Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016 91 Symptomatic Primary Selective IgM Immunodeficiency - B Lymphoid Cell Defect in Adult Man with Secondary HLH Syndrome Arun Agarwal 1 , Samiksha Sharma 2 , Mala Airun 3 1 Senior Consultant and Head, Department of Internal Medicine, 2 Consultant, Department of Pathology, 3 Clinical Director, Narayana Multispecialty Hospital, Jaipur, Rajasthan Received: 03.06.2015; Revised: 29.07.2015; Re-revised: 30.09.2015; Accepted: 28.10.2015 Introduction P rimary selective immunoglobulin M deficiency (sIgMD) is rare and usually presents early in life with recurrent or severe infections including sepsis, pneumonia or meningitis caused by encapsulated and gram-negative organisms. Primary sIgMD in adults is rare and is usually associated with autoimmune diseases or malignant neoplasm. Many patients show concurrent increase in levels of other immunoglobulins, such as IgG, IgE and IgA. We present a case of primary sIgMD syndrome who presented in adult life with serious and recurrent life threatening infections and secondary hemophagocytic lymphohistiocytosis (HLH) syndrome. Case Presentation A 27 years male was admitted on 16.04.2015 with complaints of fever, weakness and altered sensorium of 10-12 days duration. His old records showed that he developed generalized erythematic pruritic skin rash 6 months ago which was diagnosed as Erythema Gyratum Repens and managed with steroids and antibiotics (complete records not available). Later he developed bilateral severe pneumonia (community acquired pneumonia) with pancytopenia, mildly raised AST/ALT, hypoproteinemia (Table 1), and mildly raised PT-INR (1.88). ECG showed LBBB. He was further evaluated.His 2D Echo, X-ray chest, serology for HIV, HBV, HCV and EBV, ANA, ANCA, MRI brain, were normal. ACTH stimulation test was done in view of persistent hypotension with no evidence of hypoperfusion and he was confirmed to have Adrenal insufficiency. In view of serious and recurrent infections over last 6 months (skin and lung) and hypogammaglobulinemia he was evaluated for possible immunodeficiency syndrome. His immunoglobulin profile (Table 2) showed significantly low S.IgM, borderline S.IgG, normal S.IgA, and raised S.IgE levels; for persistent pancytopenia bone marrow aspiration, biopsy and flowcytometry (Table 3) evaluation were done. He was diagnosed to have secondary HLH syndrome (fever, splenomegaly, pancytopenia, hypertriglyceridemia – hypofibrinogenemia, hemophagocytosis in bone marrow (Figure 1) and raised S.Ferritin along with CNS features, and altered LFTs) (Table 3). Bone marrow flowcytometry and immunophenotyping (Table 4) showed that lymphocytes Abstract Selective immunoglobulin M deficiency(sIgMD) is a rare form of dysgammaglobulinaemia characterized by an isolated low level of serum immunoglobulin M (IgM). It was an incidence of less than 0.03% in the general population and 1% in hospitalized patients. sIgMD may occur as a primary or secondary condition. sIgMD is much more common than primary . Hemophagocytic lymphohistiocytosis (HLH) is also a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes and can be primary or secondary, characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations. We report an adult case of primary sIgMD with absent B lymphoid cells and secondary HLH syndrome who presented with recurrent infections, fever and pancytopenia. multi organ dysfunction syndrome and was admitted the critical care unit in Jaipur. He was mechanically ventilated for a week. Bone marrow examination done was unremarkable. However, pancytopenia persisted and he was again admitted in another hospital with sepsis and later transferred at our centre for further management on inotropic support. On admission he was disoriented, confused had dysarthria, diffuse muscular fasciculation, hypotension, and moderate splenomegaly. His routine labs showed mild proteinuria, Table 1: Hematology and biochemistry Hb (gm/dl) TLC (10 3 /cmm) Platelet counts (10 3 /cmm) S. total proteins (gm/dl) S. albumin (gm/dl) AST/ALT (IU/L) S.T. bilirubin (mg/dl) S. direct bilirubin (mg/dl) 16.04.15 9.8 1.58 06 4.53 2.30 70/111 1.6 1.2 18.04.15 8.7 1.63 15 20.04.15 6.9 1.37 05 3.92 1.95 48/73 1.1 0.8 21.04.15 10.8 2.20 10 22.04.15 11.0 5.73 29 23.04.15 10.5 6.71 04 24.04.15 11 25.04.15 06 26.04.15 07 19.05.15 14.2 5.48 44 17/41
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Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016 91
Symptomatic Primary Selective IgM Immunodeficiency - B Lymphoid Cell Defect in Adult Man with Secondary HLH SyndromeArun Agarwal1, Samiksha Sharma2, Mala Airun3
1Senior Consultant and Head, Department of Internal Medicine, 2Consultant, Department of Pathology, 3Clinical Director, Narayana Multispecialty Hospital, Jaipur, RajasthanReceived: 03.06.2015; Revised: 29.07.2015; Re-revised: 30.09.2015; Accepted: 28.10.2015
Introduction
Primary selective immunoglobulin M deficiency (sIgMD) is rare and
usually presents early in life with recurrent or severe infections including sepsis, pneumonia or meningitis caused by encapsulated and gram-negative organisms. Primary sIgMD in adults is rare and is usually associated with autoimmune diseases or malignant n e o p l a s m . M a n y p a t i e n t s s h o w concurrent increase in levels of other immunoglobulins, such as IgG, IgE and IgA. We present a case of primary sIgMD syndrome who presented in adult life with serious and recurrent life threatening infections and secondary hemophagocytic lymphohistiocytosis (HLH) syndrome.
Case Presentation
A 27 years male was admitted on 16.04.2015 with complaints of fever, weakness and altered sensorium of 10-12 days duration. His old records showed that he developed generalized erythematic pruritic skin rash 6 months ago which was diagnosed as Erythema Gyratum Repens and managed with steroids and antibiotics (complete r e c o r d s n o t a va i l a b l e ) . L a t e r h e developed bilateral severe pneumonia (community acquired pneumonia) with
pancytopenia, mildly raised AST/ALT, hypoproteinemia (Table 1), and mildly raised PT-INR (1.88). ECG showed LBBB. He was further evaluated.His 2D Echo, X-ray chest, serology for HIV, HBV, HCV and EBV, ANA, ANCA, MRI brain, were normal. ACTH stimulation test was done in view of persistent hypotension with no evidence of hypoperfusion and he was confirmed to have Adrenal insufficiency. In view of serious and recurrent infections over last 6 months (skin and lung) a n d h y p o g a m m a g l o b u l i n e m i a h e w a s e v a l u a t e d f o r p o s s i b l e immunodefic iency syndrome. His immunoglobulin profi le (Table 2) showed s ign i f i cant ly low S . IgM, borderline S.IgG, normal S.IgA, and raised S.IgE levels ; for persistent pancytopenia bone marrow aspiration, b iopsy and f lowcytometry (Table 3) evaluat ion were done. He was diagnosed to have secondary HLH s y n d r o m e ( f e ve r , s p l e n o m e g a l y , pancytopenia, hypertriglyceridemia – h y p o f i b r i n o g e n e m i a , hemophagocytosis in bone marrow (Figure 1) and raised S.Ferritin along with CNS features, and altered LFTs) (Table 3). Bone marrow flowcytometry a n d i m m u n o p h e n o t y p i n g ( Ta b l e 4 ) s h o w e d t h a t l y m p h o c y t e s
AbstractS e l e c t i v e i m m u n o g l o b u l i n M d e f i c i e n c y ( s I g M D ) i s a r a r e fo r m o f dysgammaglobulinaemia characterized by an isolated low level of serum immunoglobulin M (IgM). It was an incidence of less than 0.03% in the general population and 1% in hospitalized patients. sIgMD may occur as a primary or secondary condition. sIgMD is much more common than primary .Hemophagocytic lymphohistiocytosis (HLH) is also a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes and can be primary or secondary, characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations. We report an adult case of primary sIgMD with absent B lymphoid cells and secondary HLH syndrome who presented with recurrent infections, fever and pancytopenia.
multi organ dysfunction syndrome and was admitted the critical care unit in Jaipur. He was mechanically ventilated for a week. Bone marrow examination done was unremarkable. However, pancytopenia persisted and he was again admitted in another hospital with sepsis and later transferred at our centre for further management on inotropic support.
On admission he was disoriented, confused had dysarthr ia , d i f fuse muscular fasciculation, hypotension, and moderate splenomegaly . His routine labs showed mild proteinuria,
The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled:1. A molecular diagnosis consistent with HLH is
made.2. Diagnostic criteria for HLH are fulfilled (5 of
the 8 criteria below):†
FeverSplenomegalyCytopenia (affecting > 2-3 lineages in the peripheral blood): Hemoglobin < 90 g/L (in infants < 4 weeks of
age, hemoglobin < 100 g/L), Platelets < 100 X 10^9/L, neutrophils < 1.0 X
10^9/LHypertriglyceridemia and/or Hypofibrinogenemia: fasting triglycerides >3.0 mmol/L ( >265 mg/dL), fibrinogen < 1.5 g/LHemophagocytosis in BM, spleen, or lymph nodesLow or absent NK- cell activity (according to local laboratory reference)Ferritin > 500 ug/LSoluble CD25 (i.e., sIL2r) > 2400 U/mL‡
†Supportive criteria include neurologic symptoms, cerebrospinal fluid pleocytosis, conjugated hyperbilirubinemia and transaminitis, hypoalbuminemia, hyponatremia, elevated D-dimer, and lactate dehydrogenase. The absence of hemophagocytosis in the bone marrow does not exclude a diagnosis of HLH. ‡new data show normal variation by age. Level should be compared with age related norms.
predominantly expressed phenotype of T cells and almost absent B lymphoid cells. 60% of the T cells expressed HLA-DR suggesting their reactive phenotype. His NK cell panel was normal,%CD19 (B cell) zero and% CD7 (T cell) 69. He was thus diagnosed with primary sIgMD syndrome with B lymphoid cell defect and secondary HLH syndrome. He was managed with intravenous immunoglobulin (IVIG) 400 mg/kg single dose, dexamethasone and cyclosporine (HLH protocol) , fludricortisone, antibiotics, supportive treatment, packed cells and platelet t r a n s f u s i o n . Va c c i n e s P P S V 2 3 , meningococcal conjugate, seasonal Influenza and hemophilus influenza type B vaccines were given in follow up.He is under regular follow-up and
is on dexamethasone and cyclosporine as per HLH protocol.
Discussion
Immunodeficiency syndromes can be classified as primary and secondary immunodeficiency syndromes. Among primary it can be humoral immune deficiency (B cells, plasma cells, or antibodies), T cell deficiency (T cells), granulocyte deficiency (neutrophils), asplenic ( sp leen) or complement def ic iency (complement sys tem) . Secondary immunodeficiency can result from various immunosuppressive drugs, malnutrition or specific diseases directly or indirectly like cancer of the bone marrow and blood cel ls and certain chronic infections. IgM is thought to have a role in defense against blood borne bacterial infections, and viral neutralizing antibodies are often of the IgM type. sIgMD is a rare heterogeneous disorder with no known genetic background and a reported prevalence of 0.03% to 3%. The normal serum concentration of IgM is between 50 and 400 mg/dL. Although there are no strict numeric cutoff values for defining IgM deficiency, a level of IgM
less than two standard deviations from the mean, or less than 10 percent from the mean for age, is generally accepted as deficient.1 Thus, IgM levels less than 10 to 15 mg/dL in infants and children and less than 20 to 30 mg/dL in adults are compatible with IgM deficiency. Patients with selective IgM deficiency frequently show an increase in IgE levels. It is postulated that disorders in antibody production may lead to repeated chronic infection, inducing an excessive response to bacterial infection and thus increasing the level of IgE. Since our patient had no evidence of malignancy or autoimmune disease to suggest secondary IgM deficiency, primary IgM deficiency was suggested. He had low IgM with high IgE levels.
S e l e c t i v e I g M d e f i c i e n c y c a n b e a s y m p t o m a t i c o r p r e s e n t symptomatically with infections caused by encapsulated bacteria and viruses, some of which can be serious and even life-threatening. It is now well recognized that it can first present in adulthood. The largest series on sIgMD in adults consisted of 36 patients having serum IgM levels in the range of 12-46 mg/dL.2 Our patient presented at the age of 27 years and had repeated infections involving skin and lung with low IgM levels.
The pathogenes is o f s IgMD is unclear, although several postulated mechanisms include B lymphocyte defect in IgM production, disordered or inadequate T cell help, excessive T cell suppressive activity, abnormal CD4/CD8 ratios and possibly chromosomal defects (chromosome 22q11.2 deletion syndrome).3
P e r s i s t e n t p a n c y t o p e n i a , f e v e r , m o d e r a t e s p l e n o m e g a l y a n d h e m o p h a g o c y t o s i s i n b o n e marrow made us to th ink of co-existing secondary hemophagocytic lymphohistiocytosis (HLH) in this
Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016 93
patient. HLH is an aggressive and life-threatening syndrome of excessive immune activation. The pathological hallmark in secondary HLH is the aggressive proliferation of activated macrophages and histiocyte, which phagocytes other cells, namely RBCs, WBCs and platelets, leading to the clinical symptoms.4 HLH is diagnosed by a constellation of signs, symptoms, and laboratory abnormalities (Table 4).5,6 Five of eight criteria are required to make the diagnosis of secondary HLH. Our patient fulfilled 6 of 8 criteria.5,6
The management of these patients is complex. Prophylatic vaccination and antibiotics need to be given. Although, there are only trace amounts of IgM in IVIG, the rationale of IVIG in some cases may be related to the failure of even IgG responses to capsular organisms in these patients despite a normal (or elevated) level of IgG.7
Conclusion
(1) Patients with serious and repeated infections should be investigated for
immunodeficiency syndromes and possible selective IgM deficiency; (2) Evaluate for secondary HLH if patient has fever of unknown origin (FUO) or fever is unresponsive to antibiotics, o r g a n o m e g a l y , p a n c y t o p e n i a o f unknown origin, transaminitis and elevated ferritin; (3) Ferritin levels > 30,000 ng/ml are 100% specific for HLH in the absence of an inborn error of iron metabolism; (4) Management involves IVIG, prolonged courses of antibiotics,blood and blood products ,supportive treatment , vaccinations and management of HLH as per HLH protocol.
To our knowledge, this is the first case report of an adult patient with primary sIgMD with B Lymphoid cell defect and secondary HLH syndrome.Acknowledgement
Authors wishes to thank Dr. Rahul Jain, Dr. Vivek Bhargava, Dr. Pallavi Maheshwari and Dr. Upendra Sharma for their suggestions in management of this patient. We also thank Ms.Nidhi
Anand, Ms.Nita Singh of administrative depar tment and medica l records department of our institute for their help in preparation of the article and retrieving all relevant medical records.
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