Lymphoid Interstitial Pneumonia in Common Variable Immune Deficiency - Case Report With Disease Monitoring in Various Therapeutic Options: Pleiotropic Effects of Rituximab Regimens

Abstract

Lymphoid interstitial pneumonia (LIP) is a rare lymphoproliferative disease. LIP in common variable immunodeficiency (CVID) was observed in a patient during immunomodulatory therapy after progression of the disease (i.e., glucocorticoids, immunoglobulin dose escalation, and finally rituximab). Due to humoral immunodeficiency and serious serum sickness rituximab was used initially at a low dose (150 mg/m2 weekly). It resulted in temporary remission with the decrease of serum paraproteinemia, β2-microglobulin (β2M) and SUV decrease as well as increase of FVC. Owing to the relapse after 6-month remission in the second cycle a standard dose of rituximab was used (375 mg/m2). Therapeutic regimen with 375 mg/m2 of Rtx in optimal schedule (i.e., every 3 weeks) resulted in no longer remission but higher incidence of opportunistic infections. Finally, after another cycle of immunotherapy FVC, paraproteinemia and β2M level normalization were observed as well as the decrease of severe splenomegaly. In laboratory and immunological progress the increase of NK and NKT cells was observed after the initial dose but the standard one caused NK cell increase only. Unfortunately, the decrease of CD19+Bcells was comparable between both doses, as was the decline of FoxP3+ regulatory T cell. On the contrary, after the low dose absolute T cell (both CD4 and CD8) number decreased but after the standard one - it normalized. Rtx (especially in low dose) brought further increase of persistent T cell activation (CD38+ T cells made up 79%). Innate immune response and the decrease of Treg are a compensatory pathways for the decrease of B and T cells. Immunodeficiency requires a different investigative approach to a immunotherapy. Clinical Trial Registration: ClinicalTrials.gov, NCT02789397.

Keywords: FoxP3+ regulatory T cells (Treg); common variable immune deficiency (CVID); immune dysregulation; lymphoid interstitial pneumonia (LIP); lymphoproliferative disease (LPD); natural killer (NK) natural killer T-cells (NKT); rituximab, innate immune response.

Figures

FIGURE 1

Clinical course of rituximab monotherapy in lymphoproliferative disease exacerbation. Timeline of treatment of LIP with low and standard dose of rituximab following the typical therapeutic regimen (i.e., escalating dose of prednisolone and intravenous immunoglobulin) (Hurst et al., 2017). Figure show 5-year-long period, rituximab monotherapy, and PET findings contrary to clinical trial NCT027893972). (A) Quantitative and functional evaluation of leading parameters of lymphoid interstitial pneumonia (2): IgM level, β2-microglobulin (β2m), spleen size, and pulmonary restriction (FVC) were presented. All spirometric measurements were performed according to the recommendations of the European Respiratory Society. Prednisolone therapy and immunoglobulin dosage adjustment (to 0.5 g/kg repeated every 21 days) were ineffective. Progression of the disease corresponds with high β2-microglobulin and very high level of non-monoclonal IgM paraproteinemia, spleen size, but without typical signs of malignancy. After corticosteroids withdrawal and rituximab monotherapy fast and significant increase of forced vital capacity (FVC) was observed as well as decrease of splenomegaly. After rituximab therapy IgM – paraproteinemia, the sign of lymphoproliferative disease, pulmonary restrictive disease resolved. The clinical improvement corresponds with less IgG consumption/IVIG requirement. (B) PET imaging of therapeutic response in LIP (Jolles et al., 2017). Bottom panel shows corresponding PET-tomography before, after the first (150 mg/m2), second and third course (both-375 mg/m2) of rituximab monotherapy. The maximal standardized uptake value (SUV) in pulmonary granulomas are shown. Before therapy the highest uptake of (18)F-fluoro-deoxyglucose was seen in spleen and pulmonary granulomas with lymphoid tissue: SUV was shown. PET.PET findings are useful (Zdziarski et al., 2017) and more representative than high-resolution CT scans of the chest (data not shown).

FIGURE 2

Evolution of peripheral lymphocytes populations. Immunomodulatory effect of rituximab on cellular compartment. Pleiotropic influence of low (150 mg/m2) rituximab dose. Data expressed as absolute numbers per μl. The cell counts were analyzed during LIP exacerbation – multiorgan lymphoproliferative disease development. Typical low level of invariant natural killer T (NKT), natural killer (NK), and regulatory T cells (Treg) was observed. After rituximab therapy abnormal innate immunity – absolute number of NK and NKT cells increased, but gradual decrease of FoxP3+ regulatory T cells was observed with increase activated CD38+T cells (not shown). Leukocyte counts analyses were done by the Sysmex Automated Hematology System. Flow cytometry was performed using a FACS Calibur flow cytometer (Becton Dickinson) and a count of lymphocyte subset was calculated by the frequency multiply the lymphocyte counts.