasole (Bactrim®) was started for prophylaxis against Pneumocystis jirovecii. After 48 hours of treatment, fever, chest pain, and cough persisted. A diagnostic thoracenthesis was performed and examination of the pleural fluid revealed an exudate. Blood, urine, and respiratory tract cultures as well as pleural fluid cultures did not show bacteria, fungi, parasites, Pneumocystis, or acid-fast bacilli. Urine Histoplasma and Legionella antigens were negative. Serum cryptococcal antigen was positive with a titer of 1:32.

On day 5 of admission, a pleural biopsy was performed showing fibrous tissue with acute and chronic inflammation, and a poorly formed granuloma. Gomori methenamine silver (GMS) and mucicarmine stains of the pleural tissue were positive for fungal organisms with morphology consistent with Cryptococcus neoformans. (figure 2). A lumbar puncture was performed and cerebrospinal fluid gram stain, cultures, and cryptococcal antigen were negative.

Figure 1: CT of the chest evidencing a left upper lobe cavity.

Figure 2: On the left, mucicarmine stain highlights the cell wall and the thick capsule of the fungal element. GMS stain, on the right, demonstrating the pleomorphic shape of the yeast cells, consistent with Cryptococcus neoformans.

Intravenous fluconazole (Diflucan®, 400 mg Q24h) was initiated. The patient improved clinically over the next few days with resolution of the initial symptoms. Highly active antiretroviral therapy (HAART) was initiated. His antiretroviral regimen consisted of lopinavir/ritonavir (Kaletra®) and zidovudine/lamivudine (Combivir®). Repeated chest CT after 4 months of therapy showed significant decreased in the size of the left upper lobe cavity with complete resolution of the pleural effusion. Follow up CD4+ T-cell count was 91/µL. Sequential serum cryptococcal antigen determinations were undetectable. Oral fluconazole (400 mg Q24h) was continued for a total of 12 months.


Cryptococcus neoformans is an encapsulated yeast that is found ubiquitously in soil, dust, and pigeon droppings. Despite the high prevalence of the organism in the environment human cryptococcal infection is rare, except in patients with disorders of cell-mediated immunity such as AIDS or lymphoreticular malignancies, or in patients with immunosupression after steroid therapy or organ transplantation. 1, 2 Cryptococcus neoformans enters the host primarily through the respiratory tract and establishes primary infection in the lungs. From the lungs, bloodstream dissemination may occur through which the central nervous system (CNS), the skin and soft-tissues, and the genito-urinary tract are established as the most common sites of disseminated infection. 3

The natural history of pulmonary cryptococcal infection can range from a localized and self-limiting disease, usually seen in immunocompetent individuals, to a progressive and disseminated illness that is most commonly observed among immune suppressed hosts. Depending on a patient’s immune status, fungal spores may remain dormant in the lung or may undergo hematogenous spread to any organ system. It is widely accepted that the acquisition of the infection occurs early in life and that the disease is mostly related to a reactivation from a pulmonary site in immunocompromised hosts. 4, 5 Common symptoms of cryptococcal infection affecting the respiratory tract are cough, fever, pleuritic pain, dyspnea, hemoptysis, and weight loss. Headache, when present, has been reported to be a prominent sign of CNS involvement. 6, 7, 8

Radiologic abnormalities among HIV/AIDS patients with pulmonary cryptococcosis includes solitary or multiple nodules with or without halo sign, masses, patchy airspace consolidation and infiltrates, areas of ground-glass opacity, mediastinal and/or hilar lymphadenopathy, cavitation, and pleural effusion. 7, 9, 10, 11, 12 Cavitations have been uncommonly described on the thoracic imaging of patients with cryptococcal infection. 13, 14 It is believed that cavitation indicates a long-term localized pulmonary abnormality, suggesting that patients with cavitary pulmonary lesions may experience a more severe cryptococcal infection. 12, 15 Pleural cryptococcosis is extremely rare and have only been reported in a few case series. 7, 10, 12 Although infrequent, the pleura may be the only localization of cryptococcal infection 16, 17 and, when found in HIV/AIDS patients, it is usually associated with underlying pulmonary parenchymal lesions. 18, 19

The diagnosis of cryptococcosis is based on positive serum cryptococcal  antigen detection along with the presence of encapsulated yeasts at direct histopathologic examination and/or isolation of Cryptococcus from any body site. Cryptococcal antigen detection and titration are useful to evaluate dissemination, severity of disease, and response to treatment. 7, 20 High titers of serum cryptococcal antigen may indicate more extensive extra-pulmonary involvement and a worse prognosis. 21 The presence of a positive serum cryptococcal antigen triggers further clinical and microbiologic investigations to rule out disseminated disease. Lumbar puncture, blood, and urine cultures are recommended. 22 In our case, the blood and urine cultures were negative and cerebrospinal fluid (CSF) analysis did not show evidence of CNS involvement.

There have been no prospective, randomized trials of the specific outcome of cryptococcal pneumonia treatment in HIV-infected patients, because all recent controlled trials include only HIV-infected patients with CNS infection and do not deal specifically with pneumonia. Therefore, the optimal therapy for patients with cryptococcal pneumonia has not been well elucidated. With rare exceptions, such as primary skin infection, nonmeningeal and nonpulmonary cryptococcosis represents the consequence of dissemination even if the clinical syndrome is confined to a single anatomical site. Treatment regimens are similar to those for disseminated or CNS disease, and drug selection and duration of therapy depend on severity of disease, response to therapy, and host immune status, because there are no substantial specific studies for individual body sites except for the lungs and CNS. The recommendations for nonmeningeal, nonpulmonary cryptococcosis are as follow: 1) For cryptococcemia or dissemination (involvement of at least 2 noncontiguous sites or evidence of high fungal burden based on cryptococcal antigen titer >1:152, treat as CNS disease, and 2) If CNS disease is ruled out, fungemia is not present, infection occurs at a single site, and there are no immunosuppressive risk factors, consider fluconazole (400 mg per day orally) for 6-12 months. 23 For patients with mild-to-moderate symptoms, such the patient presented in this report, fluconazole is recommended for 6-12 months. 23 Severe pneumonia cases with ARDS are treated like CNS disease with a combination of amphotericin B (Fungizone®) and flucytosine (Ancobon®) for 2 weeks, followed by fluconazole for a minimum of 8 weeks. Based on the above guidelines, the patient presented in this report had localized infection since CNS disease was ruled out, blood cultures were negative, and the infection involved 2 contiguous sites such as the lung and pleura. For these reasons, fluconazole was the preferred agent and it was continued for a total of 12 months given the excellent response to therapy. The desired outcome is resolution of symptoms and abolition or stabilization of the thoracic imaging abnormalities. Surgery should be considered for either diagnosis or persistent radiographic abnormalities and symptoms not responding to antifungal therapy. 23 Early initiation of antiretroviral therapy may improve outcomes. 24 These patients should be monitored with serial serum cryptococcal antigen after the initiation of antiretroviral treatment, because preexisting cryptococcal infection puts them at risk of immune reconstitution syndrome. 25

In conclusion, since cavitations and pleural effusions are uncommon in patients with cryptococcal infection, the diagnostic possibility of cryptococcosis should be consider in patients with HIV/AIDS presenting with these radiographic abnormalities. Our case illustrates the importance of having an index of suspicion and employing a tissue diagnosis in immunocompromised patients with these findings. Pleural biopsy is an effective and rapid diagnostic tool in determining the etiology of pleural effusion in patients with acquired immunodeficiency syndrome.


1) Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine (Baltimore) 1983;62:98-109

2)  White MH, Armstrong D. Cryptococcosis. Infect Dis Clin North Am 1994;8:383-398

3)  Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Cryptococcus neoformans in organ transplant recipients: Impact on calcineurin-inhibitor agents on mortality. J Infect Dis 2007;195:756-764

4)  Goldman DL, Khine H, Abadi J, Lindenberg DJ, Pirofski LA, Niang R, et al. Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 2001;107:e66

5)  Garcia-Hermoso D, Janbon G, Dromer F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J Clin Microbiol 1999;37:3204-3209

6)  Rozenbaum R, Goncalves AJ. Clinical epidemiological study of 171 cases of cryptococcosis. Clin Infect Dis 1994;18:369-380

7)  Chang WC, Tzao C, Hsu HH, Lee SC, Huang KL, Tung HJ,  et al. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest 2006;129:333-340

8)  Wasser L, Talavera W. Pulmonary cryptococcosis in AIDS. Chest 1987;92:692-695

9)  Zinck SE, Leung AN, Frost M. Pulmonary cryptococcosis: CT and pathologic findings. J Comput Assist Tomogr 2002;26:330-334

10) Sider L, Westcott MA. Pulmonary manifestations of cryptococcosis in patients with AIDS: CT features. J Thorac Imaging 1994;9:78-84

11)Miller WT Jr., Edelman JM, Miller WT. Cryptococcal pulmonary infections in patients with AIDS: radiographic appearance. Radiology 1990;175:725-728

12) Friedman EP, Miller RF, Severn A. Cryptococcal pneumonia in patients with the acquired immunodeficiency syndrome. Clin Radiol 1995;50:756-760

13) Patz EF Jr., Goodman PC. Pulmonary cryptococcosis. J Thorac Imaging 1992;7:51-55

14) Gallant JE, Ko AH. Cavitary pulmonary lesions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;22:671-682

15) Wu TT, Wang HC, Yang PC. Pulmonary cryptococcosis: manifestations in the era of acquired immunodeficiency syndrome. J Formos Med Assoc 1999;98:621-626

16) Mauri M, Fernandez Sola A, Capdevila JA, Ruiz I, Ribera E, Ocana I, et al. Pleural cryptococcosis in patients with human immunodeficiency virus infection. Med Clin (Barcelona) 1996;106:380-382

17) Miller RF, Howling SJ, Reid AJ. Pleural effusions in patients with AIDS. Sex Transm Infect 2000;76:122-125

18) Newman TG, Soni A, Acaron S. Pleural cryptococcosis in the acquired immune deficiency syndrome. Chest 1987;91:459-461

19) Young EJ, Hirsh DD, Fainstein V. Pleural effusions due to Cryptococcus neoformans: a review of literature and report of two cases with cryptococcal antigen determinations. Am Rev Respir Dis 1980;121:743-747

20) Dromer F, Mathoulin-Pelissier S, Launay O. French Cryptococcosis Study Group: Determinant of disease presentation and outcome during cryptococcosis: the Crypto A/D study. PLoS Med 2007;4:e21

21)  Hung MS, Tsai YH, Lee CH. Pulmonary cryptococcosis: clinical, radiographical and serological markers of dissemination. Respirology 2008;13:247-251

22) Baddley JW, Perfect JR, Oster RA, Larsen RA, Pankey GA, Henderson H, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis 2008;27:937-943

23) Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: Update by the Infectious Diseases Society of America. Clin Infect Dis 2010;50:291-322

24) Deok-Jong Y, Worodria W, Davis JL, Cattamanchi A, den Boon S, Kyeyune R, et al. The prevalence and clinical course of HIV-associated pulmonary cryptococcosis in Uganda. J Acquir Immune Defic Syndr 2010;54:269-274

25) Lortholary O, Poizat G, Zeller V, Neuville S, Boibieux A, Alvarez M, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 2006;20:2183-2191

Both comments and pings are currently closed.

Subscribe to Newsletter