Rashid H. Merchant

Common Clinical Problems in Children Living with HIV/AIDS: Systemic Approach

Clinical manifestations in children living with HIV/ AIDS differ from those in adults due to poorly developed immunity that allows greater dissemination throughout various organs. In developing countries, HIV-infected children have an increased frequency of malnutrition and common childhood infections such as ear infections, pneumonias, gastroenteritis and tuberculosis. The symptoms common to many treatable conditions, such as recurrent fever, diarrhea and generalized dermatitis, tend to be more persistent and severe and often do not respond as well to treatment. The use of Anti Retroviral Therapy (ART) has greatly increased the long term survival of perinatally infected children so that AIDS is becoming a manageable chronic illness. As the immunity is maintained, the incidence of infectious complications is declining while noninfectious complications of HIV are more frequently encountered. Regular clinical monitoring with immunological and virological monitoring and the introduction of genotypic and phenotypic resistance testing where resources are available have allowed for dramatically better clinical outcomes. However, these growing children are left facing the challenges of lifelong adherence with complex treatment regimens, compounded by complex psycho-social, mental and neuro-cognitive issues. These unique challenges must be recognized and understood in order to provide appropriate medical management.

X-linked hyper IgM syndrome: Clinical, immunological and molecular features in patients from India☆☆☆

BACKGROUND X-linked hyper-IgM (XHIM) is a primary immunodeficiency disorder characterized by recurrent infections, low serum IgG and IgA and normal or elevated IgM. It results from mutations in the CD40 ligand (CD40L) gene. Confirmation of diagnosis with identification of underlying molecular defect is important for the initiation of appropriate therapeutic interventions, including immunoglobulin replacement, antibiotics and bone marrow transplantation. METHODS To investigate the molecular basis of XHIM, we evaluated 7 patients with suspected XHIM and abnormal CD40L expression on activated CD4(+) T lymphocytes. The entire coding region and intronic splice sites of the CD40L gene were sequenced from the genomic DNA of the patients. RESULTS 7 mutations; 3 nonsense (c.172delA, c.A229T, c.C478T), 1 missense (c.A506G) and 3 splice sites [c.346+2(T→C), c.289-1(G→C), c.346+1(G→T)] were identified, out of which 5 were novel. CONCLUSION A wide heterogeneity in the nature of mutations has been observed in Indian XHIM patients in the present study. Identification of mutations in this rare disorder will help in genetic diagnosis in affected families which could be further useful in prenatal diagnosis.

Pre- and post-therapy MR imaging in fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva, also known as myositis ossificans progressiva, is characterized by congenital skeletal malformations and progressive ectopic bone formation in connective tissues. The disorder presents as rapidly growing masses usually in the neck or paraspinal region with stiffness in the adjoining joints. The preosseous lesions involve the fascia, ligaments, tendons, and skeletal muscle. These lesions occasionally resolve but more often progress to form ectopic ossification. We present a boy who had a characteristic clinical presentation. Magnetic resonance (MR) imaging conducted in the preosseous stage of the lesion revealed the pathology, resulting in early therapy and resolution of the preosseous lesion without progression to ossification. To the best of our knowledge, post-therapy follow-up MR imaging in such a case has not been reported.

Efficacy and safety of deferasirox for reducing total body and cardiac iron in Thalassemia

ObjectiveTo assess the efficacy of deferasirox as an iron chelator, with specific reference to reducing cardiac iron overload.DesignProspective, open label, single arm study between 2008–2010.SetupThalassemia center at a teaching hospital.Participants30 multitransfused Thalassemia Major (TM) patients receiving deferasirox (DFX) therapy.MethodsAll patients had MRI T2*evaluation for cardiac iron load before starting DFX therapy. MRI T2* was performed on a 1.5 tesla Siemens sonata machine using thalassemia tools software and the ejection fraction measured using standard cardiac magnetic resonance sequence. Quantification of cardiac iron deposit was categorized into T2* <10 ms as high cardiac risk, 10–20 ms as intermediate risk, and >20 ms as low risk. We also estimated left ventricular ejection fraction (LVEF), end systolic volume (ESV) and end diastolic volume (EDV) using standard sequence. EF <56 % was considered to be significant cardiac dysfunction. DFX was administered in an initial dose of 20mg/kg/ day and increased to a maximum of 35mg/kg/day. Serum ferritin level was estimated in pretransfusion samples at 1–3 monthly intervals. The primary end point of the study was change in serum ferritin level and cardiac MRI T2* value after 12–18 months therapy.ResultsOf the 30 patients, cardiac iron value of >20 ms was seen in 15 (50%), whereas 9 (30% ) had 20–10 ms, and 6 (20% ) had −10 ms. The mean serum ferritin pre DFX therapy of all cases was 3859.8 ± 1690.70 ng/mL (1066–6725 ng/mL) and mean cardiac T2* was 23.8±15.2 ms (6.24–69.2 ms). After 12 to 18 months of DFX therapy on a mean dose of 33 mg/kg/day, the mean serum ferritin was 2693.4 ±1831.5 ng/mL (drop by 30.2%, P<0.001) and mean cardiac T2* was 24.2±12.9 ms (increase of 1.6 %, P=0.87). Percentage change in cardiac iron was greater in high risk (24.8%) and intermediate risk (33.4%) patients than low risk patients (8.4%), though these values were not statistically significant. LVEF was 62.0 (±7.0%) before treatment and changed to 58.9 (± 4.8%) after 18 months of therapy but the values remained within normal range and this change was not significant (P=0.061). Adverse effect of DFX included diarrhea, maculopapular skin rash and transient proteinuria that necessitated temporary stoppage of medication.ConclusionDeferasirox monotherapy has a good safety profile and effectively chelates total body iron. It is also a good myocardial iron chelator, more efficacious in moderate to severe cardiac iron overloaded patients.

Vertical Transmission of HIV-An Update

One of the greatest successes in AIDS research to date has by far been the discovery of successful interventions that interrupt the transmission of HIV from mother to child. It is however important to note that these successes have occurred largely in countries with great resources and the least burden of perinatal transmission of HIV. In the developing world wherein currently 95% of vertical transmission of HIV occurs, it is highly condemnable that still every minute an infected infant is said to be born in spite of the fact that vertical transmission is largely preventable, mainly because translating knowledge into practice is not always possible or feasible; This has led to a continuous growing numbers of children with HIV, thereby making pediatric HIV a looming problem rapidly draining the already burdened health care system of these countries. It is the need of the hour to appropriately address the challenges to achieve zero percent transmission of HIV from an infected mother to her child thereby giving a hope for an AIDS-free new generation worldwide.

Rubinstein Taybi Syndrome in an Indian Child due to EP300 Gene Mutation.

To the Editor : A 10-y-old girl was diagnosed with Rubinstein Taybi Syndrome (RTS) based on distinctive facial features (low hanging columella, high palate, grimacing smile, talon cusps), broad, angulated thumbs and great toes, short stature and moderate intellectual disability (Fig. 1). Her younger sister, who died at 11 mo of age due to acute myeloid leukemia, did not have clinical features of RTS. Complete sequencing of CREBBP and EP300 genes was done for the proband as previously described [1, 2]. No pathogenic mutation was noted in CREBBP gene. She was found to be heterozygous for c.1282C > T or p.P428S mutation in exon five of EP300 gene (Fig. 1). The mutation is predicted to affect the donor splicing [3]. The patient’s mother was heterozygous for the same mutation. Prenatal diagnosis was offered to the couple and the fetus did not carry this mutation, and was confirmed to be unaffected postnatally. This mutation was not identified in 100 normal unrelated individuals. Deletion/duplication analysis of CREBBP and EP300 gene was not available. Our patient had horizontal palpebral fissures as described with EP300 related RTS, compared with CREBBP related RTS, who have anti-mongoloid slant [4]. Although patients with EP300 mutation have broad thumbs or toes, radial deviation has not been reported [2] (Fig. 1). This mutation was inherited from her mother who had mild hypertelorism, broad nasal bridge, normal intelligence and hands/feet. Negri et al. reported a patient with mutation in EP300 gene (p.N1511T) that was inherited from a healthy mother. Low penetrance in EP300 related RTS may present a challenge during genetic counseling and prenatal diagnosis [2]. EP300 gene somatic mutations are reported in acute leukemia and RTS patients have an increased incidence of cancer [2, 5]. Thus, we report an Indian child with Rubinstein Taybi Syndrome with familial EP300 gene mutation.

Type І Hyper IgM Syndrome with Novel Mutation from India

Hyper IgM syndrome is a primary immunodeficiency disorder characterized by normal or raised levels of immunoglobulin (Ig) M with low or absent IgG, IgA, and IgE. Five genetic causes of Hyper IgM have been identified. CD40L is deficient on T cells in Type І Hyper IgM, leading to defective interaction between T and B lymphocytes and consequently an inability to switch from production of IgM to other classes of antibodies. This manuscript reports a patient with X linked Hyper IgM (XHIGM) syndrome caused by a novel mutation in the CD40 Ligand (CD40L) gene and a favorable outcome after bone marrow transplantation.

XDR TB in a Case of IL12Rβ1 Deficiency: A Case Report of Mendelian Susceptibility to Mycobacterial Disease from India

Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a relatively new term that describes a spectrum of inherited defects in the IL-12/23 and IFN- γ pathways that result in a selective predisposition to disease caused by poorly pathogenic mycobacteria. In contrast to previous reports of patients infected with environmental mycobacteria and BCG, this manuscript elucidates the clinical course and diagnosis of MSMD in a child harboring extensively drug resistant (XDR) Mycobacterium tuberculosis.

Evaluation of carotid artery dynamics & correlation with cardiac & hepatic iron in β-thalassaemia patients.

Background & objectives: Early atherosclerosis and vascular complication have been described in thalassaemia patients. There is lack of data or guidelines regarding monitoring of vascular health in thalassaemia. This study was conducted to compare carotid artery structural and functional indices such as carotid artery intima-media thickness (CIMT), stiffness index (SI) and Youngs elastic modulus (YEM) in β-thalassemia patients with age and sex matched controls, and to correlate these parameters with serum ferritin, cardiac iron, and hepatic iron. Methods: This cross-sectional study included 53 β-thalassaemia patients receiving regular blood transfusions. Carotid artery indices such as CIMT, SI, and YEM were calculated by duplex ultrasound and colour Doppler. Serum ferritin levels were measured by chemiluminescence. Cardiac and hepatic iron estimation were done using MRI T2* sequences analyzed by a special thalassaemia software. Results: Mean CIMT of cases and controls were 0.48 ± 0.04 and 0.44±0.02 mm, respectively and these were significantly different (P<0.001). Similarly significant differences were noted in SI and YEM of cases (2.45±0.79 and 96.12±34.85, respectively) as compared to controls (1.98±0.54 and 68.60±24.29, respectively) (P<0.001). There was significant inverse correlation between stiffness index and cardiac iron overload assessed by MRI cardiac T2* (P=0.03). Mean SI and YEM of cases were (2.1736 ± 0.2986 and 107.3± 41.6, respectively) significantly higher among non-splenectomized patients compared to splenectomized patients (2.0136 ± 0.263 and 86.9 ± 25.2, respectively) (P<0.05). Interpretation & conclusions: CIMT and arterial stiffness indices were significantly increased in β-thalassaemia patients compared to controls which was indicative of early atherogenic changes. This study supports the hypothesis that iron overload is a risk factor for early atherosclerosis and cardiovascular disease.

Evaluating Liver Fibrosis by Acoustic Radiation Force Impulse in Thalassemia

To the Editor: Acoustic radiation force impulse (ARFI) is an ultrasound-based elastography technique used to evaluate tissue stiffness by virtual touch tissue quantification using a conventional probe [1]. ARFI results strongly correlate with the stage of fibrosis in chronic liver disease, and it, therefore, promises to replace liver biopsy [2]. There are very few studies both internationally and in India that have evaluated the use of ARFI scan in thalassemic population [3]. A cross-sectional, non-interventional, observational study of 84 thalassemia major patients, between 8 and 18 y of age, was performed at a tertiary hospital in Mumbai from January through December 2016. Liver stiffness was assessed on a Siemens Accuson S 3000 ARFI machine using a 2.67 MHz probe, and shear velocity were documented in meters per second (m/s). Liver stiffness measurements were taken by the same person (radiologist) to minimize inter-observer variabilities. 3 Tesla MRI T2* imaging was used for iron quantification in the liver and results were converted to 1.5 Tesla MRI T2*. Serum ferritin was measured by electrochemiluminescence immunoassay and the mean serum ferritin value across each patient’s four previous readings was used for analysis. We studied the association of liver fibrosis by ARFI with age, the volume of blood transfusion, iron chelating agents and duration of therapy, mean serum ferritin and presence or absence of Hepatitis C virus (HCV) infection. ARFI scan revealed that of the 84 patients tested, 35.7% had cirrhosis (>1.8 m/s), 27.4% had severe fibrosis (1.55– 1.8 m/s), 10.7% had significant (1.35–1.55 m/s), and 26.2% had mild fibrosis (<1.35 m/s). Based on MRI T2*, 39.3% of patients had severe (<1.4 ms), 34.5% had moderate (2.7– 1.4 ms), 11.9% had mild (6.3–2.7 ms) and 14.3% had no liver iron overload (> 6.3 ms) (Table 1). The average shear velocity measurements on ARFI correlated with MRI T2* values (r = −0.278, p = 0.0104). There was also a significant positive correlation between ARFI and mean serum ferritin (r = 0.479, p = 0.000004081). There was a greater degree of fibrosis in HCV positive patients and a significant association between HCV status and severity of fibrosis (p = 0.022). ARFI is a type of shear wave elastography which targets a set anatomical area chosen to measure the shear waves propagated through it after a strong acoustic pulse is introduced (Fig. 1a). The shear velocity is proportional to the square root of tissue elasticity and expressed in m/s. The severity of fibrosis can be graded as per the propagation velocity of shear waves into absent or mild (F0 or F1,<1.35 m/s), significant (F2, 1.35–1.55 m/s), severe (F3, 1.55–1.80 m/s) or cirrhosis (F4, >1.80 m/s) (Fig. 1b) [4]. There has been only one study by Shivraja et al. evaluating hepatic fibrosis in pediatric thalassemia patients using ARFI scan [3]. A strong correlation between Transient Elastography (TE) and MRI R2* was noted by Pipaliya et al. who concluded that TE may supplement MRI as an alternative to document and monitor iron overload [5]. Liver stiffness as determined by ARFI correlates with iron overload as determined by MRI T2* (Fig. 2). Advantages of ARFI are that it is a non-invasive and cheap tool to measure liver stiffness caused by fibrosis * Pezad N. Doctor pezaddoctor@gmail.com