Dr. Rithwik Sunil, Dr. C Jayakumar, DrVinayan, Dr.Praveena N Bhaskaran, Dr.NavyaGeorge
Eight year old female child known case of Anti NMDA encephalitis presented with complaints of on and off wet cough of 3 months duration and intermittent fever
Child was diagnosed and started on treated for Anti NMDA encephalitis since 5 years of age and has completed IVIG treatment and 6 rounds of plasmapheresis. She was also initiated on Rituximab and had already received 3 doses. Child was on Mycophenolate mofetil at the time of admission.
Child was previously admitted 1 month back for right middle pneumonia and was treated with Antibiotics for 10 days.
Child also had history of multiple episodes of pneumonia prior to that after the attack of NMDA encephalitis
At admission child was afebrile with stable vitals. Examination revealed B/l wheeze. Labs done showed neutrophilic leukocytosis with elevated CRP(15mg/L). Chest xray showed B/l paracardiac infiltrates.
Differentials considered were:
Recurrent pneumonia
Tuberculosis
Autoimmune Encephalitis flare up
GERD
Bronchiectasis
Structural lung malformations
Foreign body
GeneXpert for TB done was negative
Peripheral Smear normocytic to microcytic blood picture with leucocytosis, thrombocytosis and reactive lymphocytes.
NMDA receptor antibody test showed moderately positive in 1:10 dilution .
Preop serology was negative.
CT chest plain showed bilateral posterobasal segments with diffuse airspace opacities with peribronchial cuffing, more in the right lung suggestive of persistent pneumonia.
Immunoglobulin profile done showed IgG-66mg/dl(633-1280),
IgA<5 (33-202),
IgE<1(1.03-161.3),
IgM-17 (48-207)
T,B, NK cell enumeration showed a low switched post-GC B cell count.
Whole exome sequencing is normal
Hence the diagnosis Rituximab induced hypo-gamma globulinemia
A diagnosis of Hypogammaglobulinemia secondary to Rituximab was considered as the child had a history of multiple episodes of pneumonia and profile done also suggested low Immunoglobulin levels for her age.
Child was started on antibiotics and other supportives for the pneumonia and was also started on Septran prophylaxis.
Parents were also counselled regarding the need for IVIG to be given every 3 weeks following an Immunoglobulin profile.
Anti-NMDAR antibody positive auto immune encephalitis is an immune-mediated neuroinflammatory disease characterized autoantibodies against the GluN1 subunit 2B (NR2B)/NMDA subunit 2A (NR2A) subunits of the NDMA receptor in the hippocampus causing the symptoms.
It has characteristically 4 phases:
Prodromal phase
Illness phase
Recovery phase
Late phase
First-line treatment involves teratoma resection (if present),
immunotherapy comprising of corticosteroids,
intravenous immunoglobulins or plasma exchange,
and supportive care.
Second-line treatment using Rituximab or cyclophosphamide is most often necessary when the patient does not have an underlying tumor.
Rituximab is a chimeric monoclonal antibody directed against CD20, a surface marker on all mature B cells. It leads to depletion of B cells through several mechanisms which include complement fixation, antibody-dependent cellular cytotoxicity and signaling of apoptosis .
There was a high correlation between the Immunoglobulin gamma (IgG) concentration at the time of rituximab infusion and the nadir IgG concentration post-rituximab. Despite multiple case reports of prolonged hypogammaglobulinemia post-rituximab therapy in pediatric patients, the exact prevalence of this complication in children is less clear .
Pediatric patients are more susceptible to rituximab-associated hypogammaglobulinemia than adults. This may reflect the immaturity of the immune system in children, who have a lower percentage of memory B cells .
Take Home message
It is important to consider the possibility of congenital causes of immunosuppression before establishing that immunity suppression is Rituximab induced
The onset of hypogammaglobulinemia is usually within six months of initiation of rituximab therapy, which can be associated with serious infections. Therefore,it is important to
1) obtaining an IgG level prior to starting rituximab,
2) close monitoring for hypogammaglobulinemia after the use of rituximab in pediatric patients, especially in the first six months of patients with autoimmune CNS
3) early institution of immunoglobulin replacement therapy if patients develop recurrent or severe infections.
4)Rituximab induced hypogamma globulinemia may persists up to 2 years
But there are cases reports of its persistence up to 10 years
