Journal Mobile

Author(s): 

Chuan Huan Chuah1, Yu Chen Ong2, Boon Huei Kong2, Yen Yen Woo3, Peng Shyan Wong4, Kar Nim Leong4, Ting Soo Chow4

Author Affiliations: 

1Infectious Diseases Physician, Hospital Pulau Pinang, Ministry of Health Malaysia, Penang, Malaysia; 2Nephrologist, Hospital Pulau Pinang, Ministry of Health Malaysia, Penang, Malaysia; 3Microbiologist, Hospital Pulau Pinang, Ministry of Health Malaysia, Penang, Malaysia; 4Infectious Diseases Consultant, Hospital Pulau Pinang, Ministry of Health Malaysia, Penang, Malaysia

Correspondence to: 

Dr Chuan Huan Chuah, Department of Internal Medicine, Hospital Pulau Pinang, Jalan Residensi, Georgetown, Penang, Malaysia

Email:
chchuah7@yahoo.com

Journal Issue: 
Volume 50: Issue 2: 2020
Cite paper as: 
J R Coll Physicians Edinb 2020; 50: 138–40

Introduction

Invasive fungal infections have become increasingly common during the last two decades. This is attributed to the increase of chemotherapy, bone marrow transplantation, immunosuppressive agents, invasive catheters and AIDS. As a result, there is a gradual rise of a rare fungal infection among patients in these high risk groups. Talaromycosis, caused by Talaromyces marneffei, is the third most common opportunistic infection in HIV-infected Southeast Asian patients.However, it is rare to find non-marneffei infection among non-HIV patients. While most cases reported in the literature describe infection in the lungs, we report an extremely rare Talaromyces species infection in the central nervous system confirmed by CSF culture.

Case presentation

A 61-year-old male with end-stage renal disease on regular haemodialysis was unwell for the previous two months. He presented to Pulau Pinang hospital with fever and altered mental state associated with neck pain for three days. On examination, he was confused and his Glasgow Coma Scale (GCS) score was E3 V5 M5. Neck stiffness and a positive Kernig’s sign were present. Other neurological signs were normal. On the first day, the patient went into septic shock requiring inotropic support. He was treated for meningoencephalitis with IV ceftriaxone and IV acyclovir.

Initial blood investigations showed a white blood cell (WBC) count of 13.8 (neutrophil 92.1%) and a high C-reactive protein (CRP) count of 304.1 mg/l. A CT of the brain showed a minimal right parasagittal subarachnoid bleed and cerebral atrophy. Lumbar puncture performed on the second day revealed a high opening pressure of 45cmH2O. The CSF cell count could not be interpreted due to blood staining. CSF biochemistry was suggestive of meningitis (CSF protein 1.42g/l, CSF/serum glucose ratio 39%). The CSF gram stain was negative for organisms and pus cells. After 48 hours’ incubation on Sabouraud dextrose agar (SDA) plate, fungal growth was present. IV amphotericin B was started immediately.

After two days of amphotericin B treatment, the repeated lumbar puncture showed normal opening pressure and improving CSF biochemistry. There was no CSF and blood fungal culture growth after that. A total of five aerobic blood cultures and one fungal blood culture were sent for analysis. Only the first blood culture taken on the day of admission grew Group B Streptococcus (GBS). HIV test was non-reactive. CSF bacterial antigen detection was negative for GBS and other common organisms. CSF for bacterial culture and mycobacterium tuberculosis culture showed no growth. CSF fungal polymerase chain reaction (PCR) later showed Penicillium chrysogenum. Fungal meningitis was diagnosed with superimposed GBS sepsis.

After three days of antifungal therapy, the patient’s consciousness level improved. He was orientated and able to follow instructions. The fever resolved and the inotrope was discontinued. The patient was well and ambulatory. The treatment with amphoterin B was continued for two weeks, followed by oral suspension of 200 mg itraconazole daily for another four weeks. The patient was discharged after IV treatment with amphotericin B was completed. He was well upon discharge and was scheduled for a follow-up in the Infectious Diseases clinic after one month. However, he died of unknown causes at home two weeks later.

Mycological examination

Talaromyces species are found worldwide and are potential mycotoxin producers. The initial gram stain of the CSF was negative for organisms and pus cells. The colonies grew after three days’ incubation on the Sabouraud dextrose agar (SDA) plate (Figure 1). The surface of the colony was powdery with a bluish-green border. The reverse was white. No diffusible pigment was seen. Microscopic examination of the lactophenol cotton blue stain showed the presence of hyphae with conidiophores that have secondary branches known as metulae (Figure 2). On the metulae there were flask-shaped phialides that bore round conidia. The entire structure formed the characteristic ‘brush’ appearance. These features were consistent with Talaromyces species.

Figure 1 Two colonies of Talaromyces species grew on the inoculated Sabouraud dextrose agar (SDA) plate. The small white colonies seen on top were due to contamination.

Figure 2 Microscopic view of Talaromyces species showing hyphae with conidiophores, and the characteristic ‘brush’ appearance.

Discussion

Invasive disease due to Talaromyces species other than T. marneffei is uncommon. Over the last 50 years, a total of 34 cases of invasive infection have been described in the literature, many of which were in non-immunocompromised patients.2 There have been descriptions of lung infection, endocarditis, peritonitis in continuous ambulatory peritoneal dialysis (CAPD), urinary tract infection, endophthalmitis, oesophagitis and intracranial infection. In contrast to other sites of infection, infection in the central nervous system is very rare. To date, there have been only four cases of intracranial infection reported for non-marneffei Penicillium infection.3 Two of them were in immunocompromised patients. The outcome was poor as none of them survived.

In the first case, reported in 1963, intracranial Penicillium infection followed primary lung involvement in a patient with acute leukaemia. No treatment was given. Diagnosis was made after autopsy.4 In the second case, reported in 1970, intracranial infection was the result of local spread from primary orbital-sinus infection causing a mycotic cerebral aneurysm. The patient died despite surgery and treatment with amphotericin B.5 In the third case, reported in 2002, intracranial infection was reported in a non-immunocompromised middle-aged Pakistani patient. Diagnosis was delayed as brain biopsy was done six weeks after admission. The patient died despite being treated with amphotericin and flucytosine.2 In Brazil, a fourth case was reported in 2005 with multiple brain abscess due to Penicillium species infection in a patient with Child-Pugh C liver cirrhosis.3 The patient was treated with amphotericin B and showed gradual improvement. However, he later died from oesophageal variceal bleeding.

Talaromyces species is far more commonly associated with superficial infections e.g. dermatitis and onychomycosis, and allergic diseases e.g. asthma and hypersensitivity pneumonitis. Several types of occupational hypersensitivity pneumonitis attributable to Talaromyces species are cheese worker’s lung,6 salami worker’s lung7 and malt worker’s lung.8 However, non-marneffei species are being increasingly recognised as emerging opportunistic pathogens causing invasive fungal infections worldwide, with most reports involving P. citrinum, P. digitatum, and P. chrysogenum.9 Among the 34 invasive cases reported, nine occurred in immunocompromised patients and 25 in patients not known to be immunocompromised.2 It appears that this infection can occur in both immunocompromised and immunocompetent patients.

End-stage renal disease is a well-recognized immunocompromised state leading to serious infections. Infection is just second to cardiovascular disease as the leading cause of death in patients with end-stage renal disease.10 Among dialysis patients, the most common fungal infection is candidiasis (79%), followed by cryptococcosis (6.0%) and coccidioidomycosis (4.1%).11 Uraemia is associated with a state of immune dysfunction characterised by immunodepression that contributes to the high prevalence of infections among these patients.12 In addition, fungal infections may occur after a broad-spectrum antibiotic prescription.13

P. chrysogenum, which was discovered by Alexander Fleming in 1929, has been cited as an emerging pathogen.14 These organisms are ubiquitous in nature and can be found in soil, decaying matter, sewage plantations, and construction sites. Our patient, who previously worked as a renovation contractor, may have been at risk. In this case, the fungal growth was significant, both inoculated sites on SDA grew the same colonies, there was no bacterial growth in CSF, bacterial antigen detection was negative for Group B Streptococcus and other common organisms, and at the same time there was no other SDA plates growing Talaromyces species in the laboratory to suggest contamination.

Standard treatment for non-marneffei species is not well established. Treatment with amphotericin B, flucytosine, and azoles has been described in the literature. However, treatment with amphotericin B and surgery failed to prevent death in all intracranial infection cases treated to date. Consistent with the previous experience, our patient did not survive despite early treatment. In a recent study of 118 clinical isolates, mainly from respiratory tract and bronchoalveolar lavage, terbinafine and echinocandins showed the best in vitro activity against Talaromyces species.15 More data on responses to therapy is required before recommendations can be made.

Conclusion

This case highlights a rare but life-threatening fungal meningitis. Based on the reported cases of intracranial Talaromyces species infection, the prognosis is poor, and it can occur in both immunocompromised and immunocompetent hosts. More data is needed to recommend treatment.

Acknowledgements

 

The authors would like to thank the Director General of Health, Malaysia for his permission to publish this article. The authors would also like to thank the State Health Director of Penang, Malaysia and Director of Hospital Pulau Pinang, Penang, Malaysia.

References

1 Zainudin, LD, Raja Shariff RE, Hanafiah M et al. Disseminated penicilliosis (non-Penicillium marneffei) in an immuno-competent individual in Malaysia. Proc Singapore Healthcare 2018; 27: 132–135.

2 Lyratzopoulos G, Ellis M, Nerringer R et al. Invasive infection due to Penicillium species other than P. marneffeiJ Infect 2002; 45: 184–195.

3 Noritomi DT, Bub GL, Beer I et al. Multiple brain abscesses due to Penicillium spp. infection. Rev Inst Med Trop Sao Paolo 2005; 47: 167–70.

4 Huang SN, Harris LS. Acute disseminated penicilliosis: report of a case and review of pertinent literature. Am J of Clin Pathol 1963; 39: 167–174.

5 Morriss FH Jr, Spock A, Durham N. Intracranial aneurysm secondary to mycotic orbital and sinus infections. Am J Dis Child 1970; 119: 357–62.

6 Dahl S, Mortensen JT, Rasmussen K. Cheese-packers’ disease- respiratory complaints at a cheese-packing dairy. Ugeskr Laeger 1994; 156: 5862–5.

7 Rivero MG, Basile LM, Salvatore AJ et al. Pulmon del sopleteador de salamines. Medicina (Buenos Aires) 1999; 59: 367–9.

8 Blyth W, Grant IW, Blackadder ES et al. Fungal antigens as a source of sensitization and respiratory diseases in Scottish maltworkers. Clin Allergy 1977; 7: 549–62.

9 Ramírez I, Hidrón A, Cardona R. Successful treatment of pulmonary invasive fungal infection by Penicillium non-marneffei in lymphoblastic lymphoma: case report and literature review. Clin Case Rep 2018; 6: 1153–7.

10 Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 2000; 58: 1758–64.

11 Abott KC, Hypolite I. Hospitalizations for fungal infections after initiation of chronic dialysis in the United States. Nephron 2001; 89: 426–32.

12 Kato S, Chmielewski M, Honda H et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008; 3: 1526–1533.

13 Davenport A, Wellsted D. Does antifungal prophylaxis with daily oral fluconazole reduce the risk of fungal peritonitis in peritoneal dialysis patients? The Pan Thames Renal Audit. Blood Purif 2011; 32: 181–5.

14 Geltner C, Lass-Flörl C, Bonatti H et al. Invasive pulmonary mycosis due to Penicillium chrysogenum: a new invasive pathogen. Transplantation 2013; 95: e21–3.

15 Guevara-Suarez M, Sutton DA, Cano-Liraet JF et al. Identification and antifungal susceptibility of Penicillium-like fungi from clinical samples in the USA. J Clin Microbiol 2016; 54: 2155–61.

Talaromycosis typically occurs as an opportunistic infection among immunocompromised individuals. Infection caused by species other than T. marneffei is uncommon. While most reported cases describe infection in the lungs, we report an extremely rare intracranial Talaromyces species infection. This 61-year-old with end-stage renal disease who was unwell for the previous two months, presented with fever and worsening confusion lasting for three days. Lumbar puncture was suggestive of meningitis. Cerebrospinal fluid (CSF) culture was later confirmed to be Penicillium chrysogenum. The patient was co-infected with Group B Streptococcus sepsis. He improved with amphotericin B and ceftriaxone and was discharged with oral itraconazole for four weeks. However, he died of unknown causes two weeks later at home. Talaromyces species infection in the central nervous system is uncommon. This case highlighted a rare but life-threatening fungal meningitis. Among the four reported cases worldwide, none of the patients survived.

Financial and Competing Interests: 
No conflict of interests declared