IgM plays a central role in early immune responses, yet the clinical significance of its deficiency remains poorly defined. Current diagnostic criteria focus on selective IgM deficiency (sIgMD), characterized by persistently low IgM concentrations and recurrent infections, potentially overlooking patients with isolated IgM deficiency and non-infectious manifestations. In this retrospective study, we analyzed a pediatric cohort with isolated IgM deficiency, irrespective of infectious history. Clinical features-including cytopenia, lymphoproliferation, autoimmunity, allergy, and inflammation-were similarly distributed in patients with and without infections. Importantly, 26% of patients received a molecular diagnosis consistent with inborn errors of immunity (IEIs), including several without recurrent infections. Longitudinal analysis revealed a dynamic course of IgM concentrations over time, allowing classification into chronic, intermittent, progressive, and resolved subtypes. These findings challenge the current definition of sIgMD, highlight the limitations of relying solely on infectious history, and suggest that isolated IgM deficiency may represent a broader and heterogeneous immunological phenotype. Molecular testing and extended follow-up may help identify underlying inborn errors of immunity and clarify long-term risks, even in patients initially lacking infectious complications. A redefinition of IgM deficiency is warranted.

Mycoplasma pneumoniae is widely recognized as a leading cause of community-acquired atypical pneumonia and can trigger a wide spectrum of extra-pulmonary manifestations. This report discusses a rare clinical presentation of a young female patient who was admitted with an acute-onset, severe febrile illness. Her initial symptoms included a persistent cough with minimal purulent expectoration and mild difficulty in breathing, which rapidly progressed to severe dyspnea at rest. Her condition deteriorated swiftly, resulting in acute hypoxemic respiratory failure that required emergent endotracheal intubation and mechanical ventilation. Initial diagnostic imaging revealed diffuse bilateral interstitial and alveolar infiltrates, suggestive of severe pneumonia. The initial comprehensive workup, which included routine blood analyses, blood and sputum cultures, and a viral respiratory panel, was negative for any specific pathogen. During the hospital stay, the patient developed new-onset moderate anemia. A detailed hematological investigation showed mixed autoimmune hemolytic anemia (AIHA). The presence of AIHA in a patient presenting with acute respiratory infection guided the diagnostic workup, ultimately identifying M. pneumoniae as the causative agent. Further immunological evaluation was done to explore this unusual presentation and revealed an underlying selective IgM deficiency with the presence of anti-La (SS-B) antibodies, suggesting a pre-existing state of immune dysregulation that may have predisposed her to these severe pulmonary and systemic manifestations. The management of this case was multifaceted. The patient received aggressive respiratory support along with targeted antimicrobial therapy, an extended course of azithromycin. After a prolonged hospitalization, she was successfully weaned from mechanical ventilation and eventually made a full clinical recovery. This report provides insight into the diverse clinical spectrum of M. pneumoniae infection and emphasizes the importance of maintaining a high index of suspicion in cases of unexplained AIHA. A clinical presentation of this severity in response to a common pathogen should prompt a thorough investigation for an underlying immunodeficiency state. This report is, to our knowledge, a rare clinical presentation that depicts the unique clinical triad of mixed AIHA, acute M. pneumoniae infection, and an underlying selective IgM deficiency.

22q11.2 deletion syndrome (22qDS) is a heterogeneous genetic disorder associated with a variety of clinical manifestations, including congenital heart disease, neuropsychiatric disorders, hypocalcemia, and immunological deficiencies. This study aimed to characterize the clinical and immunological features of patients with 22qDS in a cohort from Colombia. We conducted a retrospective study over a 3-year period, including 40 patients with confirmed 22qDS. Demographic, clinical, and immunological data were collected from medical records. The cohort had a median age of 3 years, with a balanced sex distribution. Heart defects were present in 75% of patients, followed by ear and craniofacial abnormalities (50%) and language disorders (45%). Immunological work-up revealed low T cell subsets in 42% of patients, with a decrease in T cell lymphopenia observed with age. Humoral deficiencies were also common, with 20% of patients exhibiting selective IgM deficiency and 17% presenting with hypogammaglobulinemia. Recurrent infections were observed in 48% of patients, particularly pneumonia and otitis. Vaccine responses to protein-based antigens and polysaccharides were frequently impaired. The findings highlight the clinical and immunological heterogeneity of 22qDS in this Latin American cohort. Multidisciplinary care, early diagnosis, and immunological management are essential for improving outcomes in these patients.

Immunoglobulin (Ig)E deficiency (<2.5 IU/mL) in adults is linked to higher risks of cancer and autoimmunity, but its significance in children remains unclear. This study evaluates the clinical importance of IgE deficiency in a nationwide pediatric cohort. A retrospective, population-based study included 123,393 Israeli children tested for IgE levels between 2002 and 2022. Participants were categorized into four groups: deficient (<2.5 IU/mL), normal (2.5-100 IU/mL), high (100-1000 IU/mL), and very high (≥1000 IU/mL). Outcomes included cancer, inborn errors of immunity (IEI), and autoimmune disorders, with up to 5 years of follow-up. The data were analyzed using univariable methods and multivariable Cox regression. Among the cohort, 2114 children (1.71%) had IgE deficiency, with a mean age of 3.73 years. Most (95.60%) were tested only once. IgE deficiency was associated with increased risks of solid tumors (HR = 2.721; 95% CI: 1.313-5.638), IEI (HR = 1.646; 95% CI: 1.095-2.474), and autoimmune disorders (HR = 1.266; 95% CI: 1.099-1.458) compared to normal IgE levels. No link was found between IgE deficiency and hematological malignancies. Selective IgM deficiency was the most common IEI associated with IgE deficiency (40%). Asthma prevalence was highest in children with very high IgE (N = 5574; 57.01%) and lowest in the normal IgE group (N = 24,171; 38.91%). The IgE-deficient group fell in the middle range (N = 903; 42.72%). In IgE-deficient children, allergic rhinitis was less common (11.26% vs. 14.09%). IgE deficiency in children is associated with higher risks of solid tumors, autoimmune disorders, and IEI, suggesting potential immune dysregulation. Close monitoring of IgE-deficient children should be considered.

Background: B-cell-depleting drugs targeting the CD20 antigen have been increasingly implemented as an "exit strategy" from natalizumab for relapsing-remitting multiple sclerosis (RRMS) patients due to the increased risk of progressive multifocal leukoencephalopathy. Data on recently approved anti-CD20 drugs, such as ofatumumab serving as a natalizumab "exit strategy", are lacking. Furthermore, due to their immunosuppressive mechanism of action, prolonged use of these "highly effective" drugs is associated with the development of hypogammaglobulinemia and, consequently, a higher risk of infections. There are no guidelines for monitoring serum immunoglobulin levels in individuals undergoing "highly effective" multiple sclerosis treatment. Methods: We present a case of a 26-year-old male RRMS patient with selective IgM deficiency and multiple sclerosis initially treated with natalizumab and later ofatumumab. Results: The patient achieved "no evident disease activity "status while undergoing treatment with natalizumab and ofatumumab, but these therapies, especially ofatumumab, greatly impacted further drops in IgM levels. However, no significant decrease in IgG levels was observed, and no infectious events occurred. In addition, the patient did not show signs of disease activity while on ofatumumab, which also offered a more convenient mode of administration. Conclusions: Our experience points to the need to further explore benefit-risk ratios of highly effective treatments, even in cases with low immunoglobulin levels. However, closely monitoring immunoglobulin levels and conducting clinical follow-ups to ensure prompt recognition of potential infectious complications constitute approaches that have been thought of for such patients.