Pulmonary cryptococcosis characteristics in immunocompetent patients—A 20‐year clinical retrospective analysis in China

Summary Background Pulmonary cryptococcosis (PC) is not considered an rare, opportunistic infection anymore. The immunocompetent population accounts for an increasing proportion of the morbidity. Objective This study investigated the clinical characteristics of PC patients spanning 20 years, in a referral centre of China. Patients/Methods We retrospectively investigated the clinical data of 99 patients with PC who were diagnosed at Peking Union Medical College Hospital (PUMCH) from January 1998 to December 2017. Results Pulmonary cryptococcosis incidence in PUMCH has seen sharp increase in two decades. There were 40.4% (40/99), 17.2% (17/99) and 42.4% (42/99) immunocompetent, mildly immunocompromised and severe immunocompromised patients, respectively. Significantly higher (P = .035) male predominance in immunocompetent and mildly immunocompromised groups (68.4%, 39/57) compared with severe immunocompromised group (45.2%, 19/42) was found. Overall, 27.5% (11/40) immunocompetent patients reported a significant difference (P = .02) in history of more than weekly drinking, higher than mildly or severe immunocompromised. No significant difference occurred in symptoms and radiographic characteristics among the groups. In pulmonary computerised tomography findings, the non‐air pathway feature was the dominant distribution characteristics in all patients with PC (P = .002). The gap in body dissemination frequency between immunocompetent combined with mildly immunocompromised (5.26%, 3/57) and severe immunocompromised (19.0%, 8/42) was marginally significant (P = .05). Conclusions Gender and alcohol drinking could be PC risk factors of concern in patients without severe immunodeficiency. No significant difference occurred in symptoms or radiographic characteristics between patients with different levels of immune status. The unique radiographic non‐air pathway distribution in the lung may be the feature of Cryptococcus invasion that may enhance accurate diagnosis.

Conclusions: Gender and alcohol drinking could be PC risk factors of concern in patients without severe immunodeficiency. No significant difference occurred in symptoms or radiographic characteristics between patients with different levels of immune status. The unique radiographic non-air pathway distribution in the lung may be the feature of Cryptococcus invasion that may enhance accurate diagnosis.

K E Y W O R D S
China, clinical characteristics, Cryptococcosis, immune status, lung, nutrition immunity, radiograph distribution, retrospective

| INTRODUC TI ON
The most common clinical manifestation of Cryptococcosis is the pulmonary system infection. 1 However, Cryptococcus also has a propensity to infect the central nervous system (CNS). 2,3 The innate mechanism of pulmonary cryptococcosis (PC) is that of an opportunistic fungal infection that mostly affects immunocompromised patients, especially patients with human immunodeficiency virus (HIV). The most common means by which Cryptococcus causes infection in the lungs is via inhalation. 1 Recently, a retrospective review of non-AIDS patients pathologically diagnosed with PC from China revealed that 60% of PC cases were diagnosed in immunocompetent non-HIV patients. 4 The prevalence of cryptococcosis in non-HIV patients especially in non-HIV non-immunocompromised patients and the mechanism of the interaction between host and pathogen are being given increasing attention. 5,6 Pulmonary cryptococcosis is easily misdiagnosed as lung cancer, pulmonary tuberculosis and other pulmonary mycoses, both clinically and radiologically. 1 Misdiagnosis and underdiagnosis is particularly common in patients with normal immunity. The clinical characteristics and the possible pathophysiologic mechanism of PC in immunocompetent individuals may become increasingly important for an accurate diagnosis.
Therefore, this study was aimed to investigate the clinical characteristics of PC patients spanning 20 years, in a single centre of China.

| PATIENTS AND ME THODS
We retrospectively reviewed the medical records of 116 hospitalised patients who were diagnosed with 'PC' from January 1998 to December 2017 in Peking Union Medical College Hospital (PUMCH), the most authoritative referral centre in the Chinese hospital rankings of Fudan University.

| Ethics statement
The study was approved by the Ethical Committee of PUMCH (protocol number: s-k 206). Because of the retrospective nature of the study, informed consent was waived. The patients' clinical characteristics data were reviewed and re-evaluated by our research team including two senior pulmonologists and one radiologist.

| Diagnostic criteria
The diagnosis of PC is usually based on a combination of clinical and radiological suspicion and laboratory confirmation. 7 Of the 116 patients reviewed, 99 met the deterministic diagnostic requirements for PC (a case was excluded if such did not meet any one out of the four diagnostic requirements). These requirements were as follows:

| Predisposing conditions
Immunocompromised conditions such as HIV infection, organ transplantation, diabetes mellitus, corticosteroid or immunosuppressive therapy, and malignancy are linked with PC. 11,12 After extensive review of the clinical data, all diagnosed 99 cases were classified into three categories by their predisposing conditions: 1. We considered patients who had major discernible immunodeficiency (such as HIV infection, haematologic malignancy) or showed a certain degree of immunocompromise due to immunosuppressive therapy (such as organ transplantation, malignancy under radiation therapy or chemical therapy, or Cushing syndrome); as well as patients who were under active immunosuppressive therapy due to their autoimmune or inflammatory disease, to be severe immunocompromised.
2. We considered patients who had relevant systematic diseases such as diabetes mellitus, chronic liver disease and other endocrine diseases like hypothyroidism that may affect immune status to be mildly immunocompromised.
3. Finally, we considered other patients who had no relevant systematic diseases or a history of certain immunocompromised, to be immunocompetent.
A single patient with one or more of the above conditions was classified by the most primary predisposing condition according to their immunity.

| Statistics
Descriptive statistics were used to characterise patient cohorts.

| Annual incidence
A total of 99 patients with PC were included in this study. As shown in Figure

| Demographic characteristics of patients with PC
The demographic characteristics of all 99 PC patients are shown in

| Symptoms
In the 99 PC patients, the most common symptoms were cough

| Dissemination
The frequency of body dissemination of cryptococcus showed significant difference between the three immune status groups (Table 5).

| D ISCUSS I ON
Cryptococcosis remains the second most common cause of AIDSrelated mortality. 13  reported in recent decades. 14 The incidence of PC in PUMCH has seen a 10 times increase in the past two decades in our data. On the one hand, the prevalence of the disease itself increased with the amount of the patients with iatrogenic immunosuppression and the survival of the immunosuppressed patients. On the other hand, the widespread application of serological tests and chest CT, video-assisted thoracoscopic surgery, transbronchial lung biopsy and CT-guided percutaneous lung puncture techniques also contribute greatly to the increase. In addition, the better awareness of this disease by physicians is also attributed to this increasing trend. 13,15,16 Cryptococcosis used to be a rare opportunistic infection that commonly affects the lungs. Individuals with compromised cellular immunity are at higher risk and were typically patients with AIDS. 17,18 In China and Japan, cryptococcosis infection is prevalent predominantly in HIV-negative populations. 6,19 These were patients who received prolonged treatments with corticosteroids and/or immunosuppressive agents, who received solid organ and hematopoietic stem cell transplantation, or who had haematologic and solid organ malignancies. 17,18,20 Although it is much less common, individuals with a milder degree of immune suppression (such as splenectomy, cirrhosis, diabetes mellitus and pregnancy) have an increased risk of Cryptococcus infections. 21,22 In our study, patients with diabetes, as the primary underlying disease, accounted for 11.1% (11/99).
Hyperglycaemia in patients with diabetes could have led to decreased cell-mediated immunity that could explain the association between diabetes and cryptococcosis. 23 The relationship between other systemic diseases and abnormal immunity remains to be further studied.
Recently, a retrospective review in China revealed that 60% of PC cases were diagnosed in immunocompetent non-HIV patients 4 and another study reported that 67% of PC in immunocompetent patients were disseminated into the CNS. 24 The prevalence of cryptococcosis in non-HIV patients especially in non-HIV nonimmunocompromised patients is being given increasing attention. In our study, 40.4% (40/99) overall were immunocompetent.
Research has found that Cryptococcus neoformans can be found globally, and that it predominantly affects the immunosuppressed, whereas Cryptococcus gattii is endemic to certain regions and often affects immune-competent individuals. 25,26 PC infection is more frequent in male than female. 27,28 The gender difference in host immune systems is a possible explanation for the male predominance among patients with cryptococcosis. 29 Our study showed significantly higher male gender predominance in immunocompetent and mildly immunocompromised groups compared with severe immunocompromised group, which also support this previous finding. Overall, 27.5% (11/40) of our immunocompetent individuals. 25 Some studies suggest that cryptococcal meningitis was less frequent in HIV-negative patients than patients with AIDS. 39 Our study also found the frequency gap in the dissemination between immunocompetent group combined with mildly immunocompromised group (5.26%, 3/57) and severe immunocompromised group (19.0%, 8/42), which was significant (P = .05). A limitation to this study was the retrospective study design, which is limited by the integrity of the medical records.

| CON CLUS IONS
Our finding suggests that gender and alcohol drinking could be PC risk factors of concern in patients without severe immunodeficiency. It is worth mentioning that in terms of the distribution of invading lung lesions, most of the patients had unique non-air path inhalation contact distribution. The possibility of lung cryptococcus infection should be considered when the patient has lung lesions with the special non-air path inhalation contact distribution pattern. Also, the mechanism of this special distribution pattern needs to be further studied according to the nutrient environment and temperature in the lung.

ACK N OWLED G M ENTS
We thank Jing Li for critical reading and advising of this manuscript.

CO N FLI C T O F I NTE R E S T
There was no conflict of interest influenced the author's objectivity.