Our patient was a 58-year-old Caucasian woman, who was referred to the Emergency Department because of dyspnoea. Her past medical history was significant for psoriatic arthritis, treated with adalimumab (tumour necrosis factor blocker) and methotrexate.
She presented with a tachycardia of 124 beats/minute and blood pressure of 126/62 mmHg. Respiratory rate was 30 breaths/min and SpO2 89% at room air. The arterial blood sample at 4L/min supplemental oxygen showed a pH of 7.54 (ref 7.35-7.45), pCO2 25 mmHg (ref 35-45), pO2 78 mmHg (ref 75-100), and lactate of 3.44 mmol/L (ref 0.5-2.2). Laboratory tests showed elevated C-reactive protein (CRP) of 150 mg/L (ref 0-5), lactate dehydrogenase of 1327 U/L (ref < 248), and a considerably elevated ferritin of 25,476 mcg/L (ref 22-204). Thrombocytes were 70 x 109/L (ref 150-400 x 109/L), whereas haemoglobin and leukocytes were within the normal range. The patient had slightly elevated alanine aminotransferase (ALAT) of 93 U/L (ref 0-34), aspartate transaminase (ASAT) of 410 U/L (ref 0-31), and gamma-glutamyltransferase of 63 U/L (ref 0-35). Chest X-ray showed patchy, bilateral infiltrates. Thoracic computed tomography (CT) scan showed bilateral, coalescent ground-glass opacities and pulmonary embolisms. An abdominal ultrasound showed no signs of cholecystitis, cholelithiasis, or hepatosplenomegaly.
On admission, the clinical presentation was not clear-cut. The initial working diagnosis was community-acquired pneumonia with concurrent pulmonary embolisms. Antibacterial treatment was started with cefuroxime, ciprofloxacin, metronidazole, and gentamicin to cover for infection of unknown origin. Low molecular weight heparin was started at a therapeutic dose. The thrombocytopenia was devoted to sepsis and disseminated intravascular coagulation. The elevated ferritin was attributed to an underlying infection, though rare causes such as HLH were also examined. On admission, our patient met only two non-specific HLH-2004 diagnostic criteria (Table 1). Nevertheless, soluble IL-2 receptor (sIL-2r) test was initiated.
Serological testing showed a prior infection with Epstein-Barr virus, cytomegalovirus, and herpes simplex virus (HSV), and no signs of human immunodeficiency virus, hepatitis B, and C virus and Mycoplasma pneumoniae. SARS-CoV-2 polymerase chain reaction (PCR) on nasopharyngeal specimens was negative twice. Anti-SARS-CoV-2 antibodies turned positive, with no known previous clinical course of COVID-19 or vaccination. A urine legionella antigen test was negative. A broncho alveolar lavage (BAL) was performed: Influenza virus A and B, respiratory syncytial virus, Pneumocystis jirovecii, Mycobacterium tuberculosis, and SARS-CoV-2 PCR were all negative. Aspergillus fumigatus and mycobacterial cultures were also negative. No acid-fast bacilli were identified by direct microscopy. A HSV type 2 PCR was positive with a cycle treshold of 37.5 and therefore considered clinically irrelevant.
Four days after admission, the patient was transferred to the intensive care unit (ICU) because of respiratory failure which prompted mechanical ventilation and prone positioning. Dexamethasone 6 mg daily for 10 days was started for treatment of acute respiratory distress syndrome following SARS-CoV-2 pneumonitis. All antibiotics were discontinued after cultures came in negative. Two days later, our patient developed a progressive thrombocytopenia accompanied by gastro-intestinal bleeding and anaemia.
During ICU admission, serum sIL-2r turned out to be elevated. A bone marrow biopsy was performed and the smear showed hypocellular bone marrow with hemophagocytosis (Fig. 1). At that moment, our patient fulfilled six HLH criteria (Table 1). Under the diagnosis of HLH, our patient was started on etoposide 100 mg weekly, dexamethasone 10 mg/m2 daily for 2 weeks, and intravenous immunoglobulins 1 g/kg daily for 2 days.
At that point, there was no clear underlying aetiology for the HLH. Infectious diseases (post-SARS-CoV-2, HSV type 2) and medication (adalimumab) were considered. No signs of malignancy or lymphadenopathy were seen on imaging.
Bone marrow biopsy did not show signs of lymphoproliferative disease. A cutaneous T cell lymphoma was excluded after biopsies of two erythematosquamous plaques.
The initial HLH treatment did not lead to improvement: respiratory failure persisted and our patient developed a pancytopenia. Three days after HLH treatment initiation, anakinra (interleukin-1 receptor antagonist) 5 mg/kg daily was added. At that moment, we noticed a decrease in ferritin levels down to 7249 mcg/L. However, despite increasing anakinra doses, respiratory failure and cytopenia worsened. Etoposide was discontinued and acyclovir (10 mg three times daily) was added to cover a HSV pneumonitis. Serial chest X-rays and thoracic CT scans showed extensive bilateral consolidations and ground-glass nodules which were repeatedly progressive. One week after start of HLH treatment, our patient developed fever with further respiratory deterioration. Despite lung protective ventilation with high FiO2 levels up to 100%, serial arterial blood gas analyses showed a progressive hypoxia (pO2 57-88 mmHg). After the initial drop in ferritin levels, there was an evident increase up to 9899 mcg/L. Anakinra was replaced by the anti-IL-6 receptor monoclonal antibody tocilizumab (8 mg/kg) and piperacillin/tazobactam (4 g/500 mg four times daily) and hydrocortisone (50 mg four times daily) were started. Despite aggressive supportive care, our patient showed no improvement and succumbed to the illness after 18 days in our ICU.
Autopsy was performed and confirmed striking hemophagocytosis in bone marrow. More surprisingly, it revealed a miliary pneumonia involving all pulmonary lobes (Fig. 2) with Ziehl-Neelsen staining showing acid-fast bacilli. In fact, epithelioid cell granulomatosis of all organs was found. Mycobacterium tuberculosis PCR was positive in paraffin-embedded lung tissue. In conclusion, our patient died as a result of HLH with underlying miliary tuberculosis.