A 67-year-old gentleman was visiting Ireland from outside New Delhi, India. He presented to hospital acutely unwell with a 3-day history of pyrexia, confusion, non-productive cough, anorexia and an inability to mobilise independently. Over the preceding 3?weeks he had suffered with gastrointestinal (GI) upset, and noted unintentional weight loss and lethargy over the past 6?months. His past medical history included poorly controlled type two diabetes mellitus (T2DM), he was non-compliant with metformin, and had previous alcohol excess, with no alcohol intake in the past 6?months. He was an ex-smoker with a 20?pack-year history and a retired crop farmer who was fully independent in all activities of daily living before this presentation. Family history was positive for an uncle with Mycobacterium tuberculosis 20?years earlier.
On initial presentation, the patient was hypotensive, tachycardic, tachypnoeic and febrile with a temperature of 38.4°C. His oxygen saturation was 92% on room air. White blood cell count (WCC) was 12×109?per L (normal range: 4.0–11.0×109?per L) and C-reactive protein (CRP) was 37?mg·L?1 (normal range: 0–5?mg·L?1). His serum creatinine was 159?µmol·L?1 (normal range: 59–104??mol·L?1), urea was 9?mmol·L?1 (normal range: 2.8–8.1?mmol·L?1) and liver function tests (LFTs) were widely deranged. A venous blood gas showed pH 7.3 (normal range: 7.31–7.41), carbon dioxide tension (PCO2) 4.98?kPa (normal range: 5.5–6.8?kPa), bicarbonate 18.6 mmol·L?1 (normal range: 23–29 mmol·L?1), lactate 2.23 mmol·L?1 (normal range: <1 mmol·L?1), ketones 3.8?mmol·L?1 (normal range: <0.6?mmol·L?1), blood sugar level 3.6?mmol·L?1 (normal range: 3.6–5.3?mmol·L?1). Viral screen and COVID-19 swab were negative.
This patient was visibly cachectic and severely dehydrated with dry mucous membranes and reduced skin turgor. Figure 1 shows a feature noted on general examination.
A full septic screen was performed with blood and urine cultures sent. He was given supplemental oxygen, fluid resuscitated with multiple boluses and commenced on intravenous piperacillin–tazobactam, a broad spectrum antibiotic. It was not possible to send a sputum sample at this time as his cough was non-productive.Serum results demonstrated this patient's cortisol level was low at 31?nmol·L?1 (normal range: 166–507?nmol·L?1) and his adrenocorticotropic hormone (ACTH) level was elevated at 112?pg·mL?1 (normal range: 7–63?pg·mL?1). He was immediately commenced on high-dose intravenous hydrocortisone (50?mg four times a day) and responded well to this.
At this point, multiple issues had been identified. First, this patient had a new, acute-onset confusion. Differentials for this included delirium, intracranial pathology, infection or hepatic encephalopathy. Secondly, he was had a new supplemental oxygen requirement with tachycardia and a recent history of a long-haul flight. A pulmonary embolus (PE) had to be considered as well as a potential source of sepsis. Thirdly, he had metabolic acidosis due to raised ketones and lactate, he was hypoglycaemic and hypercalcaemic. Finally, he had low serum cortisol, high serum ACTH and tongue hyperpigmentation and we needed to further investigate for a cause of adrenal insufficiency.
To investigate the cause of acute confusion, computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed no intracranial abnormality. Serum ammonia was within the normal range (16–60??mol·L?1). The acute confusion was likely delirium in the context of infection, dehydration and hypercalcaemia. Imaging was obtained to investigate causes of desaturation.
The patient's D-dimer was elevated at 1572?ng·mL?1 (normal range: <500?ng·mL?1). However, CT pulmonary angiography (CTPA) showed no PE and background infective changes. In terms of the metabolic acidosis, an urgent endocrinology consultation was obtained. The low pH was likely being driven by a starvation ketosis for which he was given boluses of dextrose and was commenced on a nasogastric feed with phosphate replacement, to good effect. To investigate the cause of adrenal insufficiency, cross-sectional abdominal imaging was obtained and showed morphological changes of cirrhosis, with portal hypertension (figure 3). There were bilateral adrenal masses, not suggestive of adenoma. Liver cirrhosis was in keeping with the pattern of LFT derangement and history of alcohol excess. To further determine these masses, an MRI adrenal was performed which details granulomatous involvement of the glands bilaterally.Further investigations included an interferon-? release assay, sputum for TB culture, acid-fast bacilli and GeneXpert PCR. Bronchoscopy with BAL for culture and lumbar puncture biochemistry and culture were also performed. All the above-listed investigations were negative.
After 1?week, the patient had shown a significant clinical improvement with supportive care and broad-spectrum antibiotics. Unfortunately, due to patient factors an adrenal biopsy was not performed and the patient was very keen to return to India for any further work-up. The patient was reviewed by the Respiratory TB service who advised against empirically treating for TB without having a tissue diagnosis. Treatment selection would also need consideration and close monitoring given the baseline deranged LFTs and background cirrhosis. As he remained well, he was discharged home with strong advice for further TB investigations in India.
Unfortunately, 5?days after being discharged, this man re-presented to the emergency department with acute type one respiratory failure, desaturating to 80% on room air. He was pyrexic to 39.5°C and hypotensive with tachycardia of 170?beats per min. Arterial gases showed oxygen tension of 7.6?kPa and PCO2 of 5.4?kPa. His WCC was 20×109?per L (normal range: 4.0–11.0×109?per L) and CRP was 284?mg·L?1 (normal range: 0–5?mg·L?1). Serial troponins and brain natriuretic peptide were normal. A portable chest radiograph showed new diffuse bilateral airspace opacification with associate micronodular infiltrate. A further CTPA was requested.
Peripheral blood and urine cultures and urinary antigens were negative. He was trialled on high-flow oxygen; however, despite this, he had increasing oxygen requirements and persistent respiratory distress and was transferred to the intensive care unit (ICU) for intubation and ventilation.
In ICU, ?-d-glucan was found to be elevated at 283?pg·mL?1 (normal range: 30–59?pg·mL?1). Bronchoscopy was repeated and BAL samples were once again negative for M.?tuberculosis. Samples were also sent for extended fungal culture which was positive for both Pneumocystis pneumonia (PJP) and histoplasmosis. Immunological work-up, autoimmune and viral screens were normal. Although an adrenal biopsy was not performed, considering his bilateral granulomatous adrenal enlargement and histoplasmosis detected on bronchial sampling, we had a high index of clinical suspicion that disseminated histoplasmosis was the aetiology of his adrenal insufficiency.
PJP was treated with co-trimoxazole for 3?weeks as per local guidelines. Histoplasmosis was treated with meropenem, liposomal amphotericin B, ceftazidime–avibactam and linezolid which was later de-escalated to itraconazole that the patient was to continue taking for 1?year. The patient clinically improved and completed inpatient rehabilitation post-ICU stay prior to his discharge. His adrenal insufficiency was managed with maintenance fludrocortisone (100??g once daily) and hydrocortisone 15?mg/10?mg/10?mg and he remained clinically well.
