Cryptococcosis

Background: Cryptococcus neoformans can cause serious systemic infections requiring systemic antifungal therapy in immunocompromised hosts. However, isolated pulmonary cryptococcosis in nonimmunocompromised hosts has been reported to resolve spontaneously without treatment.

Study objectives: To determine the rule of antifungal therapy in the management of isolated pulmonary cryptococcosis in nonimmunocompromised hosts. Design: Retrospective study.

Setting: Tertiary care, referral medical center

Patients: Thirty-six nonimmunocompromised subjects with isolated pulmonary cryptococcosis who received diagnoses at the Mayo Clinic (Rochester, MN) from 1976 to 2001.

Interventions: None.

Measurements and results: Of 42 nonimmunoncompromised subjects with cryptococcal infections, 36 (86%) had isolated pulmonary cryptococcosis. The mean ([+ or -] SD) age of these 36 patients was 61 [+ or -] 15 years (range, 14 to 88 years), and the groups included 17 men (47%) and 19 women (53%). Twenty-four patients (67%) were symptomatic, and 12 patients (33%) were asymptomatic. The most common presenting symptoms were cough, dyspuea, and fever. Cultures of sputum and bronchial washings most commonly yielded the diagnosis. Cerebrospinal fluid examination was performed in 11 patients (31%) and was negative in all of them. Follow-up information was available on 25 patients (69%) with a median duration of 19 months (range, 1 to 330 months). Twenty-three of these patients (92%) had resolution of their disease (no treatment, 8 patients; surgical resection only, 6 patients; and antifungal therapy, 9 patients). The condition of the two remaining patients had improved. There was no documented treatment failure, relapse, dissemination, or death in any of these 25 patients.

Conclusions: Our findings suggest that an initial period of observation without the administration of antifungal therapy is a reasonable option for nonimmunocompromised subjects with pulmonary, cryptococcosis in the absence of systemic symptoms or evidence of dissemination, as well as after surgical resection for focal cryptococcal pneumonia.

Key words: Cryptococcus neoformans; cryptococcosis: fungal lung diseases: mycosis; pneumonia

Abbreviation: CSF = cerebrospinal fluid

**********

Cryptococcal infections occur worldwide without any defined endemic areas. This fungus is ubiquitous, being commonly found in aged bird droppings but also in soil and decayed wood. (1) Cryptococcal infections in humans likely occur when the organism is aerosolized and inhaled. Human diseases caused by this fungus range from asymptomatic pulmonary, colonization to life-threatening meningitis and overwhelming cryptococcemia. (2)

Crytococcal infections occur predominantly in patients with T-cell-mediated immune defects, especially those with AIDS and transplant-related immunosuppression. (3, 4) Corticosteroid therapy and cancer chemotherapy are also predisposing factors for the development of cryptococcal infections. (4-6) The incidence of crytococcosis is also increased in subjects with hematologic malignancies, sarcoidosis, and diabetes mellitus. (4, 6)

In immunocompromised patients, cryptococcosis can be severe and rapidly progressive, requiring prolonged systemic antifungal therapy. (7, 8) However, pulmonary cryptococcosis in subjects with no identifiable immunologic defects may resolve spontaneously and not require antifungal theerapy. (5, 9) although it can occasionally be severe and deadly. (10, 11) There is general agreement regarding the need for antifungal therapy in imnnmocompromised patients with cryptococcal pneumonia, (7, 8, 11) but there are sparse data addressing this issue for non-immunocompromised subjects in whom cryptococcal infections are uncommon. (5, 9) In an attempt to answer this question of whether or not noninmmnocompromised patients with pulmonary cryptococcosis need antifungal therapy, we identified such patients who had been seen at our institution over a 26-year period from 1976 thru 2001, and examined their clinical presentation, diagnostic evaluation, treatment, clinical course, and outcome. We also assessed the unity of investigations looking for evidence of dissemination to extrapulmonary organs, including the CNS, in non-immunocompromised subjects with pulmonary cryptococcosis.

MATERIALS AND METHODS

Cases of cryptococcal infections diagnosed at the Mayo Clinic (Rochester, MN) from 1976 to 2001 were identified by a computer-assisted search of medical records. Those subjects with HIV infection and transplant recipients were excluded from the study. Patients who did not authorize their medical records to be used for research purposes as well as those subjects with only respiratory tract colonization with cryptococcus also were excluded. In addition, subjects with other immunocompromising conditions or those who were receiving immunosuppressive therapy were excluded after the review of medical records. The sites of involvement were categorized as lung, CNS (ie, meningeal or parenchymal brain involvement), and other sites leg, skin, bone, and prostate). Inclusion in the final study group required a definite diagnosis of pulmonary cryptococcosis as defined by either of the following: (1) histopathologic presence of the organism on a lung biopsy specimen: or (2) a positive finding from a culture of a respiratory specimen or positive result of a serum cryptococcal antigen test with clinical or radiographic evidence of active pulmonary infection.

The following data were abstracted from the medical records: age: sex; clinical features; results of radiologic and laboratory studies; results of diagnostic tests; antifungal and surgical therapy; and follow-up information including final outcome. Follow-up information was assessed regarding the patient's status at the time of the last follow-up, the duration of the follow-up period, the date of relapse, and the site of involvement. Final outcome was classified as follows. Resolution was defined as a complete response to therapy with no evidence of disease for at least 6 months after the completion of treatment, or for [greater than or equal to] 1 month after not receiving therapy or surgical treatment, Improvement was defined as complete or partial response to medical therapy, but within < 6 mouths of follow-up after receiving medical therapy or < 1 month after not receiving therapy or surgical treatment. Relapse was defined as clinical, mycologic, or radiographic evidence of recurrence after the discontinuation of antifungal therapy and after initial improvement. Failure was defined its the persistence or progression of disease as demonstrated through clinical, laboratory, radiographic, or mycologic evidence of disease despite receiving antifungal therapy. This study was approved by the institutional review board of Mayo Rochester Medical Center.

RESULTS

Over the 26-year period surveyed from 1976 through 2001, cryptococcal infections were diagnosed in a total of i43 patients (excluding patients who were HIV-positive and were organ transplant recipients). Of these 143 patients, 101 had immunocompromising conditions (Table 1). The most common underlying conditions included having received corticosteroid therapy and having had hematologic malignancies. Patients with these two conditions had relatively high rates of disseminated infection. Of 42 nonimmunocompromised subjects, 37 (88%) had pulmonary involvement with cryptococccal infection. One of these patients had evidence of dissemination as evidenced by a positive urine culture. Thus, in contrast to the relatively high rates of dissemination seen in immuncompromised hosts, 36 of 42 nonimmunocompromised patients (86%) had isolated pulmonary cryptococcosis.

The mean ([+ or -] SD) age of the 36 nonimmunocompromised patients with isolated pulmonary cryptococcosis was 61 + 15 years (hinge, 14 to 88 years) [Table 2]. Seventeen patients (47%) were men, and 19 patients (53%) were women. Twenty-four patients (67%) had respiratory and/or constitutional symptoms, and 12 patients (33%) were asymptomatic. The most common symptoms were cough (42%), dyspnea (33%), fever (28%), night sweats (22%), and hemoptysis (19%).

The chest radiographs demonstrated abnormal findings in all patients, including infiltrates (62%), nodules (38%), masses (19%), cavitary lesions (14%), and pleural effusions (3%). The geographic distribution of these radiographic lesions demonstrated no discernible pattern. Hilar and mediastinal adenopathy were not seen.

Fungal cultures of sputum (15 patients) and bronchial washings (13 patients) most commonly yielded the diagnosis of pulmonary cryptococcosis (Table 3). Transbronchial biopsy and surgical lung biopsy were performed in three and eight patients, respectively, and yielded a positive diagnosis in all patients.

Cerebrospinal fluid (CSF) examinations were performed in 11 patients (31%), and the findings of all were negative, including clyptococcal antigen assay (11 patients), smear (8 patients), and culture (11 patients). The baseline serum cryptococcal antigen assay had been performed in 22 patients, and the findings were positive in 3 patients (14%). None of these three patients developed dissemination on follow-up. Fungal blood cultures were performed in five patients, and the results of all were negative.

Seventeen patients (47%) were observed without receiving antifungal therapy, including 12 symptomatic patients (5 of whom had systemic symptoms, mainly fever) and 5 asymptomatic patients (Table 4). Follow-up information was available in eight patients in this cohort, all of whom had experienced complete spontaneous resolution of disease.

Twelve subjects (33%) were treated with varying regimens of antifungal therapy (Table 4). Six symptomatic and two asymptomatic patients were treated with fluconazole (dose range, 200 to 400 mg/d) for 10 to 56 weeks. Five of these fluconazole-treated patients experienced resolution of symptoms (including both asymptomatic patients), two patients had improvement, and one patient was lost to follow-up. Of the two patients who had only improvement, one had a follow-up of < 3 months and the other had severe presenting symptoms with extensive bilateral infiltrates consisting of multiple nodules and a cavity. Four other patients were treated with other antifungal agents (Table 4) and experienced complete resolution of their pneumonia.

Seven patients (19%), including three asymptomatic patients, underwent surgical resection mainly to exclude malignancy, and the procedures included wedge resection (five patients) and lobectomy (two patients). Follow-up was available in six of these patients, all of whom received no antifungal therapy and did not experience a relapse.

Overall, none of the 25 nonimmunocompromised patients with isolated pulmonary cryptococcosis (with or without symptoms) and known outcomes experienced progression of cryptococcal infection, treatment failure, relapse, or death. Eight of these patients had been observed without treatment (median duration of follow-up, 14 months), 11 patients had been treated with antifungal therapy, and 6 patients had undergone surgical resection only, The median duration of follow-up for these 25 patients was 19 months (range, 1 to 330 months).

DISCUSSION

This study was undertaken to clarify the need for antifungal therapy in the management of nonimmunocompromised subjects with isolated pulmonary cryptococcosis. Of 42 nonimunocompromised subjects identified in this survey, 36 (86%) had isolated lung involvement. Most subjects were middle-aged, and no sex predominance was demonstrated. The majority of these subjects had constitutional or respiratory symptoms, but one third of them were asymptomatic. These nonimmunocompromised patients with isolated pulmonary cryptococcosis generally experienced an excellent outcome regardless of whether they received antifungal therapy, surgical resection alone, or no treatment.

The extent of clinical evaluation and appropriate management warranted for nonimmunocumpromised patients with pulmonary cryptococcosis have been uncertain because cryptococcal infections in nonimmunocompromised subjects are very uncommon. In 1981, Kerkering mad colleagues (9) reported on 41 patients with pulmonary cryptococcosis seen over a period of 14 years. Seven of these 41 patients were nonimmunocompromised, and in 6 patients (including 5 untreated patients) the disease remained localized to the lungs. These authors recommended observation alone for nonimmunocompromised hosts with isolated pulmonary cryptococcosis. (9) Aberg and colleagues (5) reported on 10 nonimmunocompromised patients with symptomatic pulmonary cryptococcosis. None of these patients had been treated, and there were no deaths from progressive disease or evidence of dissemination. On the other hand, Nunez and colleagues (12) reported on four nonimmunocompromised patients with cryptococcal pneumonia who were given fluconazole therapy with good clinical results. Other authors have reported on the treatment of pulmonary cryptococcosis in nonimmunocompromised patients not only with fluconazole (13,14) but also with itraconazole, (15) ketoconazole, (16) flucytosine, (9) and amphotericin B. Saag et al (8) recently published guidelines for the management of cryptococcal disease and noted that few studies have been conducted to specifically evaluate outcomes among nonimmunocompromised subjects with pulmonary cryptococcosis. These authors recommended antifungal therapy for nonimmunocompromised patients with pulmonary cryptococcosis who are symptomatic, although hard evidence for such an approach was acknowledged to be lacking. (6,13,14) Other reports (13,14) of pulmonary cryptococcosis have included immunocompromised as well as nonimmunocompromised patients and did not provide relevant data.

Observations based on our patient population, as well as on data from previous studies, (5,9) suggest that observation alone with close follow-up may be a reasonable option in nonimmunocompromised patients with cryptococcal pneumonia in the absence of extrapulmonary dissemination or significant symptoms. The risk of progressive pneumonia or dissemination in these patients appears to be relatively low, and there are risks associated with empiric antifungal therapy. (16-18)

There are limitations to our conclusion based on the retrospective nature of our study and the small number of patients. Our patients were not evaluated or treated in a standardized manner. For example, only 11 of our 86 patients underwent CSF examination during the course of their initial evaluation at our institution. In addition, relevant follow-up information was lacking in 11 patients (81%), which significantly hampered the interpretation of the outcome data. However, in 25 patients on whom we had follow-up information, there appeared to be no instance of progression of disease or dissemination even in the absence of antifungal therapy. Furthermore, although the current practice is to perform serologic and CSF examinations of all patients with pulmonary cryptococcosis, our data raise questions as to whether this practice is truly necessary for nonimmunocompromised subjects. (8,19) In febrile patients with advanced HIV disease, high titers of serum ctyptococcal antigen are suggestive of invasive cryptococcal disease, (3,20,21) This correlation of serum cryptococcal antigen and systemic cryptococcal disease has been addressed by Aberg et al (5) in a small number of nonimmunocompromised patients. Until we have reliable prospective data that address these issues, we do not believe that extensive workup (with blood cultures and lumbar puncture) for possible dissemination is necessary in most nonimmunocompromised subjects with serum antigen-negative pulmonary cryptococcosis in the absence of suggestive or significant symptoms.

CONCLUSION

We conclude that antifungal therapy in nonimmunocompromised hosts with isolated pulmonary cryptococcosis may not be needed, although this decision should be made on an individual basis. Observation and careful follow-up seems to be a reasonable course, especially in subjects with no significant symptoms. However, those patients with severe or persistent symptoms, or extensive disease seen on chest radiographs may benefit from antifungal therapy and a workup for possible CNS involvement. Prospective studies are needed to assess further the natural history of pulmonary cryptococcosis in nonimmunocompromised subjects and the risk of extrapulmonary dissemination in the absence of antifungal therapy. Additionally, the potential benefit of antifungal therapy on end points other than final outcome, such as rapidity of resolution and improvement of symptoms, also would be useful to assess. However, the rare occurrence of pulmonary cryptococcosis in nonimmunocompromised subjects may make these tasks difficult to accomplish.

ACKNOWLEDGMENT: We thank Lisa Gilbertson for her secretarial assistance, and James Wentz for his medical records search.

REFERENCES

(1) Levitz SM. The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis 1991; 13: 1163-1169

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

(3) Chuck SL, Sande MA. Infections with Cryptococcus neoformans mans in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321:794-799

(4) Thomas CJ, Lee JY, Conn LA, et al. Surveillance of cryptococcosis in Alabama, 1992-1994. Ann Epidemiol 1998; 8:212-216

(5) Aberg JA, Mundy LM, Powderly WG. Pulmonary cryptococcosis in patients without HIV infection. Chest 1999; 115:734 740

(6) Pappas PG, Perfect JR, Cloud GA, et al. CLyptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33:690-699

(7) Dismukes WE. Management of cryptococcosis. Clin Infect Dis 1993; 17:S507-S512

(8) Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease: Infectious Dis eases Society of America. Clin Infect Dis 2000; 30:710-718

(9) Kerkering TM, Duma RJ, Shadomy S. The evolution of pulmonary cryptococcosis: clinical implications from a study of 41 patients with and without compromising host factors. Ann Intern Med 1981; 94:611-616

(10) Robinson GR II. Images in clinical medicine: severe cryptococcal pneumonia. N Engl J Med 1995; 3:32:1752

(11) Vilchez RA, Irish W, Lacomis J, et al. The clinical epidemiology of pulmonary cryptococcosis in non-AIDS patients at a tertiary care medical center. Medicine 2001; 80:308-312

(12) Nunez M, Peacock JE Jr, Chin R Jr. Pulmonary cryptococcosis in the immunocompetent host: therapy with oral fluconazole: a report of four cases and a review of the literature. Chest 2990; 118:527-534

(13) Dromer F, Mathoulin S, Dupont B, et al. Comparison of the efficacy of amphotericin B and fluconazole in the treatment of cryptococcosis in human immunodeficiency virus-negative patients: retrospective analysis of 83 cases; French Cryptococcosis Study Group. Clin Infect Dis 1996; 22:S154-S160

(14) Yamagushi H, Ikemoto H, Watanabe K, et al. Fluconazole monotherapy for cryptococcosis in non-AIDS patients. Eur J Clin Microbiol Infect Dis 1996; 15:787-792

(15) Denning DW, Tucker RM, Hanson LH, et al. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989; 149:2301-2308

(16) Dismukes WE, Stamm AM, Graybill JR, et al. Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients: National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study. Ann Intern Med 1983; 98:13-20

(17) Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itraconazole. Lancet 200l: 357:1766-1767

(180 Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole [letter]. Ann Intern Med 1999; 131:797

(19) Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS: 100 years after the discovery of Cryplococcus neoformans. Clin Microbiol Rev 1995; 8:515-548

(20) Kovacs JA, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:533-538

(21) Eng RH, Bishburg E, Smith SM, et al. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med 1986; 81:19-23

* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Nadrous and Ryu), and Infectious Diseases (Drs. Antonios and Terrell), Mayo Clinic. Rochester, MN.

This research was supported by Mayo Clinic institutional funds.

Manuscript received February 13, 2003; revision accepted May 19, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Jay H. Ryu, MD, Division of Pulmonary and Clinical Care Medicine, Desk East 18, Mayo Clinic, 200 Finer St SW, Rochester, MN 55905; e-mail: ryu.jay@mayo.edu

COPYRIGHT 2003 American College of Chest Physicians
COPYRIGHT 2004 Gale Group