Cryptococcal pneumonia in an adolescent with a gain-of-function variant in signal transduction and activator of transcription 1 (STAT1)

Background

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which plays a key role in mediating cellular responses to interferon (IFN) signalling. In 2011, gain-of-function (GOF) mutations in STAT1 were found to be the cause of nearly half of all cases of chronic mucocutaneous candidiasis (CMC).1 2 Since then, our understanding of the clinical spectrum of STAT1 GOF has broadened; in addition to CMC in 98% of patients, STAT1 GOF has also been found to be associated with autoimmune conditions, recurrent bacterial and viral infections, and rarely, fungal infections.3

Cryptococcus is an opportunistic fungal pathogen that is found ubiquitously in the environment manifests as pneumonia or meningitis in individuals with impaired T cell function. To the best of our knowledge, just 10 cases of Cryptococcus, including 5 with cryptococcal pneumonia have been reported in individuals with STAT1 GOF to date.3–7 Herein, we report a case of a patient with a known STAT1 GOF variant presenting with cryptococcal pneumonia and perihilar adenitis and a history of autoimmune enteropathy, autoimmune hypothyroidism, aphthous stomatitis and recurrent oral Candida infections occurring only in the setting of curative antibiotic courses.

Case presentation

The patient is a 17-year-old young man with a history of recurrent otitis media and viral and bacterial pneumonia since 4 months of age, leading to development of progressive bronchiectasis. He had six episodes of otitis media by 9 months of age, and averaged two to three episodes of pneumonia per year, with infectious agents identified in respiratory isolates including Pneumocystis jiroveci, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus, in addition to common bacterial organisms.

The patient’s course was further complicated by seven episodes of oral candidiasis and one episode of candidal esophagitis, each of which occurred in the setting of recent curative antibiotic courses and responded to treatment with nystatin or fluconazole. The patient had onset of autoimmune enteropathy at age 4 years, associated with chronic diarrhoea and complicated by separate episodes of cytomegalovirus (CMV) colitis and Clostridium difficile infection at age 7 years. He was diagnosed with autoimmune hypothyroidism at age 6 years, based on positive thyroid peroxidase antibodies and manifesting primarily with a lack of linear growth (tracking at the second percentile). His medical history was otherwise complicated by sinusitis, myositis, several episodes of aphthous stomatitis, varicella zoster infection, recurrent impetigo and chronic nasal congestion.

The patient presented to our institution with a 1-week history of a cough and worsening haemoptysis, prompting further workup. At the time of presentation, the patient had been receiving intravenous immunoglobulin therapy and weekly prophylactic azithromycin and trimethoprim–sulfamethoxazole.

Investigations

The patient’s chest CT revealed infiltrate in the lingula suggestive of infection, in addition to bilateral hilar adenopathy (figures 1–3). Bronchoscopy with bronchoalveolar fluid culture revealed Cryptococcus neoformans on fungal culture. Left hilar mediastinal lymph node biopsy was performed, revealing caseating necrosis, granulomatous inflammation and the presence of fungal yeast forms highlighted on mucicarmine stain within the lymph node (figures 4 and 5). Serum cryptococcal antigen titre by lateral flow assay was ≥1:2560. Cerebrospinal fluid cryptococcal antigen was negative. Based on characteristic microscopic and serological findings, the patient was diagnosed with cryptococcal pneumonia. In light of the patient’s history of recurrent infections, immunological investigations were undertaken at 3 years of age, suggesting a primary immunodeficiency of unclear aetiology, with findings significant for an IgA level of 2 mg/dL (reference range 27–246 mg/dL) consistent with complete IgA deficiency, and functional antibody deficiency with abnormally low tetanus, diphtheria and Streptococcus pneumonia titres despite vaccination. Investigations for adenosine deaminase deficiency, alpha-1-antitrypsin deficiency, hyper-IgM syndrome, leucocyte adhesion deficiency, complement deficiencies, cystic fibrosis and coeliac disease were all negative. The patient also had normal T cell function by cellular proliferation studies, and normal neutrophil oxidative burst ruling out chronic granulomatous disease. Flow cytometric analysis was notable for natural killer (NK) cell lymphopenia (35 cells/μL; reference range 69–691 cells/μL), a reduction in total memory B cells (1.3% of B cells, reference range 4.6%–49% of B cells) related to substantially reduced class-switched memory B cells (0.3% of B cells; reference range 1.9%–30.4%), complete absence of IgM-only memory B cells (reference range 0.3%–13.1%), normal total B cells (reference range 92–792 cells/μL) and mildly reduced CD3+ (857 cells/μL; reference range 865–3618 cells/μL) and CD4+ T cells (432 cells/μL; reference range 497–2267 cells/μL).

Figure 1

Coronal chest CT demonstrating bilateral hilar adenopathy, worse on the left, causing compression of central airways.

Figure 2

Axial chest CT demonstrating consolidation and volume loss within the lingula (arrow).

Figure 3

Axial chest CT demonstrating bilateral hilar adenopathy, worse on the left (arrow), causing compression of central airways.

Figure 4

Perihilar lymph node fine needle aspiration (H&E stain, ×400) depicting numerous cryptococcal yeast forms (arrows) and caseating necrosis.

Figure 5

Perihilar lymph node fine needle aspiration (mucicarmine stain, ×400) depicting numerous cryptococcal yeast forms (arrows).

At the time of presentation with cryptococcal pneumonia, a research-based whole exome analysis was performed, identifying a previously reported heterozygous pathogenic variant in STAT1 (c.1154C>pThr385 Met; Lal et al, manuscript in preparation), which was confirmed by Sanger sequencing.8–12 Though functional studies were not performed, the patient was presumed to have STAT1 GOF based on the identification of a genetic variant previously shown to be associated with GOF and a compatible clinical phenotype.

Differential diagnosis

Phenotypic presentations associated with STAT1 GOF variants are heterogeneous and have significant overlap with common variable immune deficiency (CVID) or combined immunodeficiency (CID). At the time initial immunological investigations were undertaken, GOF of STAT1 was not yet a known cause of disease. CID is defined by the European Society for Immunodeficiencies (ESID) by the fulfilment of at least one of the following criteria: at least one severe infection, manifestation of immune dysregulation, malignancy and having an affected family member. In addition, two of the following criteria must be met: reduced CD3, CD4 or CD8 T cells, reduced naïve CD4 and/or CD8 T cells, elevated g/d T cells and reduced proliferation to mitogen or T-cell receptor (TCR) stimulation.13 This patient had a CID phenotype with multiple severe infections requiring hospitalisation, autoimmune enteropathy and hypothyroidism, reduced CD4 T cells, and relatively low naïve CD4 T cells. CVID is defined by the ESID by the presence of a marked reduction in IgG and IgA levels, exclusion of secondary causes of hypogammaglobulinaemia, either poor antibody response to vaccines or low memory B cells, and fulfilment of at least one of the following criteria: increased susceptibility to infection, autoimmune conditions, granulomatous disease, unexplained polyclonal lymphoproliferation and the presence of affected family members with antibody deficiency.13 Though this patient had complete IgA deficiency, evidence of functional antibody deficiency and T cell lymphopenia, he did not meet diagnostic criteria for CVID because of his normal total IgG.14

Since the discovery of the significance of GOF of STAT1 in 2011, several studies characterised the clinical and immunological features associated with this disease. The largest cohort described to date reported CMC in 98% of cases, bacterial infections in 74% and autoimmune manifestations in 37%, with the most common being thyroid disease. About 1% of cases have been reported with autoimmune gastrointestinal involvement.3 While our patient had recurrent bacterial infections, autoimmune hypothyroidism and recurrent oral candidiasis as observed in other STAT1 GOF patients, he also had several atypical manifestations, including occurrence of Candida infections only in the setting of curative antibiotic courses, in addition to the presence of cryptococcal pneumonia and autoimmune enteropathy.

Despite this atypical presentation, genetic investigation ultimately facilitated the diagnosis of STAT1 GOF after a diagnostic odyssey of approximately 14 years. This case suggests that STAT1 GOF variants may underlie the aetiology of a subset of patients with a diagnosis of CVID, CID or unknown primary immunodeficiency, and in this era of easier accessibility to genetic testing, may have shorter time to diagnosis and effective and personalised therapy.

Treatment

On day 10 of a planned 14-day course of amphotericin B liposomal and flucytosine, the patient developed acute kidney injury and was therefore transitioned earlier than anticipated to a 2-month course of high-dose fluconazole at 800 mg once daily (12 mg/kg/dose). One month into therapy, his serum cryptococcal antigen titre had dropped to 1:640. His cough and haemoptysis resolved. He was then continued on prophylactic fluconazole 200 mg daily indefinitely. Eleven months later, repeat chest CT showed near-complete resolution of mediastinal and hilar adenopathy, as well as decrease in nodular consolidation in the lingula.

Because of the patient’s recurrent infections and quantitative and functional immunological anomalies, he was initiated as a child on long-term intravenous immunoglobulin therapy and weekly prophylactic azithromycin and trimethoprim–sulfamethoxazole. With the new diagnosis of STAT1 GOF, the patient will be initiated on a trial of ruxolotinib, a Janus kinase inhibitor which has been shown to restore immune defects and address autoimmune conditions in some patients in whom immunosuppressive regimens have failed.6 15–17

Outcome and follow-up

The patient continues on prophylactic fluconazole therapy and at 6-month follow-up is clinically doing well.

We are still fighting for insurance authorisation for ruxolotinib.