In Egypt, several highly pathogenic infectious bursal disease isolates were reported to break through high levels of maternal immunity in commercial flocks. This study investigated viral tropism and immune profiling of circulating very virulent strains in broiler farms. Samples from 19 suspected outbreaks were collected. RT-PCR was conducted for genetic differentiation between very virulent strains and other circulating strains. Immunohistochemical staining applied on positive samples for describing the topographic distribution of viral antigens in bursa of Fabricius, thymus and spleen. Anti-chicken CD3 and CD79A markers were used to study the immune profiling of B and T cells. Among 19 flocks, 78.9% came out positive with RT-PCR. 57.9% were very virulent strains, 15.8% were classical or vaccinal strains, and 5.2% were coinfected. Viral antigens were most prevalent in bursa, followed by the spleen but not in thymic tissue. B cell significantly reduced in moderate and severe lesion scored bursae, while increased number of intra-bursal T cells was observed. In thymic cells, depletion of lymphocytes was obvious, although it was not associated with viral detection. Thymic sections revealed significant reduction in T-cells in moderate and severe lesion scores. However, mild affected tissue showed significant increase in T cells. In spleen, significant decrease in T and B cells was observed in moderate and severe scored samples. Very virulent isolates induced similar pathogenicity to typical UK661 strain. Providing detailed information on immune response against circulating strains may increase our understanding about the ability of the virus to frequently break through vaccination control.