COVID-19 Pneumonia with Migratory Pattern in Agammaglobulinemic Patients: A Report of Two Cases and Review of Literature.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients.

Features of COVID-19 in patients with congenital antibody deficiency

Background: Congenital/primary immunodeficiency (PID) affects about 6 million people worldwide, about 50% of whom are antibody deficient. During the COVID-19 pandemic, these people are at special risk because they have inborn errors of immunity and immune defense against infections. A number of immune mediators, in particular serum levels of interleukin 6 (IL-6), are closely correlated with severity and mortality from COVID-19. Method(s): The clinical course of COVID-19 and IL-6 levels in 14 patients with PID were studied. The age of patients ranged from 18 to 46 years. Among 14 patients with PID, 5 were diagnosed with common variable immunodeficiency (CVID), 4 with IgG4 deficiency, 4 with X-linked agammaglobulinemia (XLA), and 1 with WHIM syndrome. All patients with PID received replacement immunoglobulin therapy. The control group was randomly selected from 25 patients with COVID-19 without immune deficiency disease. The level of IL-6 was determined by ELISA. Result(s): Among 14 patients with PID, 10 patients (71.4%) had mild COVID-19 and 4 patients (28.57%) had moderate COVID-19. Importantly, all 4 patients with IgG4 deficiency, 1 patient with WHIM syndrome, 3 out of 5 patients with CVID, and 2 out of 4 patients with XLA had mild COVID-19. It should be noted that the clinical course and level of IL-6 in all patients with PID and control group did not differ statistically. Conclusion(s): More than 70% of patients with congenital antibody deficiencies had a mild form of COVID-19. The predominantly mild course of COVID-19 confirms the important role of cellular immunity in protecting against SARS Cov-2. Interestingly, all patients with XLA experienced mild or moderate COVID-19 without elevated IL-6 levels likely due to decreased activity of Bruton tyrosine kinase, which mediates development of a cytokine storm through activation of NF-kappabeta. Mild forms of COVID-19 in XLA may reflect a decrease in cytokine storm, in particular IL-6 production.

SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Show Markedly Reduced Cross-reactivities Against Omicron Variants.

PURPOSE: Patients with antibody deficiencies often receive maintenance treatment with donor plasma-derived immunoglobulin (Ig) preparations to decrease the incidence and severity of infections. We have previously shown that IgG antibodies to the original SARS-CoV-2 strain were not consistently present in off-the-shelf Ig batches produced up to approximately 18 months after the first identified case of COVID-19 in the USA and that Ig batches with anti-SARS-CoV-2 IgG primarily contained vaccine-induced spike specific antibodies. This study aimed to investigate the degree of cross-reactivity between vaccine-induced anti-SARS-CoV-2 antibodies against Wuhan strain and subsequent viral variants. METHODS: Samples were collected from 74 Ig batches supplied by three different commercial manufacturers. All batches were used at the Immunodeficiency Unit at the Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until September 2022. Antibody quantity and potential to neutralize virus entry into host cells were assessed against the original SARS-CoV-2 Wuhan strain and the following nine variants: Alpha, Beta, Delta, IHU, and the Omicron BA.1, BA.1.1, BA.1 with spike mutation L452R, BA.2, and BA.3. RESULTS: Ig batches produced approximately 18 months after the SARS-CoV-2 outbreak (from around July 2021) and later consistently contained high quantities of antibodies that bind the Wuhan strain. The Ig batches had overall low reactivity to the SARS-CoV-2 nucleocapsid, which implies that plasma donor spike IgG essentially is the result of vaccination. We assessed the degree of cross-reactivity towards each virus variant by plotting the variant/Wuhan strain ratio, which was consistent regardless of production date, suggesting cross-reactivity with vaccine-induced antibodies rather than virus exposure in the plasma donor population. Viral variants that emerged later during the pandemic systematically had a lower reactivity ratio, except for the Delta and IHU variants. The Ig batches displayed markedly low neutralizing potential towards the Beta variant and all tested Omicron variants. CONCLUSION: Commercial Ig batches currently contain large quantities of SARS-CoV-2 vaccine-induced antibodies. Cross-reactivity with variant strains is evident but varies, with markedly low neutralizing potential observed against Omicron variants.

Phenotype of BTK-lacking myeloid cells during prolonged COVID-19 and upon convalescent plasma.

XLA patient with 7-month course of COVID-19 with persistent plasma SARS-CoV-2 load revealed a sustained non-inflammatory profile of myeloid cells in association with contained severity of disease, arguing in favor of the use of BTK inhibitors in SARS-COV-2 infection.

SARS-COV-2 infections in inborn errors of immunity: A single center study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). One of the main topics of conversation in these past months in the world of immunology has been the issue of how patients with immune defects will fare if they contract this infection. To date there has been limited data on larger cohorts of patients with Inborn Errors of Immunity (IEI) diagnosed with COVID-19. Here, we review the data of COVID-19 infections in a single center cohort of 113 patients from the Mount Sinai Immunodeficiency program, who had 132 infections between January 2020 and June 2022. This included 56 males and 57 females, age range 2 - 84 (median 42). The mortality rate was 3%. Comparison between admitted patients revealed a significantly increased risk of hospitalization amongst the unvaccinated patients, 4% vaccinated vs 40% unvaccinated; odds ratio 15.0 (95% CI 4.2 - 53.4; p <0.00001). Additionally, COVID anti-spike antibody levels, determined in 36 of these patients post vaccination and before infection, were highly variable.

Response to mRNA COVID-19 vaccination in three XLA patients.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity characterized by insufficient production of immunoglobulins and lack of measurable antibody response to vaccines. The rise of novel infections limits the protective effect of immunoglobulin replacement in immunodeficient patients though. While XLA patients are not expected to mount an antibody response to COVID-19 vaccination, it has been demonstrated that XLA patients can mount a T-cell response to COVID-19 vaccines, similar to the influenza vaccine. We present three patients with XLA who received an mRNA COVID-19 vaccine. One patient demonstrated positive antibody response. Many XLA patients do not receive routine vaccinations due to ongoing immunoglobulin replacement therapy and lack of native antibody production, but in addition to T-cell response to vaccination, select XLA patients may mount a positive antibody response. Therefore, COVID-19 vaccination should be encouraged for all XLA patients.

COVID-19 IN A PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA: A CASE REPORT

X-linked agammaglobulinemia (XLA), characterized by a pro-found deficiency of B lymphocytes, is caused by mutations in the gene encoding Bruton tyrosine kinase (Btk).. XLA patients have a susceptibility to viral infections. In this report, we present a 45-year-old man with known XLA, with about a 2-week history of fever, chills, diarrhea and vomiting. He was diagnosed with COVID-19 infection, which was confirmed by a real-time reverse-transcriptase-polymerase chain reaction. The antiviral drugs, antibiotics, and interferon-beta were administered to him. Unfortunately, the patient passed away after 5 days. During an epidemic of infectious diseases, the best strategy to overcome the potential challenges of treating XLA may be prevention. Early detection of biomarkers such as D-dimer and IL-6 might be more helpful for initiating more aggressive therapy and decreasing the duration of illness in these patients.

Neutralizing SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Give Patients with X-Linked Agammaglobulinemia Limited Passive Immunity to the Omicron Variant.

Immunodeficient individuals often rely on donor-derived immunoglobulin (Ig) replacement therapy (IGRT) to prevent infections. The passive immunity obtained by IGRT is limited and reflects the state of immunity in the plasma donor population at the time of donation. The objective of the current study was to describe how the potential of passive immunity to SARS-CoV-2 in commercial off-the-shelf Ig products used for IGRT has evolved during the pandemic. Samples were collected from all consecutive Ig batches (n = 60) from three Ig producers used at the Immunodeficiency Unit at Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until January 2022. SARS-CoV-2 antibody concentrations and neutralizing capacity were assessed in all samples. In vivo relevance was assessed by sampling patients with XLA (n = 4), lacking endogenous immunoglobulin synthesis and on continuous Ig substitution, for plasma SARS-CoV-2 antibody concentration. SARS-CoV-2 antibody concentrations in commercial Ig products increased over time but remained inconsistently present. Moreover, Ig batches with high neutralizing capacity towards the Wuhan-strain of SARS-CoV-2 had 32-fold lower activity against the Omicron variant. Despite increasing SARS-CoV-2 antibody concentrations in commercial Ig products, four XLA patients on IGRT had relatively low plasma concentrations of SARS-CoV-2 antibodies with no potential to neutralize the Omicron variant in vitro. In line with this observation, three out the four XLA patients had symptomatic COVID-19 during the Omicron wave. In conclusion, 2 years into the pandemic the amounts of antibodies to SARS-CoV-2 vary considerably among commercial Ig batches obtained from three commercial producers. Importantly, in batches with high concentrations of antibodies directed against the original virus strain, protective passive immunity to the Omicron variant appears to be insufficient.

Do reduced numbers of plasmacytoid dendritic cells contribute to the aggressive clinical course of COVID-19 in chronic lymphocytic leukaemia?

Infections with SARS-CoV-2 have been unduly severe in patients with haematological malignancies, in particular in those with chronic lymphocytic leukaemia (CLL). Based on a series of observations, we propose that an underlying mechanism for the aggressive clinical course of COVID-19 in CLL is a paucity of plasmacytoid dendritic cells (pDCs) in these patients. Indeed, pDCs express Toll-like receptor 7 (TLR7), which together with interferon-regulatory factor 7 (IRF7), enables pDCs to produce large amounts of type I interferons, essential for combating COVID-19. Treatment of CLL with Bruton's tyrosine kinase (BTK) inhibitors increased the number of pDCs, likely secondarily to the reduction in the tumour burden.

PASC, reinfections and variants: COVID-19 in patients with inborn errors of immunity in São paulo-Brazil

Background: Inborn Errors of Immunity (IEI) are a heterogeneous group of diseases which immune defect may be related to a complications by COVID 19. Although there are few studies on the evolution and the real clinical impact of infection by SARS-CoV 2 in this group of patients. The aim of the study was to describe the clinical evolution of COVID-19 in patients with different IEI, in a reference center in Brazil. Method: Retrospective and longitudinal study, with analysis of electronic medical charts of patients with IEI and diagnosis of suspected/ confirmed COVID-19 from March 2020 until now. Results: Eighteen patients (61% male), with a median age of 26.6 years (range 12,3-53,4 y), were included in the study. Four X-linked agammaglobulinemia (XLA), 7 common variable immunodeficiency (CVID), 1 specific antibody deficiency, one Good Syndrome-GS, 2 STAT1-GOF, 2 MSMD and one AT. Ten patients (55,5%) had mild flu syndrome and only one patient was asymptomatic. Hospitalization was necessary for 7 patients (38,8%) due to respiratory complications and 3 (16.6%) deceased (2 XLA and 1 GS). Two patients were reinfected (STAT1-GOF and MSMD), with no need for hospitalizations or long-term complications. One of the XLA patients remains hospitalized, with fever for more than 90 days. Five patients experience coughing and tiredness after more than three months of the disease, one also persists with anosmia. Conclusion: Almost 40% of our sample required hospitalization and 16% died. This rate is worrying and reveals how much immunological competence is required by SARS-CoV-2 as well as the fact that Brazil has increasing death rates from COVID-19. Post-acute COVID-19 syndrome (PASC) has presented in more than 25% of IEI patients infected with SARS-CoV-2.

X-linked agammaglobulinemia presenting with pseudomonas skin abscesses: A case report

Introduction : The skin may be involved in inborn errors of immunity (IEI) and serve as important clues for diagnosis. We report a boy presented with subcutaneous abscesses caused by Pseudomonas aeruginosa and diagnosed as X-linked agammaglobulinemia (XLA). Case Report : A 13-months-old boy patient was referred to our immunology clinic with a history of recurrent fever and skin lesions resistant to conventional therapies on his limbs and cyclic neutropenia. He was the first child of consanguineous parents. His past medical history revealed that he had been suffering from recurrent otitis media, sinopulmonary infections, and conjunctivitis since the age of four months. He was hospitalized with a diagnosis of otitis media, and his fever persisted despite the given antibiotic treatment. Skin abscesses on his extremities occurred and were drained. On physical examination, there were a total of 16 erythematous, hemorrhagic subcutaneous nodules with central black eschar. His tonsils were rudimentary. Peripheral blood sampling showed a white blood cell count 41.3 × 109 /L with 52.3 × 109 /L neutrophils, 33.1 × 109 /L lymphocytes, %2.6 × 109 /L eosinophils, hemoglobin 9.9 g/L, and a platelet count of 397 × 109 /L. Sedimentation 18 mm/h. COVID-19 real-time PCR was negative. His immunological screening revealed that agammaglobulinemia and absence of B cells, consistent with X-linked agammaglobulinemia (Table 1). BTK gene sequence analysis showed the presence of a BTK:c.404-406delACA and BTK:c.407-408insCTTTA hemizygous mutations. To our knowledge, it has never been described before that the compound heterozygosity of these mutations causes X-linked agammaglobulinemia. These variants were classified as likely pathogenic according to the ACMG guidelines and confirmed as XLA. His mother is the carrier. Pseudomonas aeruginosa was isolated in his abscess cultures. Abscess lesions on the right and left leg were drained again, but they repeated. Hereby, the abscess lesions and subcutaneous nodules were evacuated by plastic surgery, and the daily dressing was done with silver material. In the follow-up, the skin lesions improved gradually. The patient was discharged with immunoglobulin replacement therapy and prophylactic antibiotic. Conclusion : Pseudomonas skin infection is common among IEIs, especially patients with neutropenia. XLA should be kept in mind in the evaluation of unexplained cyclic neutropenia and skin abscess resistance to therapy. (Table Presented).

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

X-Linked Agammaglobulinemia and COVID-19: Two Case Reports and Review of Literature.

Introduction: The Centers for Disease Control and Prevention (CDC) has listed primary immunodeficiency disorders as being predisposed to severe coronavirus disease 2019 (COVID-19). However, patients affected with X-linked agammaglobulinemia (XLA) have shown contrary results. In this study, we present 2 boys in late adolescence from south India with XLA who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as a review of cases reported in the literature. Case Presentation: Two patients with XLA had been diagnosed late and were started on regular immunoglobulin prophylaxis only during adolescence. Both of them had developed bronchiectasis, an irreversible suppurative lung disease. However, both patients made an uneventful recovery without the need for artificial ventilation or convalescent plasma. Conclusion: Successful outcomes of patients with XLA and COVID-19, except for delayed recovery, from our experience and from global reports are intriguing and the role of B cell depletion is being studied as well. Further research and clinical experience are necessary to fully elucidate the reasons for these observations.

BTK inhibitors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A systematic review.

INTRODUCTION: The Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe COVID-19, however clinical outcome data is inconclusive. OBJECTIVE: To evaluate the clinical outcomes of BTK inhibitors (BTKinibs) in patients with COVID-19. EVIDENCE REVIEW: We searched PubMed, Embase, and Web of Science:Core on December 30, 2020. Clinical studies with at least 5 COVID-19 patients treated with BTKinibs were included. Case reports and reviews were excluded. FINDINGS: 125 articles were identified, 6 of which met inclusion criteria. The most common clinical outcomes measured were oxygen requirements (4/6) and hospitalization rate or duration (3/6). Three studies showed decreased oxygen requirements in patients who started or continued BTKinibs. All three studies that evaluated hospitalization rate or duration found favorable outcomes in those on BTKinibs. CONCLUSIONS AND RELEVANCE: BTKinib use was associated with decreased oxygen requirements and decreased hospitalization rates and duration.

Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.

BACKGROUND: The recent SARS-CoV-2 pandemic, which has recently affected Italy since February 21, constitutes a threat to normal subjects, as the coronavirus disease-19 (COVID-19) can manifest with a broad spectrum of clinical phenotypes ranging from asymptomatic cases to pneumonia or even death. There is evidence that older age and several comorbidities can affect the risk to develop severe pneumonia and possibly the need of mechanic ventilation in subjects infected with SARS-CoV-2. Therefore, we evaluated the outcome of SARS-CoV-2 infection in patients with inborn errors of immunity (IEI) such as X-linked agammaglobulinemia (XLA). METHODS: When the SARS-CoV-2 epidemic has reached Italy, we have activated a surveillance protocol of patients with IEI, to perform SARS-CoV-2 search by nasopharyngeal swab in patients presenting with symptoms that could be a manifestation of COVID-19, such as fever, cough, diarrhea, or vomiting. RESULTS: We describe two patients with X-linked agammaglobulinemia (XLA) aged 34 and 26 years with complete absence of B cells from peripheral blood who developed COVID-19, as diagnosed by SARS-CoV-2 detection by nasopharyngeal swab, while receiving immunoglobulin infusions. Both patients developed interstitial pneumonia characterized by fever, cough, and anorexia and associated with elevation of CRP and ferritin, but have never required oxygen ventilation or intensive care. CONCLUSION: Our report suggests that XLA patients might present with high risk to develop pneumonia after SARS-CoV-2 infection, but can recover from infection, suggesting that B-cell response might be important, but is not strictly required to overcome the disease. However, there is a need for larger observational studies to extend these conclusions to other patients with similar genetic immune defects.