Case report
A 39-year-old Caucasian man presented in 2009 with an 8-week history of fevers, night sweats, nausea, abdominal pain and distension and 5 kg weight loss. He reported no respiratory or other gastrointestinal symptoms and did not have any unwell contacts or history of overseas travel. He cared for an aviary of Gouldian finches (Erythrura gouldiae), which included cleaning and removing dead birds. There is no personal or family history of recurrent or opportunistic infections.
Three years earlier, he was diagnosed with acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG) after presenting with ptosis, dysarthria and dysphagia. A type B2 thymoma was confirmed on surgical resection and treatment with prednisolone and pyridostigmine was commenced.
In 2008, he suffered a myasthenic crisis with severe bulbar and respiratory muscle involvement necessitating a feeding tube (Myasthenia Gravis Foundation of America (MGFA) grade 4b). This improved with treatment (3-weekly plasma exchange, cyclosporine 150 mg two times per day, azathioprine 50 mg daily and prednisolone 25 mg alternate days) and he remained clinically stable until this presentation. At presentation, he had mild residual bulbar features, including dysarthria, dysphagia and fatigable chewing.
On examination, he was afebrile, and had splenomegaly, periumbilical and epigastric tenderness. There was no palpable lymphadenopathy.
Full blood examination showed haemoglobin of 111 g/L (130–170 g/L) and lymphocytes of 1.0×109/L (1.2–2.7 x 109 /L). C reactive protein was 63 mg/L.
Lymphocyte subsets, including CD4 T-cell counts, were all within normal limits except for reduced CD19 pan B-cell count at 0.03×109/L (0.05–0.41×109/L). Immunoglobulin levels were not reduced, and HIV screen was negative. Bacterial and mycobacterial blood cultures were unrevealing.
CT scan demonstrated splenomegaly (15 cm) and periaortic and mesenteric lymphadenopathy with no evidence of thymoma recurrence or residual thymic tissue. Gastroscopy showed a macroscopically abnormal duodenum with a fine, nodular appearance. Gastric and duodenal biopsies revealed broad, shortened villi (figure 1A) and marked diffuse to confluent infiltrates of histiocytes in the lamina propria. Innumerable acid-fast bacilli were seen on Ziehl-Neelsen stain (figure 1B). Mycobacterium genavense was identified on molecular sequencing, leading to a diagnosis of disseminated M. genavense infection in an immunocompromised patient. Empirical therapy with rifampicin, ethambutol, moxifloxacin and clarithromycin was started. Cyclosporine and azathioprine were discontinued and the frequency of plasma exchange was increased with sequential intravenous immunoglobulin.
Despite treatment, interval abdominal CT scan revealed progressive splenomegaly (17.8 cm) and intra-abdominal lymphadenopathy, raising concerns of refractory infection or lymphoma, as well as potential splenic rupture. Further biopsies of the mesenteric lymph nodes, stomach and duodenum demonstrated countless mycobacteria, consistent with ongoing infection. Drug sensitivities were unavailable as M. genavense could not be cultured.
Following a multidisciplinary discussion, subcutaneous interferon-gamma (IFN-γ) was trialled, resulting in substantial fever. Dose was reduced to induce only low-grade fevers and chills (25 μg three times a week). Over the next 12 months, the patient’s symptoms resolved. Repeat CT scan demonstrated a reduction in the degree of splenomegaly and intra-abdominal lymphadenopathy. Antimicrobials were slowly weaned off over 6 years and he remains well 11 years later, with controlled myasthenia.
Given the rare opportunistic infection, stored and newly collected blood samples were investigated for cytokine antibodies producing immunodeficiency. Due to ease of use and wide availability, the tuberculosis IFN-γ release assay was used to screen for reduced IFN-γ production. After incubation, a multiplex assay was used to measure cytokine production within the supernatant. The patient’s sample showed a markedly reduced IFN-γ response to mitogen stimulation compared with healthy controls (figure 1C). Moreover, the analysis also revealed a reduced concentration of interleukin-12 (IL-12).
Research-based inhibition studies showed that adding the patient’s sample to IL-12p40 resulted in inhibition of analyte recovery at sample concentrations above 1:16 (figure 1D), suggesting the presence of an IL-12p40 inhibitor. This inhibitory effect was similar to that seen with ustekinumab, a human monoclonal antibody specifically directed against the p40 subunit shared by IL-12 and IL-23. Interestingly, plasma exchange did not substantially reduce inhibition (figure 1E), suggesting that the patient had a very high inhibitor concentration.