The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

Background: Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods.Methods: A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children\u27s Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH.Results: A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons.Conclusion: PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality

Invasive community acquired methicillin-resistant staphylococcal aureus (CA-MRSA) infections in children

Staphylococci are gram-positive bacteria divided into coagulase positive and coagulase negative classes, Staphylococcus aureus is the most important bacterium of this class. Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) has changed a lot. It is no more the problem of only hospitalised patients. Children coming from community has also been increasingly affected by MRSA-called community acquired methicillin-resistant (CA-MRSA) infection. The higher severity of CA-MRSA is due to its ability to produce the toxin Panton-Valentine Leukocidin (PVL) associated with staphylococcal cassette chromosome mec (SCCmec) type IV gene. Here, we are presenting five cases of CA-MRSA infection in children having age range 0.5 months to 11 years. All of them had invasive MRSA infection finally diagnosed as causing empyema thoracis, infective endocarditis, psoas abscess and necrotising fasciitis. Early surgical intervention, quick microbiological recognition of the pathogen, and appropriate antimicrobial therapy helped save their live

Determinants of in-hospital mortality in COVID-19; a prospective cohort study from Pakistan.

A prospective cohort study was conducted at the Indus Hospital Karachi, Pakistan between March and June 2020 to estimate the in-hospital mortality among hospitalized COVID-19 patients and its determinants. A total of 170 adult patients were enrolled and all-cause mortality was found to be 39% (67/170). Most non-survivors were above 60 years of age (64%) while gender distribution was quite similar in both groups (males: 77% vs 78%). Most (80.6%) non-survivors came with peripheral oxygen saturation less than 93% while 95% of them had critical disease on arrival. Use of non-invasive ventilation in emergency room was higher among non-survivors (56.7%) versus survivors (26.2%). Median Interleukin-6 levels were higher among non-survivors (78.6: IQR = 33.8-49.0) compared to survivors (21.8: IQR = 12.6-36.3). Most patients in the non-survivor group (86.6%) required invasive ventilator support during hospital stay compared to 7.8% in the survivors. The median duration of ICU stay was longer for non-survivors (9: IQR = 6-12) compared to survivors (5: IQR = 3-7) days. Univariable binary logistic regression showed that age above 60 years, oxygen saturation below 93%, Neutrophil to lymphocyte ratio above 5, procalcitonin above 2ng/ml, unit increase in SOFA score and arterial lactate levels were associated with mortality. We also found that a unit decrease in Pao2/FiO2 ratio and serum albumin were associated with mortality in our patients. Multivariable regression showed that age above 60 years (aOR = 3.4: 95% CI = 1.6-6.9), peripheral oxygen saturation below 93% (aOR = 3.5:95% CI = 1.6-7.7) and serum pro-calcitonin above 2ng/ml (aOR = 4.8; 95% CI = 1.9-12.2) were associated with higher odds of mortality when adjusted by month of admission. Most common cause of death was multisystem organ failure in 35 (56.6%) non-survivors while 22 (35.5%) died due to respiratory failure. Larger prospective studies are needed to further strengthen these findings

A novel mutation in the JH4 domain of JAK3 causing severe combined immunodeficiency complicated by vertebral osteomyelitis

JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T-B+NK- severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity

Rare and heterogeneous manifestations of leucocyte adhesion deficiency type 1: report of two cases with diagnostic dilemmas and novel ITGB2 mutation

Abstract Background Primary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death. Case Presentation LAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases. Conclusions These cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications