Rapidly enlarging pulmonary mass due to immune reconstitution inflammatory syndrome (IRIS) in an immunocompetent host with pulmonary Cryptococcus neoformans

Abstract

An immunocompetent man presented with Cryptococcus neoformans disease manifesting as a large pulmonary mass (cryptococcoma). Despite an initial induction course of 4 weeks of liposomal amphotericin B (LAmB), followed by 8 weeks of fluconazole, the cryptococcoma enlarged in size. Ten days into a second course of induction therapy with LAmB and flucytosine, the cryptococcoma markedly increased in size with encroachment on critical vascular structures. Due to concern for immune reconstitution inflammatory syndrome (IRIS), prednisone was added with significant decrease in the size of the mass. To our knowledge, this is the first reported case of pulmonary cryptococcal-IRIS in an immunocompetent host.

Background

Cryptococcus neoformans and Cryptococcus gattii are encapsulated yeast found worldwide that can affect many organs, most commonly leading to pulmonary and central nervous system (CNS) infections. Pulmonary disease can manifest as nodules, infiltrates, miliary disease, pleural effusions, lymphadenopathy or mass formation in the form of a cryptococcoma.¹ C. neoformans is more often thought of as an opportunistic infection, though it can infect immunocompetent hosts. C. gattii can infect both immunocompromised and immunocompetent hosts.² A large nationwide study involving C. neoformans from Australia showed that formation of cryptococcomas in the lungs and/or brain was more common in immunocompetent than immunocompromised hosts.³

We present a case of an immunocompetent man who developed a large pulmonary cryptococcoma due to C. neoformans. Despite receiving guideline-directed therapy for severe disease in an immunocompetent host consisting of liposomal amphotericin B (LAmB) plus flucytosine,⁴ the patient developed worsening disease both symptomatically and on radiologic imaging. It was determined that he had cryptococcal immune reconstitution inflammatory syndrome (c-IRIS). This case demonstrates the challenges of diagnosis and management of c-IRIS in immunocompetent patients.

Case presentation

Initial presentation

A healthy man in his 30s with no significant medical or surgical history presented with hoarseness to an ENT clinic. He had mild dyspnoea and a non-productive cough. He did not have weight loss, night sweats, fevers or chills. He was not on any medications. He had no family history of malignancy. He lived in a rural area in the USA. He had a pet dog, but he did not recall any exposure to pigeons or birds. He worked in a water treatment facility. He often chopped large amounts of firewood. He did not smoke, rarely drank alcohol and had no illicit drug use.

Initial workup

He underwent a direct laryngoscopy, that showed left vocal cord paralysis. A neck CT showed the upper part of a mediastinal mass encasing the recurrent laryngeal nerve. A chest CT showed a 5.2×3.3 cm irregular mass within the left mediastinum and hilum encasing the left main pulmonary artery and part of the left mainstem bronchus (figure 1). Given concern for malignancy, he underwent diagnostic bronchoscopy.

Figure 1.

Timeline of treatment. CT scans are shown at various intervals along the treatment course. (A) At initial diagnosis (B) After completion of first induction course with LAmB and fluconazole (C) After second induction course with LAmB and flucytosine, CT scan shows significant worsening (D) After addition of prednisone for c-IRIS, CT showed significant improvement. c-IRIS, cryptococcal immune reconstitution inflammatory syndrome; LAmB, liposomal amphotericin B.

Initial diagnosis and treatment

An endobronchial ultrasound-guided lymph node biopsy of a subcarinal and left lower paratracheal lymph node was performed, which showed fungal organisms on Grocott-Gomori’s methenamine silver stain (GMS). The mucicarmine stain was consistent with cryptococcus, and fungal culture grew C. neoformans. No malignancy was found. Initial serum cryptococcal antigen (CrAg) titre was 1:64. He underwent a lumbar puncture: white cell count was 8 x10⁹/L, red cell count was 3x10¹²/L, glucose 63 g/dL, protein 27.8 g/dL and CrAg was negative. He was referred to an infectious disease physician who treated him as an outpatient with LAmB for 4 weeks, followed by fluconazole for 8 weeks. A CT scan after 12 weeks showed interval enlargement of the mass to at least 5.4×5.6 cm (from 5.2×3.3 cm at the same level) with invasion into the left mainstem bronchus (figure 1). The patient had mild dyspnoea and a dry nonproductive cough but was otherwise asymptomatic. Due to concern for the enlarging mass on CT scan, he was admitted to a tertiary care centre for further workup and management.

Hospital management

On admission, the patient’s temperature was 37°C, heart rate 83, beats/min, respiratory rate 18/min, blood pressure 128/68, mm Hg, oxygen saturation 99% on room air. On examination, he was well-appearing. Inspiratory wheeze was heard anteriorly in the left upper lung field. Cardiac and abdominal exams were normal. There was no lower extremity oedema. No rashes were noted. The white blood cell count was 8.4 K/µL with a normal differential, haemoglobin 101 g/L, platelets 242 x10⁹/L. Basic metabolic panel and liver function tests were within normal limits.

A CT angiography of the chest showed the mass, stable in appearance from the recent CT chest, as well as intravascular invasion into the left interlobar pulmonary artery. On hospital day 3, he was started on another course of induction therapy with L-AmB and flucytosine. On hospital day 13, a repeat CT scan showed an increased size of the mass with new clustered nodules in the left upper and lower lobes, as well as enlarging lymph nodes (figure 1). The case was discussed with thoracic surgery, who did not feel that it was operable without significant risk of morbidity and mortality.

Investigations

An extensive immunological workup was conducted with the help of the allergy and immunology consulting team. An HIV antigen/antibody test was negative. A CD4 count was 581 cells/ul, with a CD4/8 ratio of 2.53. Flow cytometry for leukaemia/lymphoma was negative, and T-cell rearrangement was negative for T-cell lymphoproliferative disorder. Immunoglobulins IgA, IgM, IgG (subclasses 1–4), and IgE were within normal limits. An SPEP and free kappa/lambda ratio were normal.

On the first day of hospitalisation, a serum cryptococcal antigen (CrAg) was negative. On hospital day 14, a serum CrAg was positive at 1:320. Cerebrospinal fluid (CSF) analysis was not repeated.

Differential diagnosis

We considered a number of possibilities to explain why the pulmonary cryptococcoma was enlarging on appropriate therapy. The differential included: (1) Alternative diagnosis (eg, malignancy or other infection); (2) Cryptococcus resistant to current antifungal therapy; (3) Inadequate penetration of the antifungals due to large size of mass and (4) IRIS-like reaction in an immunocompetent host. Non-adherence to therapy was not an issue, especially since he significantly worsened on observed therapy in the hospital. We review these options in turn:

Alternative diagnosis

In the literature, there have been cases of co-occurring pulmonary cryptococcosis and lung adenocarcinoma.^{5 6} A repeat ultrasound-guided endobronchial biopsy of the left paratracheal mass performed on hospital day 8 confirmed the diagnosis of Cryptococcus without evidence of malignancy or other infection (figure 2).

Figure 2.

Histopathological stains of lung tissue from an endobronchial biopsy obtained 8 days after L-AmB and flucytosine were started during hospitalisation. The histopathology shows granulomatous and suppurative inflammation, with abundant histiocytes, lymphocytes and neutrophils. (A) H&E stain at low power; (B) Periodic acid-Schiff (PAS) stain at low power; (C) Mucicarmine stain of a different field at low power; (D) PAS stain at medium power. L-AmB, liposomal amphotericin B; PAS, periodic acid-schiff.

Antifungal resistance

According to a recent review, of the three currently available antifungal therapies for Cryptococcus, there is rare resistance to amphotericin, some resistance to flucytosine (which is why it is only used as an additive agent), and recently increasing resistance to fluconazole.⁷ The original cultures were not sent out for sensitivity testing and were no longer available. Fluconazole was transiently added but discontinued after 1 day. We thought that resistance to first-line combination therapy was unlikely.

Inadequate antifungal penetration

We considered that the cryptococcoma may have been too large for antimicrobial treatment alone and explored the possibility of debulking surgery. In a retrospective study of 53 immunocompetent patients with pulmonary cryptococcomas, some patients were diagnosed only after complete surgical resection of the cryptococcoma and had good outcomes without further antifungal treatment.⁸ In one case report of fatal CNS cryptococcus in a man with HIV, the authors proposed that the organism’s propensity for vascular invasion led to infarct (as seen on autopsy specimens), which in turn may have led to poor penetration of antifungals to the infected area.⁹ Given the size of the mass in our patient, it is possible that antifungal delivery was compromised. Continued discussions with thoracic surgery were pursued, but due to invasion of the pulmonary artery, the surgical team felt it was unsafe to operate.

IRIS-like reaction in an immunocompetent host

This was a diagnosis of exclusion. Due to the rapidity of radiologic worsening when reinduction therapy was started, an IRIS-like reaction was thought to be the most likely cause of the radiographic worsening of disease. The addition of steroids was considered.

Treatment

On hospital day 14, the patient was started on a 2-day course of methylprednisolone 40 mg intravenous then was switched to prednisone 60 mg/day for 6 more days. LAmB and flucytosine were continued throughout this course.

Outcome and follow-up

On hospital day 20 (day 7 of steroids), the patient had a follow-up CT scan that showed significant improvement in the size of the cryptococcoma (figure 1). He was discharged on LAmB and flucytosine, with a plan to complete a 6-week course as well as a 4-week prednisone taper. After completion of 6 weeks of LAmB and flucytosine, the serum CrAg was 1:64, and he was switched to fluconazole 400 mg orally daily for 1 year. Nine months after switching to fluconazole, his serum CrAg was negative. At 1 year, the fluconazole dose was reduced to 200 mg/day and a serum CrAg turned positive with peak titres of 1:8; fluconazole dose was increased to 400 mg/day. After 1 month on fluconazole 400 mg/d, CrAg titres became negative. He has been followed with chest CT and CrAg every 6 months. A CT chest from 3.5 years after his initial diagnosis shows a stable 4–5 mm irregular pulmonary nodule in the medial left upper lobe, with otherwise clear lungs. He has remained on fluconazole 400 mg/day.

Discussion

This case highlights a unique presentation of a large pulmonary cryptococcoma in an immunocompetent host, which was further complicated by a paradoxical IRIS reaction in the setting of antifungal therapy. In immunocompetent hosts, pulmonary cryptococcus more typically presents as asymptomatic pulmonary nodules with incidental diagnosis made on imaging studies.^{10 11} Fluconazole alone is recommended for mild-moderate disease,⁴ and a short course of azole therapy for 3–6 months is often adequate.¹¹ In contrast, our patient presented with a large mass. Large pulmonary cryptococcomas in immunocompetent hosts are rare and can occasionally resemble lung cancer as reported in another patient who had well-controlled diabetes and presented with an 8.5 cm LUL mass which resolved with a 6-month course of fluconazole¹²; no IRIS presentation was described. We were unable to diagnose an underlying immunocompromised state in our patient and we speculate that he may had a high-volume initial exposure due to his job at a water treatment plant where it is possible that there was aerosolisation of bird droppings. There is some literature to suggest that some persons have a genetic predisposition to cryptococcal disease,^{13 14} but our patient was not able to undergo further genetic testing. Interestingly, our patient continues to have a pulmonary nodule on chest CT after >3 years of antifungal therapy and it is unclear if this is residual cryptococcal disease; the patient and the treating ID physician are hesitant to stop the fluconazole therapy given concerns for potential relapse.

c-IRIS, particularly in the CNS, is well described in immunocompromised hosts, most notably in patients with HIV or who are otherwise immunosuppressed such as in patients with solid-organ transplants. In immunocompetent patients, there have been several case reports describing cryptococcal IRIS in the central nervous system. Our case represents the first report in the literature of an immunocompetent patient with pulmonary c-IRIS. Interestingly, in our patient and the previously reported patient with a large pulmonary cryptococccoma,¹² there were a paucity of pulmonary complaints, suggesting that within the lungs, c-IRIS is better tolerated compared with the CNS. It is possible that in contrast to the closed space of the CNS where inflammation from IRIS can lead to life-threatening herniation, the lungs represent a relatively open space which might more readily accommodate a large mass or a secondary inflammatory response.

In patients with HIV and low CD4 counts who are starting antiretroviral treatment (ART), the proposed mechanism of IRIS is that with reconstitution of the host immune response as evidenced by CD4 recovery, excess inflammation occurs in areas with opportunistic infections such as cryptococcus.¹⁵ In patients with generally advanced AIDS who have known cryptococcal disease and are started on ART, the timing of paradoxical c-IRIS is highly variable—with reports ranging from 4 days to 3 years, with a median of 1–10 months after ART initiation.¹⁶ Given concern for IRIS, the NIH/DHHS guidelines recommend delaying ART initiation in persons with HIV for at least 2 and up to 10 weeks after treatment initiation for cryptococcal meningitis.¹⁷

The 2010 Infectious Disease Society (IDSA) guidelines for Cryptococcus treatment mention the possibility of IRIS in immunocompetent hosts and give general recommendations for patients with c-IRIS.⁴ For patients with major CNS or pulmonary complications attributed to IRIS, these guidelines recommend considering corticosteroids with a range of acceptable dosages of 0.5–1.0 mg/kg/day of prednisone equivalent, or possibly higher doses of dexamethasone for more severe disease. The IDSA recommends continuation of antifungals and does not give definitive recommendations for the course of steroids, suggesting that 2–6 weeks of steroids is reasonable to start.

The mechanisms of IRIS in immunocompetent hosts are less clear, however the effects of cryptococcus itself on the immune system may account for the phenomenon of IRIS in otherwise immunocompetent hosts. Cryptococcus has been shown to interfere with both the innate and adaptive immune system, with effects on dendritic cells, macrophages, phagocytes, neutrophils and T-cells.¹⁸ One immunological study showed decreased Th1 and Th17 responses in the lungs of mice infected with C. gattii.¹⁹ Based on this evidence, it is possible that there is local downregulation of the immune system in areas of infection with cryptococcus. It could be hypothesised that killing cryptococcus can lead to local reconstitution of the immune system at infected sites.

Table 1 outlines cases reported in the literature of c-IRIS in immunocompetent hosts.^20–30 Notably, while some of these cases describe patients initially with both CNS and pulmonary manifestations of cryptococcus, all describe IRIS in the setting of CNS disease. In several cases, there were difficulties with initial diagnosis of CNS IRIS—for example, some patients with ventricular drains were empirically treated for superimposed bacterial meningitis.^{20 23} In at least one patient, anticryptococcal treatment was reintensified before the diagnosis of IRIS.²⁴ Timing of initial IRIS diagnosis ranged from 2 weeks to over 2 months. All cases except for one showed clinical improvement with steroids—in this case the patient did not improve with steroids and only improved after adding thalidomide.²³ In all cases where treatment was described, antifungal treatment was continued along with steroids when IRIS was identified. Several of the cases described recurrent IRIS when steroids were weaned or stopped,21 22 27 28 with improvement after increasing steroid doses. In one of these cases there were five recurrences of IRIS noted over 12 months.²² There was a wide range in steroid doses used and duration of treatment with steroids. Based on the current guidelines and case reports, steroids are recommended but the dose and duration are not clear, and often seems to be tailored to patients’ clinical responses in real time. None of these cases identified pulmonary c-IRIS, highlighting the uniqueness of our case.

Table 1.

Cases in the literature of Cryptococcus iris in immunocompetent hosts

Case	Species	Age/sex	Initial disease	Initial treatment	IRIS manifestation	IRIS timing	IRIS treatment	Outcome
Kathiresu20	Cryptococcus neoformans	41 F	Meningitis, pulmonary cryptococcoma	LAmB +flucytosine → fluconazole	Fever, worsening vision, confusion, headache	7 weeks	Intravenous steroids+oral prednisolone	Survived, legally blind
Tanu21	C. Neoformans var. grubii	34 M	Meningitis	LAmB +flucytosine (2 weeks) → fluconazole (2 weeks) → LAmB +flucytosine (2 weeks) → LAmB alone	Headaches, vomiting, imbalance	8 weeks	Dexamethasone 12 mg/day (tapered over 1 month, worsened after stopping → slower 3 months taper).	Survived
O’Brien22	Cryptococcus gattii	13 M	Meningitis, possible CNS cryptococcoma	LAmB +flucytosine	Severe headaches, fever	5 weeks	Oral prednisolone 50 everyday; 5 IRIS relapses in 12 months whenever steroids weaned—on steroids 20 months	Survived, no neurological sequealae
	C. Gattii	11M	Meningitis, pulmonary cryptococcoma	LAmB +flucytosine (6 weeks) → fluconazole	Headaches, fever, vision changes	10 weeks	Intravenous methylprednisolone (4 days) → prednisolone 50 mg x 2 weeks→ 8 month taper	Survived, no long-term neuro sequelae
	C. Gattii	8M	Meningitis, CNS cryptococcomas; pulmonary cryptococcoma	LAmB +flucytosine (6 weeks) → fluconazole	Fever, seizures, decreased consciousness	5 weeks	Dexamethasone PO 8 mg two times daily × 3 days → prednisolone 32 mg x 3 weeks. Steroids weaned over 6 months	Survived, severe visual impairment due to optic atrophy
Somerville23	C. Neoformans	36W	Meningitis, CNS cryptococcoma	LAmB +flucytosine	Fever, headache, vomiting, agitation	3–5 weeks	Dexamethasone (no improvement) thalidomide added (improved within 3–7 days)—both weaned over 1 month	Survived, neuro deficits—R leg spasticity
Kulkarni24	C. Neoformans var. grubii	61M	Meningitis	L-Amb +flucytosine	Headache, hearing loss, disorientation, confusion	2 weeks	Prednisolone 1 mg/kg/day—tapered over 2 months	Survived
Andreou25	C. Gattii	31F	Meningitis, CNS cryptococcomas, pulmonary cryptococcoma	LAmB +flucytosine (2 days) → L-AmB +fluconazole → fluconazole → LAmB +vori (week 12)	Neurological deterioration	13 weeks	High-dose steroids 0.5 mg/kg two times daily x2 days → 0.5 mg/kg/day oral prednisolone x4 weeks (weaned over 5 months)	Survived, no neurological deficits
Chen26	C. Gattii	? 5 patients	N/A	N/A	N/A	N/A	N/A	N/A
Panackal27	C. Neoformans	58M	Meningitis	LAmB +flucytosine (2 months) → trial of recombinant interferon-gamma (IFN-gamma) 1b (10 days)	Worsening mental status with hypersomnolence	~8–10 weeks	Stopped IFN-gamma, started prednisone 1 mg/kg/day	Survived, severe neuro sequelae (blind, deaf, gait disturbance, urinary retention)
	C. Gattii	46F	Meningitis, CNS cryptococcomas, pulmonary cryptococcoma	LAmB +flucytosine + prednisone 50 (steroids stopped day 24)	Deterioration requiring intensive care unit (ICU)	Day 34	Dexamethasone equivalent to pred 50 (tapered over 8 months)	Survived, some residual memory deficits
Lane28	C. Gattii	29M	Meningitis, possible pneumonia	Amphotericin B+flucytosine (2 weeks) → fluconazole	Headaches, photophobia, fevers, ataxia	5 weeks	Dexamethasone 4 mg q6h (2 wks) → recurrence after weaning → pred 25 (8 wks)	Survived, asymptomatic
Einsiedel29	C. Gattii	18F	Meningitis, central nervous system (CNS) cryptococcomas	Amphotericin B+flucytosine	Fever, worsening meningitis	1–2 months	?	Survived, severe visual impairment
Phillips30	C. Gattii	40F	Meningitis±CNS cryptococcoma	Ampho B+flucytosine	n/a	31 days	Dexamethasone	Improved neurological symptoms
		46F				43 days
		63M				37 days
		62M				26 days

F, female; IRIS, immune reconstitution inflammatory syndrome; LAmB, liposomal amphotericin B; M, male; N/A, not available.

Patient’s perspective.

All things considered, I think I am pretty lucky. When I first experienced the symptoms, I thought I had a bad cold. Then, possibly walking pneumonia. After discovering there was a tumour growing in my chest, a doctor told me he was 99% sure it was lung cancer. A cryptococcus neoformans infection is a better situation than lung cancer. I was also told some people have a hard time tolerating liposomal amphotericin B treatments. But in my experience, it wasn’t too bad. Lastly, I knew the doctors and nurses were worried about my recovery and mortality when seeing that the mass increased in size after the antifungal IV treatments when it should have done the opposite. It has been about 5 years since that all began. They saved my life and I am grateful for that. I feel good and periodic testing shows that the mass hasn’t changed and I am otherwise healthy.

Learning points.

• Cryptococcal immune reconstitution inflammatory syndrome (c-IRIS) can occur even in immunocompetent hosts but has more often been described in the CNS than in the lungs.

• Isolated pulmonary cryptococcal disease can occur in immunocompetent hosts and may resolve without specific antifungal treatment. However, if a patient with pulmonary cryptococcoma undergoes antifungal treatment and demonstrates radiologic worsening on treatment, consider the possibility of c-IRIS.

• Steroids are indicated in treating c-IRIS, but the recommended dose and duration are not known and must be tailored based on clinical response.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).