Congenital Immunodeficiency Disorders Research Articles

СИНДРОМ «ГОЛЫХ» ЛИМФОЦИТОВ (ДЕФИЦИТ МОЛЕКУЛ MHC II КЛАССА): КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Article represents a clinical case of severe combined immune deficiency (SCID), deficiency of MHC class II molecules which was coupled with normal levels of TREC and KREC in a pediatric patient. Simultaneous determination of TREC and KREC in dried blood spots during neonatal screening makes it possible to diagnose various forms of congenital immunodeficiency disorders. For example, a dramatic decrease in TREC is observed in most SCIDs and combined immune deficiencies. However, in some SCIDs associated with a defect primarily in T-cell function rather than T-cell differentiation, TREC levels do not exceed established threshold levels and therefore some rare forms of SCIDs may be missed by neonatal screening programs and consequently lead to its late diagnosis.

ОЦЕНКА ОСОБЕННОСТЕЙ ПРОЯВЛЕНИЙ ЗАБОЛЕВАНИЯ У ПАЦИЕНТОВ С ВРОЖДЕННЫМИ ДЕФЕКТАМИ ИММУНИТЕТА, ПОЛУЧАЮЩИХ АЛЛОГЕННУЮ ТРАНСПЛАНТАЦИЮ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК

Congenital immunodeficiency disorders (CIDs) are a group of rare and diverse diseases that are based on dysfunction of the immune system. The only therapy that radically cures CIDs is allogeneic hematopoietic stem cell transplantation (HSCT). Despite the expansion of indications for HSCT in CIDs, making a decision on the need for HSCT in many diseases still remains a difficult task requiring an assessment of the risk for the life-threatening complications development in a patient. The purpose of this research was to assess the diseases developing in patients with CIDs who received allogeneic HSCT. Materials and methods used: the study included 312 patients with CIDs under the age of 18 y/o who had received allogeneic HSCT at the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) in 2012-2020. The analysis was performed in 5 main groups of CIDs: immunodeficiencies with cellular and humoral defects (n=71), combined immune deficiency with associated or syndromic pathology (n=98), immune dysregulation defects (n=56), qualitative and quantitative defects of phagocytosis (n=57) and other CIDs nonmentioned above (n=30). Results: the presence of diseases uncontrolled by the therapy at the time of HSCT was noted in 160 (51%) patients. 73 (23%) had infection, 109 (35%) had autoimmune and/or autoinflammatory diseases, 15 (5%) showed absence of remission of an oncological disease. 33 patients had a combination of various diseases: 29 had infectious and autoinflammatory ones, two had infectious and tumor ones, another two had autoinflammatory and tumor. Active infections were observed in 48% of patients with immunodeficiencies with cellular and humoral defects and 33% of patients with other CIDs, active autoinflammatory processes in 43% of immune dysregulation defects and 63% of other CIDs, active tumors in 12% of patients with defects of phagocytosis. Conclusion: solutions have been proposed for assessing the pre-transplant status of patients with CIDs for the presence of infectious, autoimmune/autoinflammatory and oncological complications, age and nutritional status of the patient, which in tis turn underlie the choice for the optimal HSCT technique.

РАСШИРЕННЫЙ НЕОНАТАЛЬНЫЙ СКРИНИНГ ДЛЯ ВЫЯВЛЕНИЯ ВРОЖДЕННЫХ ДЕФЕКТОВ ИММУННОЙ СИСТЕМЫ: ОПЫТ МОСКОВСКОГО ЦЕНТРА НЕОНАТАЛЬНОГО СКРИНИНГА

Starting Jan., 2023 the extended neonatal screening (ENS) has been carried out in Russia that includes the determination of TREC/KREС markers, which in its turn allow suspecting severe combined immunodeficiency (SCID), phenotypical T-cell immunodeficiencies and X-linked agammaglobulinemia (XLA) prior to possible development of severe infectious complications. The purpose of the research was to evaluate the results of ENS for congenital immunodeficiency disorders (CIDs) in newborns in Moscow and to subsequently identify the most problematic issues in organizing of its implementation. Materials and methods used: the study was conducted in the Morozov Children's City Clinical Hospital (Moscow, Russia) among the 116,584 children born in Moscow in Jan. 01-Dec. 31, 2023 (this was the first year since the ENS introduction in Moscow) with a decrease in TREC/KREC below 100 copies per 105. Results: a total of 14 patients with CIDs were identified, of which 4 patients had a genetically confirmed form of SCID; 2 patients with immunophenotype of SCID; 3 patients with XLA; 2 patients with DiGeorge syndrome; single patient with a syndrome associated with a mutation in the PI4KA gene; and 2 patients with syndromic pathology without genetic confirmation. Thus, the frequency of detection of patients with the immunophenotype of SCID was a single case per 19,430 children, the frequency of patients with XLA was 1:38,861. 5 of 14 had already received hematopoietic stem cell transplantation, single patient was preparing for it at the time of the manuscript finalization. All of the patients receive regular immunoglobulin replacement therapy. Conclusion: the experience of an integrated approach to the provision of medical care based on neonatal screening in a municipal children's multidisciplinary hospital is presented; the results of the study helped identifying organizational shortcomings and determined the vector for its further development in order to improving of medical care provision to children with CIDs.

CONGENITAL IMMUNODEFICIENCY DISORDERS IN THE PEDIATRIC PRACTICE

Introduction. Congenital immunodeficiency disorders are genetic pathology that affect the immune system function and is important problem of modern medicine.
 Material and methods. This dates are performed the clinical case of the child with congenital complement deficiency.
 Results. Patient was diagnosed with allergic skin symptoms (atopic dermatitis, eczema), persistent bacterial infections of the upper and lower respiratory tract, late teething, diarrhea, chronic diseases of the gastrointestinal tract. That signs were manifestations of immunodeficiency states. During clinical and paraclinical examination the following data was detected in immunological blood test: decreased levels of CD3+-lymphocytes, CD3+CD8+-cytotoxic lymphocytes, CD19 +-lymphocytes. Gene panel of boy identifies one pathogenic variant in С8B (c. 1282C>T (p.Arg428*)), heterozygous, one pathogenic variant in C3 (c.2402C>T (p.Thr801Met)), heterozygous, which is associated with autosomal recessive and dominant. Uncertain significance variants were detected. Genetic signs in family members were also detected.
 Conclusion. Genetic testing for identifying of congenital defects is very important in primary immunodeficiency diagnostic process.

НЕТИПОВИЙ ПЕРЕБІГ ЛІМФОМИ ХОДЖКІНА: ТРУДНОЩІ В ДІАГНОСТИЦІ

Hodgkin’s lymphoma (HL) is a malignancy of B-cell origin that mainly affects the tissue of the lymph nodes, spleen, disease and bone marrow. In majority of patients the diagnosis is made in the age between 15 and 30 years, followed by another peak at age ≥ 55 years. The cause is not known for certain, but there are various risk factors such as: genetic disease (family history); environmental associations (woodworking industry, etc.); history of phenytoin treatment, altered therapy, or chemotherapy. An important is a role of infection: Epstein-Barr virus (EBV), mycobacterium tuberculosis, herpesvirus type 6, and human immunodeficiency virus (HIV — human immunodeficiency virus). Immunosuppression (post-transplant patients who take immunosuppressants), congenital immunodeficiency disorders (Klinefelter syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome), some autoimmune diseases (rheumatoid arthritis, celiac disease, Sjogren’s syndrome, systemic lupus erythematosus) increase the risk of the disease. The WHO (World Health Organization) classification divides LC into two main types: classic (which accounts for about 95% of cases) and nodular — with a predominance of lymphocytes (occurs in 5 % of patients). Typically diagnosis is not to complicated, when routine methods of examination are used. In 2022, approximately 8,540 LC cases were diagnosed in the United States, and 920 patients died from the disease. Primary lesions of the lungs are rare and account for 0.5 % of all primary lung neoplasms. Lung involvement usually indicates the stage IV of the disease. About 85-90% of patients with limited-stage classical Hodgkin lymphoma are treated, compared with 75–80 % of advanced-stage disease. Patients who do not achieve complete remission after treatment or who relapse within 12 months have a poor prognosis. Current report presents atypical clinical case of Hodgkin’s lymphoma causing difficulties in diagnosis. Conclusions. The initial manifestations of Hodgkin’s lymphoma as the primary lung disease is an extremely rare, therefore, in order to shorten the time from the moment the patient enters the clinic to the verification of the diagnosis, it is better to use mini-invasive diagnostic methods (videothoracoscopic biopsy of the mass, transthoracic needle biopsy), which allows obtaining a diagnosis and choose the safest and most optimal type of treatment. Key words: Hodgkin’s lymphoma, transthoracic needle biopsy of the lung, computed tomography, young age, lungs.

Respiratory viruses among pediatric inpatients with acute lower respiratory tract infections in Jinan, China, 2016-2019.

The viral etiologies responsible for acute lower respiratory tract infections (ALRI) are a major cause of pediatric hospitalization, and some develop severe diseases requiring pediatric intensive care unit (PICU) admission. The aim of this study is to determine the prevalence of viruses and risk factors associated with PICU admission among patients hospitalized for ALRI. Nasopharyngeal swabs were collected to detect human rhinovirus (HRV), influenza A and B viruses (IAV andIBV), parainfluenza viruses (PIV), and respiratory syncytial virus (RSV) by reverse transcription-polymerase chain reaction (PCR) and adenovirus (ADV) by PCR. Of the 5590 pediatric inpatients enrolled, respiratory viral infection occurred in 2102 (37.60%) patients, including 1846 (33.02%) single and 256 (4.58%) mixed viral infections. Among the nasopharyngeal swabs from pediatric inpatients, HRV accounted for the highest detection rate (16.48%), followed by PIV (8.35%), RSV (7.41%), ADV (4.63%), IAV (3.51%), and IBV (2.08%). The positive rate of viral tests decreased with increasing age and was higher in males (39.29%) than females (34.67%). The prevalence of viral infection was the highest in winter (41.57%) and lowest in autumn (31.78%). Each virus had a seasonal pattern, with peaks occurring in months of their epidemic seasons. RSV infection and the presence of comorbidities including congenital tracheal stenosis, congenital heart disease, metabolic disorder, immunodeficiency, renal disease, gastrointestinal disease, and neurological disorder might be associated with the need for PICU admission. Therefore, this study provides useful information for the prevention and control of virus-related respiratory diseases and the early identification of and intervention in severe cases.

Insight into Ocular Genetic Research: Trends in Oman.

Insight into Ocular Genetic Research: Trends in Oman.

Should all children admitted with community acquired pneumonia have blood cultures taken?

To evaluate the yield of blood cultures and the impact of blood culture results on the adjustment of empiric antibiotic treatment in children hospitalised with community acquired pneumonia (CAP). This was a prospective study conducted at a tertiary hospital in Malaysia, from 1st August 2010 until 31st July 2011. Children aged between 1mo and 12y who were admitted for CAP and had blood cultures performed before starting intravenous antibiotics were recruited. Children with congenital pneumonia, immunodeficiency, chronic cardiac or respiratory disorders, nosocomial pneumonia or those on corticosteroids, were excluded. Decision for admission was made by the attending Accident and Emergency physician. One hundred and seventy-one children were enrolled. The median age was 13mo (range: 38d-10y 3mo) and 59% were males. Blood cultures were positive in 1.2% (2/171) of patients while the contamination rate was 1.8% (3/171). Doctors altered antibiotics based on blood culture results in only one patient. Both the yield and the impact of blood culture results on the adjustment of empiric antibiotic treatment were very small. There was a high contamination rate. The recommended practice of performing blood cultures in all children admitted with CAP should be reviewed.

WHIM syndrome: presumptive diagnosis based on myelokathexis on bone marrow smear

The WHIM syndrome is a rare congenital immunodeficiency disorder characterized by human papillomavirus (HPV)-induced warts, hypogammaglobulinemia, bacterial infections and myelokathexis. Myelokathexis refers to abnormal retention of mature neutrophils in the bone marrow leading to severe neutropenia. We report the case of a 20 year old man presenting with chronic and severe neutropenia since early childhood without established diagnosis. He was addressed for chronic parodontal disease treatment. Examination of bone marrow smear showed morphological abnormalities of mature neutrophils strongly suggestive of myelokathexis. Diagnosis of WHIM syndrome was confirmed by molecular analysis: a nonsense mutation was identified in the gene encoding CXCR4, the CXCL12 (or SDF-1) chemokine receptor which notably controls cell adhesion to the marrow stroma and thereby regulates mature leukocytes release from the bone marrow. Treatment of the disease usually consists in prophylactic anti-infective measures including intravenous immunoglobulins administration, oral antibiotic prophylaxis and more recently HPV vaccination. Long term G-CSF therapy did not show any significant efficiency in preventing recurrent infections. The use of specific CXCR4 antagonist is being currently evaluated.

Risk factors of hospitalization for lower respiratory tract infections in infants with 33 weeks of gestational age or more: a prospective Italian cohort study on 2210 newborns

Lower respiratory tract infections (LRTI) caused by the Respiratory Syncytial Virus (RSV) represent the major cause of hospitalization among young children, especially infants under 12 months of age [1]. Children at high risk of hospitalization for RSV-LRTI include preterm infants [2] and infants who are affected by chronic lung disease (CLD), congenital heart disease (CHD), immunodeficiency and neuromuscular disorders [3]. For these high-risk infants, RSV prophylaxis with humanized RSV monoclonal antibodies (palivizumab) is effective in reducing the risk of developing severe RSV infections and hospitalization [4]. Several epidemiological studies have found other determinants of severe RSV infections [5] but results show variability, probably because performed in different countries or with alternation in the RSV epidemic season, and even for the different methodologies adopted. Several potential risk conditions are identified to be age at the time of RSV infection or birth early during the RSV season, younger age, male gender, day care attendance, presence of siblings, household crowding, exposure to tobacco smoke or to air pollution, and lack of breastfeeding [6–9]. Despite several epidemiological studies have identified some risk factors for RSV infection in preterm babies, only few epidemiological data in healthy and at term infants are available. Aim of this study was to evaluate the role of prenatal, perinatal and postnatal/

Embryonic Development of Hematopoietic Stem Cells: Implications for Clinical Use

Hematopoietic stem cell (HSC) transplantation is an important treatment modality for hematological malignancies or to correct congenital immunodeficiency disorders. Several stem cell sources are currently applied clinically, with a recent increased application of umbilical cord blood. The low number of HSCs available, particularly in umbilical cord blood, is a limiting factor, and different lines of research are ongoing to circumvent this issue. In this review, we will describe the research strategies developed to expand adult HSCs in vitro and to generate new HSCs from pluripotent stem cell lines. We will also discuss the importance of studying the embryonic microenvironment since it allows both generation and extensive expansion of HSCs. Understanding the mechanisms that underlie HSC production, self-renewal and differentiation is necessary for the establishment of optimal in vitro HSC cultures, where a limitless and manipulatable resource of HSCs would be available for both clinical and fundamental research.

Roles of p53 in Various Biological Aspects of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of “cell integrity” under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

AbstractWHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4R334X, in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http://www.clinicaltrials.gov as NCT00967785.

Genetic disorders with immune dysregulation.

We summarize the clinical presentation and molecular basis of a unique group of congenital immunodeficiency disorders in which defects in immune tolerance mechanisms result in severe autoimmunity. Patients with severe, familial forms of multi-organ autoimmunity have been recognized and clinically described for more than 40 years (Clin Exp Immunol 1: 119-128, 1966; Clin Exp Immunol 2: 19-30, 1967). Some are characterized primarily by autoimmunity and others by autoimmunity combined with susceptibility to specific infectious organisms. The first mechanistic understanding of these disorders began to emerge approximately 10 years ago with the initial identification of causative genes. As a result, our understanding of how immune tolerance is established and maintained in humans has expanded dramatically. Data generated over the last 3-4 years including identification of additional gene defects and functional characterization of each identified gene product in human and animal models have added clarity. This, in turn, has improved our ability to diagnose and effectively treat these severe, life-threatening disorders. Inherited disorders characterized by immune dysregulation have dramatically expanded our understanding of immune tolerance mechanisms in humans. Recognition and diagnosis of these disorders in the clinic allows timely initiation of life-saving therapies that may prevent death or irreversible damage to vital organs.

Defective innate immunity in inflammatory bowel disease: a Crohnʼs disease exclusivity?

This review summarizes the recent developments in support of the immunodeficiency model of Crohn's disease. The demonstration of impaired acute inflammation in Crohn's disease provides a novel mechanism for its pathogenesis, with diminished macrophage cytokine production and neutrophil recruitment leading to reduced bacterial clearance. The innate immune response may be further overwhelmed by other factors. The mucosal barrier in Crohn's patients is disrupted, with abnormal ultrastructure as well as antibacterial defensin deficiency. Specific bacterial agents may contribute and one promising candidate, adherent-invasive Escherichia coli, has recently been described. An interaction between Nod2 and the autophagy system has been elucidated, with direct consequences for bacterial clearance, and the most recent genome-wide association study meta-analysis has extended the number of Crohn's disease susceptibility loci to 71. The spectrum of congenital immunodeficiency disorders recognized to develop Crohn's-like inflammatory bowel disease is also expanding. Conversely, no specific immunodeficiency has so far been observed in ulcerative colitis, in which the defect appears to be failure of inflammation termination and resolution. Recent advances continue to highlight defects in innate immunity in Crohn's patients. Similar abnormalities may extend to other granulomatous disorders, but not diseases such as ulcerative colitis.

CXCR4 blockade reverses panleukopenia in patients with WHIM syndrome (153.11)

Abstract WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections and myelokathexis (neutropenia due to impaired egress from bone marrow); most patients also have severe panleukopenia. The disease is caused by autosomal dominant gain-of-function truncation mutations in the C-terminus of chemokine receptor CXCR4. CXCR4 normally controls neutrophil and hematopoietic stem cell distribution between blood and bone marrow, T cell development and B cell lymphopoiesis. Here we present preliminary data from a Phase 1 study of the safety and efficacy of the FDA-approved CXCR4 antagonist Mozobil as mechanism-based therapy in WHIM syndrome, using a 7-day dose-escalation protocol. To date, we have recruited two unrelated adult patients, both having the most common WHIM mutation, CXCR4 R334X. In both patients, Mozobil increased lymphocytes and monocytes in blood to the normal range, and neutrophils in blood to the safe level (>500 cells/microliter). One patient has now been treated with Mozobil daily for 6 months with no loss of efficacy. No side effects were noted in either patient. Thus, our data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is due to CXCR4-dependent leukocyte retention in storage sites, and justify continued study of Mozobil as mechanism-based therapy for patients with this disease.

GI-lymphomas in immunosuppressed patients (organ transplantation; HIV)

Gastrointestinal lymphoma plays a major role complicating different diseases presenting with immunosuppression, both primary and acquired immunodeficiency (incl. HIV, transplantation, immunosuppression following chemotherapy, or inflammatory bowel disease). Lymphoma in diseases with immunosuppression are clinically and pathologically heterogeneous, but share some features such as frequent involvement of extranodal sites, diffuse aggressive histology, B-cell lineage derivation, viral association with EBV and clinically aggressive courses. While gastrointestinal lymphoma in congenital immunodeficiency disorders seems to be a rare event inspite of higher prevalences, in post-transplant lymphoproliferative disorders (PTLD) the gastrointestinal tract is one of the most important organs of lymphoma. In HIV-associated non-Hodgkin's lymphoma, gastrointestinal lesions as the most frequent extranodal localisation occur in 30-50% of lymphoma patients, are late events of HIV infection with severe immunosuppression and are mainly diagnosed with advanced disease stages Ann Arbour III or IV. They are characterised by unusual, often multifocal localisation in the gastrontestinal tract, high rates of life-threatening complications (bleeding, perforation or obstruction) and high-grade B-cell histology. With the introduction of highly active antiretroviral therapy (HAART) in the therapeutic concept in AIDS, a decrease of AIDS-related GI lymphoma was noted with improved survival rates and prognosis of lymphoma. Therapy strategies including chemotherapy, immunotherapy and HAART will show promising results in response and survival rates.

Survival Following Allogeneic Stem Cell Transplantation for Congenital Immunodeficiency and Metabolic Disorders

We compared outcomes of allogeneic stem cell transplantation (SCT) for congenital immunodeficiency and metabolic disorders to children of a similar age who received SCT for acute leukemia in first or second complete remission. This analysis was undertaken to address a reluctance among many physicians to refer children with certain congenital immunodeficiency or metabolic disorders for early SCT. The study population includes 343 children (≤5 years) with congenital immunodeficiency (129 with severe combined immunodeficiency [SCID]; 214 with non-SCID) and 354 children with metabolic disorders.

Congenital immunodeficiencies and sepsis

Because a hallmark of congenital immunodeficiency disorders is susceptibility to recurrent, unusual and/or severe infections, an effort was undertaken to identify a subset of these patients with an increased risk for sepsis. Literature review. Twenty congenital immunodeficiency disorders were identified with increased sepsis susceptibility. Distinguishing patients with congenital immunodeficiencies from others with sepsis has important implications for the future well-being of the immunodeficient patient because many of the diseases are modified favorably by appropriate treatment. In addition, better understanding of sepsis in the setting of congenital immunodeficiency has numerous implications for both immunodeficiency and sepsis research. As a group, these disorders define components of the human immune system that are essential for defense against severe infection and demonstrate immunologic themes underlying sepsis susceptibility.

Adult non-Hodgkin's lymphoma

Adult Non-Hodgkin’s Lymphoma (NHL) is a diverse group of lymphoid malignancies, with an increasing annual trend world over. NHL has shGwn an increase by 39% in Caucasians and 46% in black population and is at least three times more frequent than Hodgkin’s disease, as shown by the SEER study.Intermediate grade lymphoma still constitutes the largest proportion of NHL. Increased incidenceof NHL is largely because of large share from NHL in older age groups. Increased incidence rates of NHL in younger age grouj are attributed to its association with AIDS in recent times and also to classify a large number of cases as NHL which previously used to be labeled as unspecified malignant lymphoma. NHL is more common in developing world and shows a wide geographic variation in its pathobiological characteristics. Extranodal lyinphoina is reportedly 26% of all lymphomas and has increased by 4%, with most frequent sites being stomach, skin, oral cavity, pharynx, small intestine and brain in that orde?. Some of the sub-types like diffuse large cell NHL, large cell immunoblastic NHL and small non-cleaved cell NHL are increasing. NHL can be aB cell or T cell type as cell of ongin. In a local population based study malignant lymphorna are 5.7-8.7% in males and 1.2-1.7% in females. The national cancer database organized by Pakistan Medical Research Council indicates that 6.3% of all male tumors and 1.9% of all females tumors are lymphoma. About 14.8% male lymphoma is NHIL, while 18.4% of female lymphoma are NHL. Inununogenetic sub-typing, flow cytornetty and gene re-arrangement studies and molecular biology tecimiques are increasingly being incorporated in lymphoma management and diagnosis and have changed over concepts tremendously. Hair dyes and herbicides are currently new entities in addition to genetic and envimmnental factors inetiology of NHL. Viruses (HTLV-1, HIVandEBV), congenital immunodeficiency, organ transplantation and autoimmune disorders are otherprecipitating factors. The treatment options are surgety, radiotherapy, chemotherapy (CHOP, M-BACOD, m-BACOD, ProMACE/cytaBOM, MACOP-B), with PBST/BMT9. The clinical presentation is vague with symptoms like decreased appetite, loss of weight, excessive night sweats, tiredness, itching, insomnia, discomfortorpain. Excision biopsy is preferred over FNAB where possible. Other tests are complete physical evaluation, CBC with ESR, biochemistry, XR, CT/MRI, bone marrow biopsy, Gallium scan of nodes, lymphangiogram, biopsy/exploration, endoscopy and biopsy. NHL usually shows centrifugal nodal involvement. Overall median survival is 8-9 years and increasing condition to early diagnosis combined withprompt and effective treatment. Currently REAL (Revised European American classification of lymphoid neoplasm) is widely used and accepted. The prognosis and overall survival in good in NHL, with early diagnosis and prompt treatment. The same can be achieved in our local lymphoma patients with improvement in diagnostic and therapeutic approach. There is an immense need for impfovement in histopathology training, incorporation of new diagnostic modalities and evaluation of cost effective treatment protocols for our population of patients. There is no reason not to achieve the same level of life expectancy and quality of life in our patients, if these above-mentioned considerations are given the due attention.