A 72-year-old man with a past medical history of AA, amegakaryocytic thrombocytopenia and chronic kidney disease (CKD) stage 3 presented in April 2020 with high fever, cough, and progressive fatigue.
Aplastic anemia had been diagnosed in 2014 and initially responded to therapy with horse anti-thymocyte globulin (ATG), methylprednisolone and cyclosporine A. Nine months later, his disease progressed and he was treated with rabbit ATG, methylprednisolone, and cyclosporine A. In late 2019, his disease progressed primarily as thrombocytopenia due to acquired amegakaryocytic thrombocytopenia (AAT). He received four doses of rituximab in early 2020 for treatment of AAT without response. Bone marrow biopsy performed 2 months prior to presentation was hypocellular with 15-20% bilineage hematopoiesis and near absence of megakaryocytes without evidence of dysplasia or increased blasts. While his diagnosis is most accurately classified as AAT at the time of presentation, he had been consistently pancytopenic for 4 months despite treatment with cyclosporine A and remained dependent on platelet transfusions. Family and psycho-social history were non-contributory.
Physical examination at the time of presentation was notable for fever of 103.7F and mild tachycardia (HR 104) with normal oxygen saturation (97%) without supplemental oxygen. He appeared in mild respiratory distress, but pulmonary examination was unremarkable. His initial laboratory studies were notable for severe lymphopenia, which was different from his baseline pancytopenia and elevated C-reactive protein (CRP) and IL-6 as noted in Table 1. Chest radiograph revealed a consolidation in the left midlung, possibly representative of pneumonia (Figure 1A).
The patient was treated empirically with hydroxychloroquine (400 mg twice a day for 1 day, followed by 200 mg twice a day for 4 days) for possible COVID-19 in the setting of immunosuppression. Ceftriaxone and azithromycin were added for possible community acquired pneumonia. On admission day 0, SARS-CoV-2 PCR nasal swab came back positive. For the first several days of the hospitalization, the patient had persistent fever (range 100-104F) and intermittently required oxygen up to 2 L/min via nasal cannula to maintain oxygen saturation above 94%.
By hospital day 5, he had developed progressive pancytopenia and required near daily transfusion of packed red blood cells and platelets. Due to persistent high fever, and now neutropenia, antibacterial coverage was broadened to cefepime, then meropenem, and antifungal prophylaxis with posaconazole was added. He was also started on tbo-filgrastim and eltrombopag for management of severe neutropenia and thrombocytopenia.
On hospital day 9, the patient developed lethargy and hypoxia requiring supplemental oxygen of 6 L/min via nasal cannula and subsequently Venturi mask at 50% FiO2. Repeat chest radiograph demonstrated significant worsening with bilateral pulmonary infiltrates (Figure 1B). Inflammatory markers, including ferritin and CRP were significantly increased and acute on chronic renal failure worsened (Table 1).
The clinical picture was consistent with cytokine storm due to severe COVID-19 and the patient promptly received tocilizumab 5 mg/kg (400 mg) on hospital day 11. The patient received a single dose of methylprednisolone 60 mg IV immediately prior to tocilizumab administration but did not otherwise receive corticosteroid treatment during his admission. The same day, the patient's fever resolved and he developed mild hypothermia (minimum 94.6F). Over the next several days, his temperature normalized, oxygen requirements steadily declined, inflammatory markers decreased and acute renal failure resolved. The patient remained pancytopenic and transfusion dependent. Meropenem was discontinued and he was transitioned to oral levofloxacin prophylaxis due to persistent neutropenia.
On hospital day 18, the patient developed mild recurrent fever (100.5F, repeat 100.9F). The following day, his fever increased significantly to 103.9F and his oxygen requirement increased to 10 L/min. Chest radiograph revealed new pulmonary infiltrates (Figure 1C). Cefepime was resumed and vancomycin and therapeutic voriconazole were added. Despite these efforts, the patient developed mild hypotension (BP 90/40) which resolved with fluid resuscitation. Antibiotics were further broadened to meropenem and the patient received a single dose of tobramycin. Inflammatory markers at this time were relatively stable.
By hospital day 20, the patient had again clinically improved. His blood pressure remained within normal range and his oxygen requirement decreased to 6 L/min by nasal cannula. The exact cause of his brief clinical deterioration was unclear but was presumed to be due to a secondary bacterial pneumonia. Over the subsequent days, he completed a 7-day course of meropenem and vancomycin. He remained afebrile on this treatment and his oxygen requirement slowly normalized. His repeat IL-6 level on day 28 was significantly elevated at 1223.8 pg/mL.
The patient was discharged home on hospital day 31. He remained pancytopenic and transfusion dependent at the time of hospital discharge. Notably, his SARS-CoV-2 PCR testing has remained persistently positive as of hospital day 29 (with the exception of a single negative result on day 17, which was thought to be a false negative). It is unclear whether detectable viral RNA represents persistent infectiousness or whether non-infectious RNA fragments are being detected. Twenty two days after hospital discharge, SARS-CoV-2 PCR was repeated and was negative.