Profiling of Pulmonary Fungal Pathogens and the Prevalence of Pulmonary Tuberculosis Fungal Co-Infection in Presumptive Tuberculosis Patients Referred to Saint Peter’s Tuberculosis Referral Hospital, Addis Ababa, Ethiopia

Abstract

Background: The burden of pulmonary mycosis is increasing and often misdiagnosed as pulmonary tuberculosis in developing countries where the prevalence of pulmonary tuberculosis is high.

Objective: To determine the prevalence of pulmonary mycosis and pulmonary tuberculosis fungal co-infections.

 Methods: A hospital-based, cross-sectional study was conducted between October 2019 and May 2019. Sputum was collected from 636 study subjects. Part of the sputum was inoculated onto Brain Heart Infusion agar and fungi were identified following standard microbiological procedures. The remaining part of the sample was used for the investigation of pulmonary tuberculosis by GeneXpert.

Results: Among 636 sputum samples, 75.9% (483), 25.6% (163), and 20% (127) were positive for fungal pathogens, pulmonary tuberculosis, and pulmonary tuberculosis fungal co-infection, respectively. Of 690 fungal isolates, 81.4% were yeasts compromising of 46.3% Candida albicans 52.7% Non-albicans Candida species, and 1.0% Cryptococcus neoformans. The remaining 128 (18.6%) isolates were molds, where Aspergillus species (79; 61.7%), Penicillium species (16; 12.5%), Scedosporium apiospermum (13; 10.2%), and Fusarium species (10;7.8%) being the major isolates. The isolation rate of fungi was higher in males (51.6%) than in females (48.4%). There was no statistically significant association between the prevalence of pulmonary fungal pathogens and sex (P=0.239). Patients in the age group of 35-44 and above were slightly more affected than younger age groups. The association of fungal pathogens and age was not statistically significant (P=0.50).

Conclusions: Our study revealed a high prevalence of pulmonary fungal pathogens (75.4%) and pulmonary fungal co-infection (20%). The isolation rate of Non-albicans Candida species out-numbered that of C. albicans. High prevalence of pulmonary fungal pathogens in our study, especially in cases where sputum for pulmonary tuberculosis was negative alerts, the need to employ conventional microbiology tests along with clinical and radiological evidence.

Introduction

Although the true burden of fungal respiratory tract infection is elusive, the frequency of the infection has been increasing in the last few decades [1]. Pulmonary tuberculosis (PTB), HIV/AIDS, chronic obstructive pulmonary disease, and extensive use of immunosuppressive drugs are incriminated for such an increase [2]. Globally, it is predicted that 1.2 million individuals live with chronic pulmonary aspergillosis (CPA) as a sequel to PTB, in which the prevalence of CPA is the highest in Africa, Western Pacific, and South-East Asia [3]. The chromic nature of PTB along with prolonged chemotherapy with or without corticosteroids resulted in immune suppression in PTB patients eventually leading PTB patients susceptible to fungal infection [4].

Pulmonary fungal infection (pulmonary mycosis) is an infectious disease of the lungs that is caused by fungi. The infection develops after the colonization of the lungs by fungi or their spores through inhalation, or the reactivation of latent infection, or via hematogenous dissemination. Fungi or their spores are abundant and exist virtually everywhere in the human environment [5, 6]. Given the ubiquitous nature of fungi and their spores, colonization or infection of the lungs is unavoidable, but mechanisms of differentiating fungal colonization from fungal infection are not well-established and hence the subject remains a serious challenge. In this paper, isolation of fungi alone or in association with M. tuberculosis from presumptive tuberculosis patients (i.e., patients presenting signs and symptoms of pulmonary tuberculosis and having radiological pictures characteristics of PTB) was considered as fungal infection or pulmonary mycosis.

Many fungal species have been reported as etiological agents of fungal lung infection. In most literature, species of Aspergillus [7], Candida, Cryptococcus [8], Pneumocystis [9], and thermally dimorphic fungi [10] are the most significant. However, the epidemiology of fungi causing lung infection has been changing. Accordingly, many mycelial fungi, such as Scedosporium SPP., Fusarium SPP., Penicillium SPP., dematiaceous filamentous fungi, zygomycetes, and yeasts other than C. albicans have emerged as etiological agents of respiratory fungal disorders. While these fungi are rarely recovered in the respiratory tract of immune-competent individuals, they may disseminate to other systemic organs producing life-threatening invasive fungal diseases in individuals already experiencing serious illness [11].

Pulmonary tuberculosis is principally a disease of poverty, with 95% of cases and 98% of deaths occurring in developing countries [12]. Ethiopia stands 10th among the 30 high TB burden countries with an estimated incidence rate of 151/ 100000 [13]. The high rate of co-infection of pulmonary mycosis with PTB further compounded the burden of PTB in these countries as the association of the two infections is responsible for a high rate of morbidity and mortality [3]. Therefore, proper diagnosis of fungal pathogen especially in PTB patients is critical [14]. To this end, the spectrum of pulmonary fungal infections and their association with PTB in Ethiopia is lacking.

Furthermore, similarities in clinical and radiological presentation of pulmonary fungal infection and PTB have made differential diagnosis between these two infections difficult. Persistent cough for more than three weeks is a common symptom of pulmonary disorders caused by a wide range of pathogens, including fungi and other bacteria. Lack of differential diagnosis may lead to empirical treatment in which fungal infections are treated with anti‑tuberculosis chemotherapy with poor clinical outcomes, as anti‑tuberculosis drugs do not affect fungal pathogens [11]. As in most developing countries treatment of PTB patients in Ethiopia is empirical. In view of this, determining the spectrum of fungal pathogens from the sputum of patients presenting clinical and radiological characteristics similar to PTB and the magnitude of fungal and PTB co-infection is an active field of research. Therefore, the objectives of the present study are determining the distribution of fungal pathogens associated with the lower respiratory tract (lung) infection and the prevalence of fungal pathogens and PTB co-infections in presumptive PTB patients referred to the Saint Peter's Specialized Tuberculosis Referral Hospital.

High prevalence of pulmonary fungal pathogens in our study, especially in cases where sputum for M. tuberculosis was negative and study subjects with PTB recorded in this study will enforce health personnel to pay due attention to these conditions and arise the interest of researchers to conduct further work on the burden of pulmonary fungal infection and its association with Pulmonary tuberculosis which is a neglected disease in most developing countries.

Methods

Results

Discussion

The global burden of pulmonary fungal infections caused by opportunistic fungal pathogens is increasing [19]. Sustaining of patients by drugs, chemicals, and mechanical processes that compromise physical barriers to infection, suppress immune mechanisms, or upset the balance of normal flora are responsible for rendering hosts more susceptible not only to pathogenic fungi but also to all fungi with which they come in contact. The increased age of the world population that resulted in more chronic diseases with their debilitating effects is also another attributing factor for an increase in fungal lung infection by opportunistic fungal pathogen [20]. The impact of these factors may explain for the higher prevalence of fungal pulmonary infection reported in the present study.

The present study revealed that the prevalence of PTB, pulmonary fungal pathogens and PTB-fungal pathogen co-infection were found out to be 25.6%, 75.9%, and 20.0%, respectively. Our result regarding the prevalence of PTB and pulmonary fungal pathogens was consistent with the findings of Sani et al [21] but PTB- fungal pathogen co-infection in our study was three-fold (20.0% against 6%) from that of their report. On the other hand, PTB fungal coinfection in the range of 18–40% was reported by other similar studies [22, 23]. Among 163 study subjects that were positive for M. tuberculosis, 123 (77.9%) were co-infected with fungal pathogens. The high prevalence of PTB fungal pathogen co-infection in study subjects with tuberculosis in our study may support that pre-existing or residual cavity produced following tuberculosis infection are frequent places of fungal colonization and the chromic nature of PTB along with prolonged chemotherapy makes PTB patients more susceptible to fungal infection [4]. The high prevalence of PTB and fungal co-infection exhibited in this study may worsen the existing burden of PTB and, hence, due attention should be given.

Lower respiratory tract fungal infection (pulmonary mycosis) such as aspergillosis frequently occurs in middle-aged to an elderly individual, and are more commonly reported in male patients [24, 25]. Our finding was in line with the findings of Kosmidis and Denning [24] and Kohno et al [25] as the isolation rate of fungal pathogens was higher in patients above 35 years than younger age groups and male than female study participants. Other studies [26, 27], however, demonstrated that the age group of 20–34 years is most affected by fungal pathogens. Certainly, old age is a known risk factor for pulmonary fungal infection probably due to diminishing immune function as one gets aged [20]. The association of pulmonary fungal infection with age and sex in our study was not statistically significant with respective P- values of 0.239 and 0.50.

In the present study, of a total of 636 sputum cultures, 483 were positive for fungal pathogen and a total of 690 fungal isolates were recovered. Furthermore, out of 483 positive culture, 43 samples yielded more than one fungal species. Among the isolates, 562 were yeasts where NAC species comprised the most predominant yeast isolates (52.7%). At the species level, however, C. albicans was the most prevalent species accounting for 46.2% yeast isolates. This was followed by C. tropicalis and C. krusei. Numerous studies have reported that Candida species are the most frequent fungal species recovered from the sputum of patients with pulmonary tuberculosis [24, 25, 28, 29].

Even though Candida species were noted as the most frequent fungal species recovered from the sputum of patients with tuberculosis its significance has always been a matter of debate because up to 32.5% of healthy individuals harbor Candida in their throat that can contaminate the sputum during sample collection [30]. Correspondingly, our study depicted that C. albicans was the most prevalent yeast in PTB yeast co-infected patients accounting for 64.6% of yeast isolates. Similar other several studies [31–33] demonstrated a high prevalence isolation rate of C. albicans ranging from 45–92% in PTB patients co-infected with yeasts. The existence of candidiasis concurrently with PTB patients is of paramount interest in the treatment of patients as C. albicans is supposed to enhance the virulence of PTB [22]. Although C. albicans continues to be the most predominant species in pulmonary candidiasis [31–33], several NAC species are also reported in increasing frequency. C. tropicalis and C. krusei were isolated as the 2nd and the 3rd most prevalent yeasts in PTB-yeast co-infected patients with respective frequencies of 22.6% and 19.9%. our result is in line with Latha et al [31], Jain et al [32], and Baradkar et al [33]. C. tropicalis is an emerging pathogen with higher rates of severe disease and deep tissue invasion than C. albicans in immune- debilitated individuals, and C. krusei is noted as intrinsically resistant emerging yeast pathogen to azole antifungal drugs particularly to that of fluconazole [34, 35].

Fungal infections of the respiratory tract by large are considered to be identical with invasive pulmonary infections caused by Aspergillus SPP.[6]. Our finding was consistent with this report because out of 128 mycelial fungi recovered in the present study 61.7% (79) of the isolates were Aspergillus species. Among a hundred species of Aspergillus, A. fumigatus, A. flavus, A. niger, and A. terreus are pathogenic species to man. Most previous studies reported that A. fumigatus is the most common cause of chronic-pulmonary aspergillosis [21, 36–38], although its incidence appears to be decreasing in recent years with an increase in cases by other no-fumigatus species, especially A. flavus, A. niger, and A. terreus [39]. In the present study, A. niger was the most frequently isolated Aspergillus species followed by A. fumigatus and A. flavus. Our finding was in line with the findings of Park et al [40]. According to Park et al [40], non-fumigatus Aspergillus species are known to cause all forms of aspergillosis. Correspondingly, our study depicted that Aspergillus species were the most prevalent mycelial fungi in PTB mold co-infected accounting for 14.96% of mold isolates.

Pulmonary fungal infections have long been recognized as a significant complication and mainly caused by C. albicans and Aspergillus SPP. Within the past few decades, however, infections due to infrequently encountered fungi (e.g., Penicillium SPP., Scedosporium SPP., dematiaceous filamentous fungi, and zygomycetes) have become increasingly common in immunocompromised hosts [6]. Our finding supports the report of Chowdhary et al [6] in that the isolation rate of mycelial fungi other than Aspergillus SPP. was considerable. Among 128 mycelial fungi isolated 49 (38.3%) were mycelial fungi other than Aspergillus SPP. Among non-Aspergillus isolates, 16(12.5%) were represented by Penicillium SPP. of which 5(31.25%) of the isolates were P. marneffei and the remaining 11(68.75%) were other Penicillium SPP. P. marneffei is an emerging dimorphic fungal agent that can cause a deadly systemic mycosis in subjects infected with human immunodeficiency virus [41] while Penicillium SPP. other than Penicillium marneffei have been recovered most frequently in the clinical laboratory as culture contaminants. They have, however, been emerged as opportunistic pathogens in an immunocompromised individual and consequently, it should not be regarded as a contaminant without a thorough investigation [42].

In our study, S. apiospermum and Fusarium SPP. accounted for 10.2%;13 and 7.8%;10 of the isolates of mycelial fungi, respectively. S. apiospermum is among the most common filamentous fungi colonizing the lungs of cystic fibrosis patients with a frequency of 9% [43]. Fusarium species once considered to be important plant pathogens are known to cause a broad spectrum of infections including mycotic keratitis and onychomycosis. Lung involvement is common in invasive fusariosis occurring among immunocompromised patients with disseminated infection [44]. Species of Alternaria, Bipolaris, Curvularia, and Exserohilum have been reported to cause different types of human respiratory tract infections including invasive lung disease [Chowdhary [6, 45, 46]. Isolation of Alternaria and Bipolaris species in our study supports the findings of Chowdhary et al [6], Bush and Prochnau [45], and Chowdhary et al [46].

Conclusions

Our study revealed a high prevalence of pulmonary fungal pathogens (75.4%) and PTB fungal co-infection (20%). Although C. albicans has long been reported the dominant yeast associated with PTB, our study, however, demonstrated that the isolation rate of NAC out-numbered that of C. albicans. High prevalence of pulmonary fungal pathogens in our study, especially in cases where sputum for M. tuberculosis was negative and study subjects with PTB alerts, the need to employ conventional microbiology tests along with clinical and radiological evidence since clinical manifestations and radiological pictures of PTB mimic that of pulmonary fungal infection.

Declarations

Ethics approval and consent to participate

All methods were carried out in accordance with the declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects WMA General Assembly, Seoul, Korea, October 2008. Briefly the aim of the study and its benefits were explained to the study participants. Study participants who did not consent to participate in the study are not obliged to participate in the study and can withdraw from the study at any time of the course of the study. Then written informed consent for the study subject with an age of 19 years or above was completed by the study participant while written informed consent for the study subject with an age of 18 years or below was completed by parents/guardians. The study was started after obtaining an ethical clearance (Protocol number: DRER/393/19/MLS/2019) from the Internal Review Board of the Department of Medical Laboratory Science College of Health Science Addis Ababa University and permission from research directorate of the hospital.

Consent for publication

The study contains no individual person’s data in any form

Availability data and materials

All the data and materials included in the manuscript

Competing interest

The authors declare that no financial and non-financial competing interest for the manuscript.

Funding

No fund was obtained for the work

Author Contributions:

AB: Conceived and designed the work, analysis and interpretation of data, drafting of the article and revising it critically; Solomon SB: Acquisition of data, analysis and interpretation of data, drafting of the article, data collection, part of laboratory work. Both authors commented on the initial manuscript and approved the final manuscript.

Acknowledgments:

The authors would like to thank the Department of Medical Laboratory Science, College Health Sciences, Addis Ababa University, Ethiopia, and Saint Peter's Specialize Tuberculosis Referral Hospital for allowing the authors to use laboratory facilities for free. The authors also would like to acknowledge study subjects for their participation in the study. We are also very grateful to the medical Laboratory technologists for their help during sample collection.

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