A 71-year-old female, originally from Thailand, presented with fatigue, weight loss (8-10 kg), 3-4 daily loose stools, night sweats, and recurring fever. She had a medical history of diabetes mellitus (type 2), hypertension, dyslipidaemia, and paroxysmal atrial fibrillation and was a never smoker. The patient had lived in Denmark for 23 years, and during a recent 3-year stay in Thailand, she was diagnosed with tuberculosis and treated only for a shorter period for unknown reasons. In March 2017, initial physical examination revealed a pale, cachectic woman with universal lymphadenopathy. Computed-tomography (CT) scan showed a small, apical cavity in the right lung as well as small noduli and a discrete infiltrate in the left lower lobe. A cervical lymph node biopsy showed lymphoglandular bodies with multiple mature lymphocytes, but no sign of granulomas. An HIV test result was negative.
Microscopy of sputum was positive for acid fast bacilli and anti-tuberculosis treatment was initiated. However, MAC (unnamed subspecies) was subsequently cultured (Fig. 1) and the treatment was changed to a standard MAC regimen with rifampicin, ethambutol and clarithromycin. Four months later, the treatment was discontinued due to lack of pulmonary symptoms. In November 2017, a positron emission tomography-computed tomography (PET/CT) scan showed progression of infiltrates including a new infiltrate in the left upper lobe as well as enhancement in multiple lymph nodes below and above the diaphragm. Endobronchial ultrasound-guided bronchoscopy revealed fibrotic-looking tissue and MAC was again cultured from sputum and still susceptible to macrolides. Thus, MAC treatment was reinitiated. Rifampicin was replaced by with rifabutin due to in vitro drug resistance. However, five months later, the treatment was paused for one and a half months because of elevated liver enzymes (alkaline phosphatase 1080 U/L (reference 35-105)) and ALAT 198 U/L (reference [10-45]). Imaging of the liver showed hepatomegaly and fibrosis as well as irregularity of the bile ducts suggesting primary biliary cirrhosis. Moreover, antimitochondrial antibodies were measured, but due to the clinical status of the patient, a liver biopsy was never performed. The suspicion of primary biliary cirrhosis was never confirmed.
In June 2018, admission of the patient was warranted due to severe diarrhea with dehydration and continuous weight loss. Treatment was paused for a couple of weeks. Eventually, oral administration of clarithromycin was changed to intravenous for ten days and parenteral nutrition was initiated, which improved the clinical status significantly. The patient continued with oral MAC treatment and four months of intravenous amikacin.
Immunological examination showed severely reduced concentration of CD4 T-cells 0.26 x 109/L (Table 1). CD8 T-cell count was within normal range, but the distribution of CD8 T-cell subsets were distributed toward terminal differentiation 47% (defined as CD57pos) and HLA-DR expression was upregulated on both CD4 and CD8 T-cells (51% and 81% expressed HLA-DR) indicating immune activation. The fraction of CD4 recent thymic emigrants (CD45ROneg CD4RApos CD31pos) was normal but the overall concentration was low presumably secondary to the reduced total CD4 T-cell concentration. IgA, IgE and IgG and classes were all significantly increased. Whole-genome sequencing of an immunodeficiency panel did not reveal mutations associated with the patient's condition. Functionally analyses of the IFN-gamma/IL12 axis including measurement of TNF-alpha and IL-12 production following IFN-gamma boosted LPS in vitro stimulation and IFN-gamma production following IL-12 boosted phorbol myristate acetate stimulation was reduced in relation to both TNF-alpha and IL-12 production although not absent. In addition, IFN-gamma production was undetectable upon stimulation. Thus, reduced TNF-alpha and IL-12 production in the functional investigation the IFN-gamma/IL-12 signaling pathway gave evidence of dysfunction in this pathway comparable to findings like in patients with molecular defects described to cause Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The undetectable IFN-gamma production was initially interpreted as possibly secondary to severe CD4 T cell lymphopenia. However, when screening for autoantibodies (GM-CSF, IFNalpha, IFN-gamma, IL-10, IL-1alpha and IL-6) severely elevated levels of presumably neutralizing IL-1alpha- and IFN-gamma-autoantibodies were detected. Subsequently, interferon gamma-1b 60 microg subcutaneous thrice weekly was commenced.
Both clinical and paraclinical parameters continued to improve after treatment intensification. Likewise, a PET/CT showed significant regression of all infiltrates in thorax. However, after eight months of clinical improvement, the patient presented with lower back pain with radiation to the lower extremities and clinical signs of infection. MRI and PET/CT of columna were unable to exclude spondylodiscitis, but a percutaneous biopsy from the left pedicle of L5 including culture (including mycobacterial), 16S/18S PCR and pathology did not establish a diagnosis. Meanwhile, Candida lusitania was found in blood cultures, and in July 2019, a biopsy from a swollen lymph node was positive for acid fast bacilli. Once again, HRCT showed progression in infiltrates (Fig. 2). The treatment was subsequently changed to palliative care after twenty-nine months of active treatment and the patient died two weeks later.
During the entire course of disease, the patient suffered from severe chronic perianal HSV-2 skin lesions. The chronic diarrhea was examined with intestinal biopsies, which showed lymphocyte and plasma cell infiltration, but celiac antibodies were not detected. Salmonella kentucky, was cultured from feces twice. Though, the cultures were made a year a part, the patient might have contracted the bacteria in Thailand. Also, MAC was cultured twice in the blood. In addition, several different skin lesions were sporadically occurring. Histological examination of an erythema nodosum looking lesion was identified as leukocytoclastic vasculitis and another skin lesion contained granulomatous inflammation and giant cells.