|Year : 2020 | Volume
| Issue : 1 | Page : 43-48
Selective immunoglobulin M deficiency: An underestimated immunodeficiency disorder – not so rare
Department of Internal Medicine, Fortis Escorts Hospital, Jaipur, Rajasthan, India
|Date of Submission||14-Dec-2019|
|Date of Acceptance||15-May-2020|
|Date of Web Publication||6-Jul-2020|
Dr. Arun Agarwal
A-235, Shivanand Marg, Malviya Nagar, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Immunoglobulin M (IgM) is the first antibody to be produced during an immune response, and most of the primary humoral immune response is mediated by IgM. Selective IgM deficiency (sIgMD) is a rare immune disorder that has been reported in the association with serious infections. Patients with sIgMD may be asymptomatic; however, approximately 80% of patients present with infections with bacteria, viruses, or protozoa or with an associated allergic, malignant, or autoimmune condition. sIgMD is usually identified when evaluating a patient for recurrent or serious infections. Attempts should be made to document the infection, as well as the responsible organism, whenever possible. It is a diagnosis of exclusion, and formal diagnostic criteria have not been established. We report three adult cases that were diagnosed to have sIgMD during the evaluation for serious polymicrobial infections with bacteria, fungi, mycobacterium, and viruses. One of them was diagnosed to have associated lymphocytic leukemia. All were successfully managed with intravenous Immunoglobulin (Ig), antibiotics, antiviral, supportive treatment, and discharged. We conclude that patients presenting with polymicrobial infections with encapsulated bacteria, fungi, mycobacterium, and viruses should be evaluated for specific antibody deficiency responses, and they appear to improve clinically on Ig therapy. It appears that the disorder is underdiagnosed.
Keywords: Immunoglobulin, mycobacterium, polymicrobial infection, recurrent infections, selective immunoglobulin M antibody deficiency
|How to cite this article:|
Agarwal A. Selective immunoglobulin M deficiency: An underestimated immunodeficiency disorder – not so rare. Indian J Allergy Asthma Immunol 2020;34:43-8
|How to cite this URL:|
Agarwal A. Selective immunoglobulin M deficiency: An underestimated immunodeficiency disorder – not so rare. Indian J Allergy Asthma Immunol [serial online] 2020 [cited 2022 Nov 26];34:43-8. Available from: https://www.ijaai.in/text.asp?2020/34/1/43/289067
| Introduction|| |
Selective immunoglobulin M (IgM) deficiency is a rare form of dysgammaglobulinemia, characterized by an isolated low level of serum IgM. Selective IgM deficiency (sIgMD) is a disorder with serum IgM below the two standards of mean and normal IgG, IgA, and T-cell functions. It appears to be more common than originally realized and is seen in both children and adults. sIgMD is characterized by the certain clinical and laboratory features, including isolated absence or deficiency of IgM, normal levels of other Ig's (notably IgG and IgA), recurrent infections associated with susceptibility to Staphylococcus aureus, encapsulated pathogens (Streptococcus pneumoniae, Haemophilus influenza, Neisseria More Details meningitidis, Salmonella More Details typhi, etc.), and viral infections, association with autoimmune or malignant conditions (but not a prerequisites for the diagnosis), normal T-cell numbers and function and no other identifiable immunodeficiency. A number of B-cell subset abnormalities have been reported and impaired specific antibodies to S. pneumoniae responses are observed in more than 45% of cases. Innate immunity, T-cells, T-cell subsets, and T-cell functions are essentially normal.
The reported prevalence of sIgMD is 0.26% among adults and 0.03% among children, and 1% in hospitalized patients. The incidence of sIgMD in various races has not been reported, given the low overall incidence, and it occurs in both males and females, with no known discrepancies between the sexes. sIgMD may occur as a primary or secondary condition. Secondary sIgMD is much more common than primary sIgMD and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and immunosuppressive treatment. Some patients are asymptomatic, whereas others (often infants and small children) develop serious infections. Patients may develop prolonged or life-threatening infections caused by both encapsulated bacteria and viruses. All three cases discussed were elderly and admitted with bacterial and viral infection that persisted despite treatment with susceptible antibiotics and best-supportive care including bronchoalveolar lavage (BAL). About 60%–80% of patients with sIgMD suffer from repeated infections with both bacterial and viral pathogens and common clinical presentation include recurrent otitis media, bronchitis, chronic rhino sinusitis, pneumonia, and sepsis., Patients with sIgMD and recurrent infections are managed similarly to the individuals with other antibody defects and deficiencies. The replacement of IgM is not an option, as there are only trace amounts of IgM in therapeutic preparations of intravenous Ig (IVIG). However, defective antigen-specific IgG responses to capsular organisms in these patients despite a normal (or elevated) level of IgG have been demonstrated in some patients. For such symptomatic patients, IVIG replacement may be an option. All three cases were successfully treated with IVIG. We discuss the clinical presentation, diagnosis, management of these cases in this small case series, and review the current literature.
| Case Reports|| |
A 65-year-old male patient had a head injury in September 2018 with left temporal contusion, right-side hemiparesis, and was bed ridden since then. He also had hypertension, Parkinson's disease, bed sores Grade 2, and was admitted at Fortis Escorts Hospital, Jaipur (FEHJ), on 24.02.2019 with complaints of high-grade fever with chills, cough with expectoration, and breathlessness of 7–10 days duration. He was being fed orally by family despite coughing during meals and altered sensorium. On examination, his vital parameters were as follows: Pulse 124/min, Blood pressure 103/72 mm Hg, peripheral capillary oxygen saturation (SpO2) 76%, temperature 104.3°F, respiratory rate 37/min, arterial blood gas showed pH 7.36, pO2 55 mm Hg, pCO2 35.9 mm Hg, lactate 1.56 mmol/L, and HCO3 19.8 mmol/L consistent with acute metabolic acidosis with concomitant respiratory alkalosis. He had mild pallor. On systemic examination, he had bilateral basal coarse crepitations, neurological status E4V1M3 with right hemiparesis. The rest of the clinical examination was essentially normal. He had no hepatosplenomegaly or peripheral lymphadenopathy. He was intubated and mechanically ventilated. His XR chest is in [Figure 1]a and culture reports in [Table 1]. He had possibility of aspiration pneumonitis and respiratory sample on culture showed polymicrobial flora. He was managed with antibiotics piperacillin + tazobactum and clindamycin initially which were later changed to polymyxin, meropenem, fluconazole, and other supportive drugs. However, his fever persisted and his hospital stay was complicated by non ST-elevation myocardial infarction, episode of paroxysmal supraventricular tachycardia, hypotension, acute kidney injury (AKI) requiring hemodialysis, and tracheotomy was done. His differential counts showed lymphocytosis in the range of 51%–62%, and chronic lymphoproliferative disorder panel with immunophenotypic markers was done. It was consistent with the diagnosis of B–chronic lymphocytic leukemia (CLL) (score 5)/small lymphocytic lymphoma. No active intervention was done for CLL in view of his age and poor medical condition. In the presence of persistent fever with polymicrobial infection and B-CLL, possibility of immunodeficiency syndrome was considered, and he was diagnosed with sIgMD. He was given 400 mg/kg IVIG in a single dose and antibiotics as per the culture-sensitivity reports. He responded to the administration of IVIG, became afebrile, culture got sterile, weaned off from ventilator support, and could be discharged on March 17, 2019. Later, another IVIG dose was given after 14 days. He was last seen on October 28, 2019 and is doing fine.
|Figure 1: Chest X ray: Panel A (case 1) show right upper and lower zone heterogeneous infiltration. Panel B (case 2) shows bilateral bronchopneumonia with cardiomegaly. Panel C (case 3) show collapse consolidation of the right lower lobe with mild bilateral pleural effusions|
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|Table 1: Type of selective immunoglobulin M deficiency, outcome, and body fluid culture/PCR/IgM antibody detection|
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A 77-year-old female patient attended triage at FEHJ, on 06.04.2019 with complaints of watery loose stools, pain abdomen, and fever with mild chills, generalized weakness, cough, and breathlessness of 2 days duration. She had no vomiting, black color or blood in stools, coryza, and rash. She had type 2 diabetes mellitus, hypertension, and ILD-? Hypersensitivity pneumonitis and had been taking methyl prednisolone 4 mg daily for the past 6 months. She was operated almost 10 years back for incisional hernia and almost 30 years back for hysterectomy.
On examination, her vital parameters were as follows: pulse 110/min, blood pressure 99/64 mm Hg, peripheral capillary SpO2 94%, temperature 99.4°F, and respiratory rate 23/min. She had mild pallor. On systemic examination, she had bilateral extensive coarse crepitations, neurological status E4V5M6, rest of the clinical examination was essentially normal. She had no hepatosplenomegaly or peripheral lymphadenopathy. She was admitted in medical ICU. Her random plasma glucose was 297 mg/dl. She had leukocytosis (TLC 12.24 × 103 cells/cu.mm), mild azotemia (serum creatinine 2.99 mg/dl), and bilateral bronchopneumonia. Arterial blood gas showed pH 7.35, pO2 72.9 mm Hg, pCO2 25.1 mm Hg, lactate 5.12 mmol/L HCO3 13.5 mmol/L, and base excess of-10.7 consistent with acute metabolic acidosis with concomitant respiratory alkalosis. Her blood and stool cultures were positive for salmonella group B (further serotyping could not be done). She tested positive for influenza A PCR (nasopharyngeal secretions) and IgM Legionella antibodies were also detected positive. Her XR chest is in [Figure 1]b and culture reports in [Table 1]. She was managed with antibiotics ofloxacin, azithromycin, meropenem and oseltamivir, low-dose steroids, human insulin, nebulization with levosalbutamol and budesonide, and other supportive treatment.
Her hospital stay was complicated by hypotension, AKI, and Type 1 respiratory failure requiring noninvasive ventilation. Her fever persisted for about 7 days. Contrast-enhanced computed tomography (CT) of the chest with ILD protocol suggested possible ILD with nonspecific interstitial pneumonia pattern. In view of polymicrobial infection (influenza A, probable Legionella Pneumophila, and S. typhi group B) with non typhoidal salmonella enteritis and bacteremia, possibility of sIgMD was considered. Her serum Ig's are mentioned in [Table 2]. She was given single dose of IVIG 400 mg/kg body weight on April 11, 2019. She responded to above treatment and was discharged on April 17, 2019. She was last seen on April 30, 2019 and was doing fine.
A 89-year-old female, known case of hypertension and bronchial asthma – Chronic obstructive pulmonary disease, attended FEHJ triage on March 22, 2019 with the complaints of difficulty in speaking, decreased appetite, frequent coughing after taking oral feeds, abdominal discomfort, and mild cough of 4 days duration. She had gross hydronephrosis right side since 2013 with nonfunctioning right kidney. Family did not take any treatment for this. She had no history of vomiting, fever, and decreased urine output. On examination, her vital parameters were as follows: pulse 84/min, blood pressure 156/76 mm Hg, SpO2 92% on air, temperature 98.2°F, and respiratory rate 18/min. She had mild pallor. On systemic examination, she had decreased air entry over right infrascapular area, bilateral basal coarse crepitations, neurological status E4V5M6, and right side grossly enlarged kidney. The rest of the clinical examination was essentially normal. She was admitted under urology care in high-dependency unit. On March 28, 2018 morning, she was shifted to MICU for altered sensorium and diagnosed to have type 2 respiratory failures. Arterial blood gas showed pH 7.1, pO2 78 mm Hg, pCO2 100 mm Hg, lactate 1.82 mmol/L, and HCO3 31 mmol/L consistent with chronic respiratory acidosis with concomitant metabolic acidosis. She was intubated and mechanically ventilated. Her routine biochemistry showed mild leukocytosis with lymphopenia (Lymphocytes 6%–9%), mildly deranged renal functions (AKI), hypoalbuminemia, and mild transaminitis.
Right side PCN (per cutaneous nephrostomy) was done under local anesthesia on March 23, 2019, and 2000 ml of urine was drained. In view of collapse consolidation of right lower lobe on X-ray chest [Figure 1]c, CT scan of the chest was done on March 26, 2019 which showed hypodense-filling defect in the right main bronchus extending into lower lobe secondary and tertiary level of bronchial territory leading to near complete obliteration of lumen causing right lower lobe collapse without patent bronchial communication with ipsilateral shift of mediastinum, bilateral mild pleural effusion (R > L) with adjacent atelectasis changes, air space opacity with ground-glass haziness in bilateral basal segments – squeal of aspiration pneumonitis. Bronchoscopy was done, and right main bronchus was full of undigested food particles. Bronchial toileting and lavage was done [Figure 2].
|Figure 2: Bronchoscopy image of case 3. Mucus plugging completely obstructing right main stem bronchus/Segmental branches|
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She had aspiration pneumonitis and respiratory sample on culture showed polymicrobial flora. Mycobacterium tuberculosis polymerase chain reaction test was reported positive twice. She was managed with antibiotics, antifungal, antitubercular treatment (ATT), and other supportive drugs. Tracheotomy was done on March 30, 2019. However, she could not be weaned off from the ventilation, and her respiratory samples were persistently positive for microbial infection [Table 1]. Her hospital stay was complicated by AKI, large bowel paralytic ileus that required colonoscopy decompression, critical illness neuromyopathy, sepsis, dyselectrolytemia, and metabolic encephalopathy. In view of persistent polymicrobial infection in the lungs, she was evaluated for immunodeficiency syndrome [Table 2]. She was diagnosed with sIgMD, and she was given 400 mg/kg IVIG in a single dose, and antibiotics were continued as per culture-sensitivity reports. She responded to administration of IVIG, and her last respiratory sample culture became sterile. However, she had difficult weaning and was discharged for home care on April 15, 2019, as per family wishes.
| Discussion|| |
sIgMD is a disorder with serum IgM below two standard of mean, and normal IgG, and IgA and T cell functions. In 1967, Hobbs et al. first described two children with sIgMD (type V dysgammaglobulinemia) presenting with fulminant meningococcal meningitis. Since then, number of patients with sIgMD has been reported. However, there are no large-scale studies reported for the prevalence of sIgMD. We earlier reported a case of an adult male with B-cell lymphoid disorder and secondary hemophagocytic lymphohistiocytosis diagnosed with sIgMD. He presented with serious and recurrent life-threatening infections. The cause of sIgMD is unknown. Although occasional symptomatic familial cases of sIgMD have been reported, no definitive inheritance pattern is known for sIgMD.,,,
As seen in other primary immunodeficiency disorders, patients with sIgMD commonly presents with recurrent infections with common microbes, and increased frequency of allergic and autoimmune diseases. Recurrent infections are the presenting feature in more than 80% of cases and can even become serious and life-threatening. The clinical infectious presentations include recurrent otitis media, chronic sinusitis, bronchitis, bronchiectasis, pneumonia, urinary tract infections cellulitis, meningitis, and sepsis. Some of the common microbial organisms include S. pneumoniae, H. influenzae, N. meningitidis, Pseudomonas aeruginosa, Aspergillus fumigatus, and Giardia lamblia.,,, Many of these organisms express epitopes of phosphorylcholine in their cell walls that are similar to those expressed on apoptotic cells and recognized by natural IgM. Cases of possible primary sIgMD in adults with no evidence of autoimmunity or malignant neoplasm have been reported. Adult patients usually present with mild infections.
We have described three adult cases who presented with serious life-threatening polymicrobial infection with capsulated bacterias, fungi, and viruses. In all these cases, polymicrobial and serious life-threatening infections rather than recurrent infection lead us to investigate them for immunodeficiency disorder.
Case 1 had Enterococcus faecium in urine and P. aeruginosa, Escherichia More Details coli, S. aureus, and Klebsiella pneumoniae in respiratory sample. All these microbes are encapsulated organisms. Besides these, he also had Candida albicans isolated from urine and respiratory sample. We could not find any case report in the literature of Candida infection in sIgMD patients. It has been shown that mutant mice deficient in secreted IgM, are unable to control viral, bacterial, and fungal infections due to impaired induction of a protective specific IgG antibody response and lack of serum IgM.,, Case 2 had salmonella Group B (encapsulated microbe) isolated from blood and stool samples and influenza A from respiratory sample. She also tested positive for Legionella pneumophilia serogroup 1 IgM antibodies. However, Legionella antigenuria was negative. Isolation of nontyphoidal salmonellae group B (further serotyping could not be done) causing bacteremia and acute enteritis, associated with life-threatening viral (influenza A) bilateral community-acquired pneumonia and possibly Legionella pneumophilia infection lead us to evaluate her for immunodeficiency disorder. Case 3 had life-threatening pneumonia with collapse consolidation of the right lower lobe. K. pneumoniae (encapsulated microbe) and Candida albicans were isolated from BAL. Mycobacterium tuberculosis PCR was also reported detected twice from BAL. Patients of sIgMD with lymphopenia and Mycobacterium infection have been reported in literature and may represent a distinct clinical entity. It is associated with severe T-cell lymphopenia (predominantly CD4+ T cells), decreased NK cell activity and decreased interferon alpha production., Mice unable to secrete IgM have been shown to be more susceptible to aerosol Mycobacterium tuberculosis fection than those lacking all other Ig isotypes with increased mortality during chronic tuberculosis. However, sIgMD in an adult patient with miliary tuberculosis without any T-cell disorder has also been reported. Although case 3 had severe lymphopenia (6%–8%), we did not evaluate her for NK cell activity and lymphocytes subset. It might be possible that she had increased susceptibility to aerosol mycobacterium tuberculosis infection due to sIgMD as has been reported in other case reports. Improvement in lymphopenia after starting ATT has also been reported., Is there any possibility of direct relationship between the occurrence of secondary IgMD and MTB is not known. Case 3 was lost to follow-up, and we could not monitor the improvement in lymphopenia with ATT.
Several studies have previously reported and classified IgMD in primary or secondary type. Case 1 was diagnosed to have associated B-cell–CLL (score 5)/small lymphocytic lymphoma along with polymicrobial infection and sIgMD, representing secondary sIgMD. The other two cases had no history of autoimmune disease or malignancy, as demonstrated in secondary IgMD, so primary IgMD was suggested.
sIgMD is usually identified when evaluating a patient for recurrent or serious infections. Serious and polymicrobial infection led us to diagnose sIgMD in these patients. Patients with sIgMD and recurrent infections are managed similarly to the individuals with other humoral immune defects, although there are no studies to evaluate the effectiveness of these interventions specifically in patients with sIgMD. Measures to prevent recurrent infections include vaccinations, aggressive management of allergic respiratory disease, and in some cases, prophylactic antibiotics or IVIG therapy. The replacement of IgM would be an ideal therapy for sIgMD patient. However, there are no commercial Ig preparations available that is highly enriched in IgM.
Commercially available immunoglobulin contains very little IgM. However, it appears that the propensity of patients with sIgMD to get infections is likely not simply related to low-serum IgM. Patients with frequent infections, despite preventive measures, who were treated with IVIG and had an excellent clinical response, had been reported in literature., All these cases were managed with IVIG, antimicrobial drugs, and supportive treatment with favorable prognosis.
We conclude that sIgMD although rare is underestimated. The presence of recurrent or serious microbial infection, particularly polymicrobial infections should lead clinician to evaluate the patient for the errors of immunity. Furthermore, mycobacterium infections, especially miliary tuberculosis without T-cell disorder in a healthy adult should lead to further investigation of underlying diseases including primary immunodeficiencies. Patients with sIgMD presenting with recurrent or serious infections and specific antibody deficiency responses appear to improve clinically on Ig therapy. For autoimmune manifestations of sIgMD, highly enriched IgM preparations may be the most desirable therapeutic modality.
Author AA was the primary consultant in these cases. He contributed to the conception, design, and analysis of the case study. He also did the tabulation work, literature searches, and final grammar correction of the manuscript.
The authors have obtained written consent from the family for the publication of the case reports.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2]