Invasive pulmonary fungal infection Discussion

Abstract

Results: A total of 228 patients, had a median age of 49years, which included 130 (57%) males and 98(43%) females. The most common fungal species identified were aspergillus (39.5 %), cryptococcus (18.4%), and mucormycosis (3.5 %).The main imaging findings were nodules or mass in 144 patients (63.2%), cavitation in 57 patients (25%),consolidation shadows or ground glass infiltrates in 15 patients (6.6%), and reverse halo sign in 12 patients (5.3%). The main infection sites were right upper lobe (26.8%), right lower lobe (21.5%) and the bronchus infection were 18 (7.9%) persons. For the underlying diseases, the prevalence of diseases was pulmonary tuberculosis (17.5%), bronchiectasis (16.2%), diabetes mellitus (9.2%) and the previous thoracic malignancy (6.6%) was common. The number of patients using steroid was 50% and the number of patients using immunosuppressant was 7%.

Conclusions: The imaging findings and the underlying diseases of patients should be taken into account when making diagnosis of pulmonary funga1disease for the purpo se to speculate the probable fungal pathogen and choose the most appropriate diagnostic tool.

Keywords:Pulmonary fungal disease; pathogen; imaging manifestation; Underlying disease; Clinical analysis; Chinese

(pneumomycosis; pulmonary mycosis?)invasive mould infection (IMI)Invasive fungal infections (IFIs),invasive aspergillosis

invasive mold disease, invasive aspergillosis, diabetes mellitus.

1. INTRODUCTION

2. METHODS

2.1 Study design

A retrospective cohort study was conducted by reviewing the medical records of patients who had been diagnosed with pulmonary fungal disease, verified by pathological examination or histological culture, over a period of 7 years (October 2011 to July 2018) at a university teaching hospital with the aim of investigating the demographics, types of fungus, sites of infection, radiologic features, underlying diseases, laboratory investigations, in addition to the information on steroid and immunosuppressive medications. Laboratory examinations including white blood cell (WBC) count, lymphocyte, neutrophils, albumin, globulin and hemoglobin. The Ethical Review Committee of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology approved the study.

2.2 Study subjects

Definite(proven) case of pulmonary fungal disease requires hist0opathological examination or histological culture, and the case files of patients with evidence of mould infection (e.g., hyphae seen on smears, positive culture for a mould) were then assessed for eligibility within the study. (PFD was defined and categorized into proven, probable and possible based) All cases were diagnosed according to the 2008 European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infection Diseases Mycoses Study Group definition criteria.(or ISDA).

The information about the types of fungus came from the histopathological examination, as well as fungi culture and other indirect tests of fungal antigens (galactomannan test), obtained from various samples, such as biopsy sample，bronchoalveolar lavage fluid. and sputum.

The infection sites were verified mainly by the puncture site of pathological biopsy, and two authors also manually screened the CT images for additional information.

For microbiology data as a source, appropriate laboratory records were reviewed.

For histopathology, case records of patients with histology/cytology showing septate hyphae invading tissue were reviewed to assess eligibility within the study.

Patients were excluded if :1) incompletely recorded data; 2) lacking inclusion criteria;

3) With lung tumor simultaneously; 4)they had endemic mycoses (e.g. histoplasmosis), sporotrichosis, penicilliosis, yeast infections, allergic fungal diseases like allergic bronchopulmonary aspergillosis, or infection limited to the skin or eye.

2.3 Assessments

2.4 Statistical Analysis

Categorical variables were compared using the Chi- square test or Fisher’s exact test and continuous variables with t test or Kruskal-Wallis K sample test where appropriate. Statistical analysis was executed with SPSS version 25.0 statistical analysis software. All tests used were two-tailed, and statistical significance was defined as a P value＜0.05.

3. RESULTS

3.1General data

Two hundred and twenty-eight patients were diagnosed with pulmonary fungal diseases during the 7-year period between 2011 and 2018. The patients had a median age of 49 years, which included 130 (57.0%) males and 98 (43.0%) females. Clear pathogen infection was performed in 155(68.0%) patients. The identified pathogens included aspergillus (39.5 %), cryptococcus (18.4%), mucor (3.5 %), coccidioides(2.2%), candida(1.8%), histoplasma (1.3%) and actinomyces(1.3%).

Chest computed tomography (CT) was performed in 190 (83.3 %) patients before diagnosis of pulmonary fungal infections, which gave us the required evidence to evaluate the radiological characteristics of pulmonary fungal infection. Among the 190 patients with CT images, the most frequently observed CT abnormality was nodules or mass in 144 patients (63.2%), cavitation in 57 patients (25%), consolidation shadows or ground glass infiltrates in 15 patients (6.6%), and reverse halo sign in 12 patients (5.3%).

The main infection sites were right upper lobe (26.8%), right lower lobe (21.5%), Left upper lobe (14.5%), Left lower lobe (16.7%) and the bronchus infection were 18 (7.9%) persons. The numbers of other sites were 9(3.9%), including multiple lung lobes (8, 3.5%) and pleura (10.4%).

For the underlying diseases, pulmonary tuberculosis (17.5%) was most dominant followed by bronchiectasis (16.2%), diabetes mellitus (9.2%), and the previous thoracic malignancy (6.6%) was common. Treatment with glucocorticoids were recorded in 114 (50.0%) and the number of the usage of immunosuppressant such as cyclosporine and azathioprine was 16(7%). A total of 12 patients were administrated glucocorticoids concomitantly with immunosuppressant.

Of the 228 patients, 195 patients had a clear pathological biopsy approach. There were 138 patients had pneumonectomy, 36 patients performed transbronchial lung biopsy and 21 patients underwent percutaneous pulmonary biopsy.

The baseline data are given in Table 1.

TABLE 1 Characteristics of the study participants

a Data is represented as n (%) or as the mean ± standard deviation

b Some patients had more than 1 underlying medical problem.

c Prolonged Steroid Used-At a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks.(≥3 weeks in past 60 days)

dImmunosuppressants include methotrexate, cyclosporin, azathioprine, cyclophosphamide, tacrolimus, mizoribine, occurring in the past 90 days.

COPD, Chronic obstructive pulmonary disease

3.2 Differences between bronchus and non-bronchus infections

A comparison of patients with infection of bronchus and those without infection of bronchus is shown in Table 2.Due to a lack of the site of pathological examination, 7 cases (1 pulmonary aspergillosis patient, 3 pulmonary cryptococcosis patients, and 3 other pulmonary fungal infection patients) were not involved.

Among the 221 patients, 18 in the trachea group and 203 in the non-trachea group. The mean age of the patients with infection of trachea was 51.06±18.34 years, older than non-bronchus group (P = 0.013). The types of fungus showed no difference overall, but further investigation found aspergillus (P = 0.033) and cryptococcosis (P = 0.021) were more inclined to present in non-bronchus group.

For the predisposing factors, underlying diseases of previous extrathoracic malignancy seemed that had a higher probability of infecting the bronchus (P = 0.001). And the blood routine tests suggested lower hemoglobin (P = 0.016) and neutrophil percentage (P = 0.024) in the bronchus group.

The radiological presentations were non-specific in the different groups, as well as the information on steroid and immunosuppressive medications.

TABLE 2 Clinical manifestations (Features)of infection of trachea

aData are represented asn (%) or as the mean ± standard deviation

bSome patients had more than 1 underlying medical problem.

cAt a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks.

dImmunosuppressants include methotrexate, cyclosporin, azathioprine, cyclophosphamide, tacrolimus, mizoribine, occurring in the past 90 days.

COPD, Chronic obstructive pulmonary disease

*P ＜0.05

COPD, Chronic obstructive pulmonary disease

3.3 Differences between the different type of fungal

As the research above shows, the chief type of fungal were aspergillosis (n = 90), cryptococcosis (n = 42) and mucormycosis(n = 8). Then an analysis was performed to examine the differences between 3 types of fungi (Table 3).

Among the 140 patients, radiologic findings that nodule or mass (P<0.05) and cavitation (P =0.041) showed different distribution in 3 groups.And the lobar distribution of infection site showed difference (P<0.05). As the underlying diseases,pulmonary tuberculosis(P =0.021), bronchiectasis(P =0.005), and diabetes mellitus(P =0.013) were more inclined to occur in aspergillosis group, what means that aspergillus largely infected persons with those diseases.what's more, the lowest hemoglobin values(P =0.002) ​​and albumin values(P =0.008) were more likely to occur in the group of mucormycosis.

There were no statistically significant differences between the subgroups with 3 types of fungi cases with regard to the information on steroid and immunosuppressive medications.

TABLE 3Clinical manifestationsFeatures of 3 types of fungi

aData represented as n (%) or as the mean ± standard deviation

bSome patients had more than 1 underlying medical problem.

cAt a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks.

dImmunosuppressants include methotrexate, cyclosporin, azathioprine, cyclophosphamide, tacrolimus, mizoribine, occurring in the past 90 days.

COPD, Chronic obstructive pulmonary disease

*P ＜0.05

COPD, Chronic obstructive pulmonary disease

3.4 Differences between the different underlying diseases

It showed that aspergillus (P =0.004) and cryptococcus (P =0.004) largely infected those patients with destruction of lung structure and/or immunocompromised, and nodule or mass (P =0.001) was mostly found in healthy individuals without underlying disease. what is more, the laboratory tests pointed out those patients with destruction of lung structure and immunocompromised had the lowest lymphocytes percentage (P =0.018) and the highest neutrophilic granulocyte percentage(P =0.017).

TABLE 4Clinical manifestations of the underlying diseases (Patients characteristic)

aData are represented as n (%) or as the mean ± standard deviation

*P ＜0.05

COPD, Chronic obstructive pulmonary disease

3.5 Differences between lobe infections

An analysis was performed to examine the differences between different lobe infections (Table 3). Among the 194 patients, right upper lobe (61, 31.4%) was the most likely to occur pulmonary fungal diseases, followed by right lower lobe (49, 25.3%), left lower lobe (38, 19.6%).And the site with the lowest probability was right middle lobe (13, 6.7%).

For the types of fungus, the number of unidentified fungus were 64, of the 130 patients that had a clear fungal type, the data were statistically significant (P< 0.05), and further analysis found that aspergillus (P =0.001), cryptococcus(P =0.001) and coccidioides(P< 0.05) had a different probability of infection in different lung lobes.

For the underlying diseases, bronchiectasis (P =0.025) and diabetes mellitus (P =0.004) may attributable to the different pulmonary lobe infections.

TABLE 5Clinical manifestations of infection of different lobe

aData is presented as n (%) or as the mean ± standard deviation

bSome patients had more than 1 underlying medical problem.

cAt a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks.

dImmunosuppressants include methotrexate, cyclosporin, azathioprine, cyclophosphamide, tacrolimus, mizoribine, occurring in the past 90 days.

*P ＜0.05

COPD, Chronic obstructive pulmonary disease

4. DISCUSSION(From here on delete)

Several observations from our study have relevant implications with regards to pulmonary fungal disease.

As expected, Aspergillus spp. (39.5%) were responsible for the majority of pulmonary fungal disease, followed by cryptococcus (18.4%), mucor (3.5 %), and coccidioides (2.2%). This rate is similar to the frequency of

This has been noted previously and may related to

Some radiologic features might be indicative of the possibility of a pulmonary fungal infection. Radiographic signs and patterns, their specific imaging features and possible association with certain pulmonary fungal infections are described in Table 1. Consolidation is one of the more common radiologic manifestations of a pulmonary infection. However, none of these patterns are specific for fungal infections in general or for any particular fungus and can be seen in other diseases.In our study,the most frequently observed CT abnormality was nodules or mass (63.2%), cavitation (25%), consolidation shadows or ground glass infiltrates (6.6%), and reverse halo sign (5.3%).And the main infection sites were right upper lobe (26.8%) and right lower lobe (21.5%). Fungal infections are an important consideration in the differential diagnosis of necrotizing and non-necrotizing granulomatous inflammation in the lung. However, fungal infections are not always associated with granulomatous disease, especially in the immunocompromised host, or in small biopsies, where granulomas might not have been sampled.

A key finding from the present work was that pulmonary tuberculosis wasan important underlying condition, found in 17.5% of the subjects in this study. Previous reports have also noted this link.Furthermore,

It suggests that DM and rheumatologic conditions be considered as risk factors for pulmonary fungal infection and demonstrates that pulmonary fungal infection should not be ruled out in patients whose chest features on CT do not fit the conventional criteria.(not for real use in article just an assumption)

Previous reports have also noted this link.

5. CONCLUSION

There are some limitations to this study. First,ours was a non-interventional study and lack of attributing symptom and treatment outcomein patients with pulmonary fungaldisease.Second,we collected data only for patients with pulmonary fungaldisease and not for those without fungal infections, thus, we were unable to calculate the attributable risk for mortality due to pulmonary fungaldisease, which would have been a novel result from the current study. In addition, the single-center study may not be sufficient,further evaluation in a multi-center, prospective, randomized controlled study is required.

Despite these limitations, this study provides a valuable insight into

ACKNOWLEDGMENTS

REFERENCES