Monoclonal Antibodies for COVID-19 in X-linked Agammaglobulinemia: a Case Series

Abstract

To the editor, X-linked agammaglobulinemia (XLA) is an inborn error of immunity (IEI) caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene, leading to impaired cytoplasmic signalization essential for B cell differentiation in its early stages of development. The first published cases of COVID-19 disease in XLA individuals described mild presentations with favorable outcomes, suggesting a less important role than expected of B cell and antibody function in viral clearance and disease control [1]. Subsequent publications reported severe presentations of acute respiratory failure and persistent infections with good response to convalescent plasma [2], providing further insight on the true role of humoral immunity in a host’s defense against COVID-19 disease. This case series reports five XLA patients diagnosed with COVID-19 disease between October 2021 and February 2022, all treated with monoclonal antibodies (mAbs) targeting SARS-CoV-2 spike protein. Underlying XLA diagnosis was based on prior BTK gene sequencing, agammaglobulinemia, absent CD19 lymphocyte counts and recurrent infections to bacteria. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection was diagnosed with a positive polymerase chain reaction (PCR) or rapid antigen test. All five patients had received at least 2 doses of mRNA vaccine at the time of infection. Features of XLA and COVID-19 disease in the five patients are summarized in Table 1. Table 1 Summary of clinical features of underlying XLA and COVID-19 disease Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Underlying XLA diagnosis   BTK mutation c.1559G > A c.1559G > A g.1690 T > C c.325_325delG c.76A > T   Protein change p.Arg520GIn p.Arg520GIn p.Ser564Pro p.Pro110Lfs*11 p.Lys26*   Age at diagnosis 4 years 6 months 3 years 4 years 1 year   Immunoglobulin titers (IgG-A-M) (g/L) n/a – 0 – 0 n/a – 0 – 0 n/a – 0 – 0.05 0 – 0.078 – 0.076 0 – 0 – 0   CD19 count (cells(/uL) 0 0 0 0 0   Prior infections Sinusitis, otitis pneumonia Sinusitis, otitis, giardiasis/ campylobacter enteritis and bacteremia Sinusitis, bronchitis, viral enteritis Extensive staphylococcal skin infection, otitis, sinusitis Sinusitis, otitis, bronchitis   Comorbidities CRS, right upper lobe ground glass opacities, mild intermittent asthma CRS, Bronchiectasis, mild asthma CRS CRS Bronchiectasis CRS with polyposis, bronchiectasis   Current treatments SCIG, TMP-SMX 800–160 daily SCIG, TMP-SMX 800–160 daily IVIG, Cefprozil 500 daily IVIG IVIG, Azithromycin 3 × /week   IgG through (g/L) (N 7–16) 12.60 13.40 12.60 12.50 12.20 COVID-19 disease   Age in years (gender) 38 (M) 33 (M) 32 (M) 37 (M) 46 (M)   Vaccination status prior COVID-19 infection 2 doses of BNT162b2 (Comirnaty) 2 doses of BNT162b2 (Comirnaty) 3 doses of BNT162b2 (Comirnaty) 2 doses of mRNA-1273 (Spikevax) 3 doses of mRNA-1273 (Spikevax)   Date of positive test (modality) 2021–12-01 (PCR) 2021–10-12 (PCR) 2022–01-04 (PCR) 2022–01-12 (RAT) 2022–02-20 (RAT)   Delay from last COVID vaccine dose to infection (weeks) 24 15 12 11 8   P681R mutation associated with Delta variant Positive Positive Negative n/a (RAT) n/a (RAT)   Most likely SARS-CoV-2 Variant Delta Delta Omicron Omicron Omicron   Symptoms Fever, sinusitis, SOB, purulent cough Recurrent fever and SOB, productive cough, myalgia, headache Fever, cough, rhinitis, myalgia Rhinitis, cough headache, myalgia Rhinitis, asthenia   Respiratory failure Yes—hypoxemia No No No No   Sepsis Yes No No No No   Fever duration 1 day 24 days n/a n/a n/a At initial presentation: -Lymphocyte count -CRP -LDH 300 × 109/L 400 mg/L 646 U/L 800 × 109/L 87.87 mg/L 298 U/L n/a n/a n/a Chest X-ray Bilateral opacities Bilateral opacities n/a n/a n/a Hospitalization 8 days 24 days None Non No ICU stay 5 days No No No No Supplemental oxygen (duration) 65% FiO2 by HFNC (5 days) No No No No Highest level of care setting ICU Hospitalized – Standard Care Unit Outpatient Outpatient Outpatient Disease severity (WHO Clinical Progression scale) 6 (severe) 4 (moderate) 2 (mild) 2 (mild) 2 (mild) Treatments received (timing of drug administration from initial symptom onset) IV Piperacillin-Tazobactam, Azithromycin Dexamethasone (day 15) Tocilizumab 8 mg/kg + Casirivimab 1.2 g/ Imdevimab 1.2 g (day 16) Doxycycline (day 14) Levofloxacin, Meropenem (day 18) Casirivimab 1.2 g/Imdevimab 1.2 g (day 38) Sotrovimab 500 mg (day 10) Sotrovimab 500 mg (day 5) Sotrovimab 500 mg (day 2) Reinfection (time from first infection) No Yes (2.5 months) Yes (6 months) No No Abbreviations: CRP C-reactive protein, CRS chronic rhinosinusitis, DIE daily, FiO2 fraction of inspired oxygen, HFNC high flow nasal canula, ICU intensive care unit, Ig immunoglobulin, IV intravenous, IVIG intravenous immunoglobulin replacement therapy, LDH lactate dehydrogenase, PCR polymerase chain reaction test, RAT rapid antigen test, SCIG subcutaneous immunoglobulin replacement therapy, SOB shortness of breath, TMP-SMX trimethroprim-sulfamethazol *As defined by the SEPSIS-3 consensus (2016) Patient 1 Patient 1 is a 38-year-old male who presented with symptoms of sinusitis and a positive PCR for SARS-CoV-2 delta variant 6 months after having received a second dose of mRNA COVID-19 vaccine. Despite a 10-day course of oral antibiotics, he developed shortness of breath to minimal effort and a purulent productive cough leading to urgent consultation. His vitals showed a pulse oximetry saturation of 77% on ambient air, a respiratory rate of 35/min, a heart rate of 115/min with a normal blood pressure and a temperature of 38.9° Celsius. His bloodwork showed lymphopenia (300 × 109/L), neutrophilia, and an elevated C-reactive protein (400 mg/L). The chest X-Ray (CXR) showed diffuse opacities in bilateral lower lobes of the lung. The patient was promptly treated for hypoxemic respiratory failure and sepsis in the setting of multifocal COVID-19 pneumonia and admitted to the intensive care unit (ICU). He received oxygen supplementation by high nasal flow canula, as well as intravenous broad-spectrum antibiotics and Dexamethasone. The following day, he received Tocilizumab 8 mg/kg and Casivirimab/Imdevimab (1.2/1.2 g). He was rapidly weaned off the high flow nasal canula after 5 days and discharged from the hospital within 8 days from admission. During the course of his illness, he also developed acute kidney injury and elevated liver enzymes. Follow-up 1 month later showed important regression of the lung opacities, normalization of the liver enzymes and kidney function. A control chest CT obtained 8 months later due to persistent cough and dyspnea revealed signs of post-COVID pneumopathy following a pattern of nonspecific interstitial pneumonitis (NSIP). Patient 2 Patient 2 is a 33-year-old male, brother of patient 1, who presented to the emergency department (ED) for worsening fever up to 39.1° Celsius, fatigue, cough and dyspnea. He tested positive on SARS-CoV-2 PCR test for the Delta variant. He showed no respiratory distress or hypoxemia upon evaluation and was hemodynamically stable. He was discharged with oral antibiotics but represented to the ED 5 days later with persistent fever. Bloodwork revealed lymphopenia (800 × 109/L), elevated lactates (3 mmol/L), lactate deshydrogenase (259 U/L) and C-reactive protein (55.8 mg/L). Chest CT showed bilateral and diffuse nodular ground glass opacities. He was admitted to a standard care unit and treated with intravenous Levofloxacin and Meropenem. Sputum cultures did not identify any pathogen and the patient was discharged once again with antibiotics after a negative SARS-CoV-2 PCR was obtained. He was readmitted 5 days after discharge with persistent fever and fatigue. A bronchoalveolar lavage was done by bronchoscopy and came back positive for SARS-CoV-2. Casirivimab and Indevimab (1.2 g/1.2 g) was then administered at day 38 from symptom onset because of persistent disease. Great improvement was seen the following day of monoclonal antibody administration. The patient was afebrile, asymptomatic and his chest X-ray improved greatly. He was discharged 4 days later with a negative PCR test. Clinical outcomes were favorable, although the patient was reinfected with SARS-CoV-2 31 days after discharge. He presented mild symptoms that did not require consultation or specific treatments. Patients 3, 4, and 5 The other three patients, aged between 32 and 46 years old presented with mild symptoms and did not require urgent care. Patient 3 was infected by the Omicron variant and although patients 4 and 5 lacked confirmatory variant identification on PCR testing, they were most likely infected with the Omicron variant considering the epidemiologic context of that period. As reported by the local public health authorities, the prevalence of Omicron variant was 93.3% at the time that patient 4 tested positive for COVID-19 and 100% at the time that patient 5 tested positive. They were treated in an outpatient setting with a single infusion of Sotrovimab (500 mg) with rapid resolution of their illness within few days of administration. Patient 3 got reinfected 6 months later, but presented only mild symptoms. He received a combination of oral Nirmatrelvir-Ritonavir (300 mg/100 mg) in the community and recovered quickly. In this case series, three patients likely infected with the Omicron variant presented with mild symptoms and were treated in an outpatient setting (patients 3, 4, 5), while the other two patients were infected with the Delta variant and presented complicated disease courses. This finding reflects clinical practice where the Omicron variant seems to cause less severe disease than the Delta variant. One patient was admitted shortly in an ICU due to acute hypoxemic respiratory failure (patient 1) and one patient required repeated hospitalizations for persistent non-severe disease (patient 2). Interestingly, these two patients are brothers bearing the same genetic mutation, suggesting a possible genetic susceptibility to severe COVID-19 in some XLA patients. The heterogenicity of these clinical presentations in patients with the same underlying IEI is in line with the cases published to date and highlights the host’s complex immune response to COVID-19, including the neutralizing role of antibodies against SARS-CoV-2 and T-mediated anti-SARS-CoV-2 cellular immunity. In fact, a recent report from Gao et al. showed that XLA patients have a comparable cell-mediated response to SARS-CoV-2 immunization compared to healthy individuals [3]. From all five cases, only patient 1 presented a severe systemic inflammatory response, suggesting a protective role of BTK deficiency for cytokine storm syndrome by limiting macrophage activation and interleukin-6 production. Persistent disease due to impaired viral clearance is most likely for patient 2 because he presented with persistent fever and fatigue even when a negative PCR was obtained. The viral load was possibly too low to be detected in the nasopharyngeal specimen considering that the PCR done on bronchoalveolar lavage was positive. Hence, the absence of an asymptomatic window in between the two positive PCRs does not go in favor of a re-infection. This case highlights the potential long-term carriage and shedding of SARS-CoV-2 in XLA patients. Furthermore, the delay between the last vaccine dose and SARS-CoV-2 infection was slightly longer for patients 1 and 2. In patients with profound antibody deficiencies, the potential protective cellular response induced by vaccination might have decreased substantially during that time, leading to the multicomplicated disease courses in these two patients. Two of the three mild cases had received three vaccine doses prior to infection, while the moderate and severe cases only had received two. On the counterpart, the delay between symptom onset and monoclonal antibody administration is inversely proportional to disease severity. The patients 3, 4 and 5 had mild symptoms and received the infusion of mAbs within the first 10 days of symptom onset. Also, no correlation was seen between underlying chronic pulmonary disease (bronchiectasis, asthma) and COVID-19 severity. Except the comorbidities listed in Table 1, no patients had comorbidities associated with severe COVID-19, such as obesity, diabetes, chronic liver or renal disease, etc. In sum, this case series suggests that the type of SARS-CoV-2 variant, the vaccination status, the delay from last dose to infection and the timing of monoclonal antibody administration might all influence disease course. Patients were all treated, at some point during their illness, with SARS-CoV-2 mAbs. The ones with mild presentations recovered swiftly without complications. After monoclonal antibody administration, the severe case of hypoxemic respiratory insufficiency was quickly weaned off oxygen therapy, while the case of unremitting disease became rapidly symptom free. Fortunately, patient 1 who also received Tocilizumab, did not present infectious complications as anticipated. However, the distinct effect of each monoclonal antibody treatment administered to patient 1 cannot clearly be made, although it is most likely the combination of both treatments that provided a synergistic benefit on the patient’s systemic inflammatory response. On one part, anti-spike protein mAbs reduced viral load and activation of innate immunity, while mAbs against interleukin-6 reduced cytokine effects. Nonetheless, despite very heterogenous presentations, all five patients had favorable outcomes with anti-SARS-CoV-2 mAbs, suggesting its efficacy in patients with profound antibody deficiencies like XLA. Hence, monoclonal antibodies may be considered in the treatment of XLA patients, especially in the setting of severe or persistent disease since their antibody response to mRNA COVID-19 vaccination is absent [3] and neutralizing SARS-CoV-2 antibodies in commercial immunoglobulin products give insufficient passive immunity to the Omicron variant of concern (VOC) [4]. Other treatments, such as antiviral therapies, have been reported in the treatment of XLA patients with COVID-19 with successful outcomes and could also be considered for these patients. Nonetheless, since May 2022, Omicron VOC is dominant worldwide and has reduced in vitro susceptibility to various mAbs, including Casivirimab plus Imdevimab. The favorable response to this combination of mAbs in our patients is probably because they were infected with the Delta variant and not the Omicron variants which are less susceptible to this treatment. Likewise, although no subvariant identification was done to confirm this, the three patients likely infected with Omicron were probably the BA.1 and BA.1.1 subvariants, as they all tested positive months before the emergence of the BA.2, BA.4 and BA.5 subvariants. They were treated with Sotrovimab, which has shown some neutralizing activity against the BA.1 and BA.1.1 subvariants, but poor activity against other subvariants [5]. The good clinical response observed in our patients was likely because of susceptibility of the subvariants to the specific mAbs used. It is therefore important to recognize the emergence of new mutations in the viral genome of SARS-CoV-2 and to tailor the treatment to the variants identified. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 1929 KB)