The 64 years-old female, born in Campania region, is affected by arterial hypertension, potential occult HBV infection under prophylaxis with lamivudine and follicular variant of non-Hodgkin lymphoma, diagnosed in January 2018 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. She was under maintenance therapy with subcutaneous rituximab 14 mg every two months, with last dose administered in June 2020.
She started complaining low-grade fever and dysgeusia on the 31st of August 2020. A nasopharyngeal swab (NFS) resulted positive for SARS-CoV-2 RNA on the 5th of September 2020. She was admitted to a peripheral hospital of the metropolitan area of Naples on the 26th of September for development of dyspnea and low peripheral oxygen saturation. At the admission, the high-resolution chest CT-scan (HRCT) showed bilateral ground-glass opacities (GGO) and peripheral bilateral consolidation. She was treated with intravenous methylprednisolone 20 mg BID, ceftriaxone 2 g i.v. QD and enoxaparin 4000 IU BID. A second HRCT evaluation was performed on the 14th of October, resulting in a significant reduction of the previously descripted parenchymal lesions. Nonetheless, at the beginning of December 2020, she started complaining low-grade fever and she showed a three-fold increase of C-reactive protein (CRP) level. Therefore, the third HRCT achieved, showed again bilateral increase of GGO. Since NFS continued to be positive for SARS-CoV-2 RNA, the patient was then transferred to Federico II University Hospital within the Infectious disease Department on date 11th of December 2020, for both the infectious disease and hematologic assessment.
On admission she was in good clinical conditions, good hemodynamic values, oxygen saturation of 93% on room-air, with PaO2 of 68 mmHg, low grade fever (Tmax 37.8 C). Omeprazole 20 mg QD, atorvastatin 10 mg QD, folic acid 14 mg QD, lamivudine 100 mg QD, olmesartan/hydrochlorothiazide 20/12.5 mg were administered.
Blood tests at the admission showed high glucose level (150 mg/dL), blood ferritin (860 ng/mL), LDH (319 U/L), PCR (1.43 mg/dL), WBC (4.230/mm3), with absolute lymphocyte count of 423/mm3, CD4+: 28% (absolute count: 118/mm3), CD8+: 50% (absolute count: 211/mm3) and CD56+ 10% (absolute count: 42/mm3); hemoglobin (10 g/dL) and normal neutrophil count.
Blood, urine, and sputum cultures, as well as serological test for intracellular bacteria, resulted negative for Legionella pneumophila and molecular assay for respiratory viruses. Due to the concomitant IgG hypogammaglobulinemia (IgG level 2.6 g/L), she received 20 g of intravenous immunoglobulins for two consecutive days.
The superficial and deep ultrasound on lymph nodes resulted normal: moreover, the hematologic consultation confirmed the complete remission from the disease and withheld further administration of rituximab until the resolution of COVID-19.
The patient was therefore scored as class four following the WHO clinical progression scale.
She was treated from the 11th to 17th of December with ceftaroline 600 mg BID and levofloxacine 750 mg QD, in a suspicion of bacterial superinfection, with no improvement. Two consecutive Beta-D-Glucan assays resulted negative.
On the 26th of December, another HRCT was performed, that showed bilateral GGOs with a severity score of 11/20. A bronchoalveolar lavage fluid (BALF) was then collected two days later: galactomannan antigen, CMV-DNA, VZV-DNA, PCR for respiratory viruses, microscopic and bacteria, fungi and mycobacteria cultures were performed. GeneXpert assay for Mycobacterium tuberculosis resulted negative, while P. jiroveci direct immunofluorescence was positive. SARS-CoV-2 RNA was detected on BALF with a cycle threshold of 24. Trimethoprim-sulfamethoxazole (CTX) 20 mg/kg p.o. daily together with prednisone 20 mg BID were started, with improvement of blood gas exchanges and CRP reduction. Therapy with CTX was stopped after 21 days, with prednisone tapering.
A HRCT performed on the 26th of January 2021 showed improvement of GGOs, with a score of 6/20. Nonetheless, despite the clinical and radiologic improvement following the therapy for Pneumocystis pneumonia, our patient started to have low-grade fever, increased CRP, leukopenia and persistence of hypogammaglobulinemia, with IgG level of 4,4 g/dL. Thus, she received a further i.v. immunoglobulin administration 30 days apart from the previous. CMV DNA, beta-D-glucan, galactomannan resulted as negative on new repeated samples, with blood, sputum and urine cultures negative. On date 5th of February 2021, she was still recovered in the isolation hospital unit, in discrete respiratory conditions, still febrile, with increased CRP (last determination 2.3 mg/dL), negative procalcitonin, leukopenia (WBC 1790/mm3, Neu 870/mm3, lymphocytes 570/mm3) with confirmed positivity for SARS-CoV-2 RNA on NFS after 150 days from the first detection. The WBC cytometry typing on the peripheral blood, one week after the admission to our Medical School resulted in: absolute lymphocyte count (1043/mm3), with the absence of B-cells (i.e., 0/mm3), CD4+: 27% (absolute count: 282/mm3); CD8+: 58% (absolute count: 605/mm3) and CD56+: 7% (absolute count: 73/mm3).
She never developed anti-nuclear and anti-spike SARS-CoV-2 antibodies. The hematologic consultation for bone marrow examination was requested, together with SARS-CoV-2 RNA sequencing, to evaluate the presence of potential viral mutations associated to the persistence of detectable viral load. She could not yet be treated with rituximab, according to a board of hematologist from our hospital. On date 26th of February she was administered with hyperimmune serum-based therapy: two weeks later she finally became negative at NFS molecular assay.