Pituitary Volume and Iron Overload Evaluation by 3T MRI in Thalassemia.

OBJECTIVE: To evaluate pituitary volume and iron overload in beta thalassemia major, with the objective of assessing the reliability of this method in predicting hypogonadism. METHODS: 3T MRI was used to measure pituitary R2 and T2* in 57 beta thalassemia major patients and 30 controls. Anterior pituitary volume was evaluated by MRI planimetry. Cardiac, hepatic, and pancreatic iron overload were also assessed using MRI T2*. Mean serum ferritin was estimated by sandwich immuno-assay. Short stature was defined as height < 3 rd percentile for age, and clinical hypogonadism defined as absence of secondary sexual characteristics at ages ≥ 13 y for females and ≥ 14 y for males. RESULTS: Short stature was present in 32 patients (56.1%). Of the 47 patients in the pubertal age group, 11(23.4%) had hypogonadism. Serum ferritin correlated positively with pituitary R2 (p = 0.004) and negatively with anterior pituitary volume (p = 0.006), whereas pituitary R2 correlated negatively with cardiac T2* (p = 0.001). Patients with hypogonadism had lower pituitary R2 (p = 0.186), T2* (p = 0.048), and anterior pituitary volumes (p = 0.012) compared to those with normal sexual maturity. Regardless of stature, no significant difference was observed between pituitary R2 (p = 0.267) and T2* (p = 0.451). Mean pituitary R2 in patients (78.99 Hz) was higher than in controls (20.8 Hz) (p = 0.0001). Anterior pituitary volume was lower in patients (264.83 mm3) than in controls (380.87 mm3) (p = 0.0001). A threshold value of 22.85 Hz for pituitary R2 gave a sensitivity of 84.2% and a specificity of 73.3% in distinguishing pituitary iron content of patients from controls, with an area of 0.864 under the ROC curve. CONCLUSIONS: 3T MRI is a reliable method to detect pituitary iron overload and predict risk of hypogonadism in beta Thalassemia.

Wrist Deformity in Children and Adolescents with b-thalassemia on Oral Iron Chelation Therapy.

OBJECTIVE: To describe a novel wrist deformity in b-thalassemia major patients, and their radiographic and magnetic resonance imaging findings. METHODS: 30 patients with b-thalassemia major who were noticed to have ulnar deviation at wrist joint were evaluated for previous history of medications, serum ferritin levels, presence of pain and swelling at the wrist joint, and the duration of iron chelation therapy. Radiographs of wrist and limited magnetic resonance imaging (MRI) sequences were obtained in 30 and 15 patients, respectively. RESULTS: Radiographs revealed varying severity of distal ulnar shortening, distal radial slanting and presence of soft tissue distal to the ulna. MRI showed similar deformities along with abnormal marrow signal at distal ulnar ends; in 8 patients, a soft tissue distal to the distal end of ulna was noted. CONCLUSIONS: Varying severity of radiological abnormalities, predominantly affecting the distal ulna, are present in children and adolescents with b-thalassemia receiving oral chelation therapy.

Ophthalmic Evaluation in Beta-Thalassemia.

OBJECTIVES: To determine the association of ocular manifestations in beta-thalassemia with the patient's age, blood transfusion requirements, average serum ferritin and dose and duration of iron chelation therapy. METHODS: Sixty multi-transfused beta thalassemia patients of 12 to 18 y of age on chelation therapy were included in this cross-sectional analysis. Structural and functional evaluation of the retina was done using Optical coherence tomography (OCT) and Electroretinography (ERG), including flash ERG and Pattern ERG (PERG). Routine ophthalmic examination and B scan of the eye was also done. Flash ERG a-waves and b-waves were recorded, however only a-wave amplitude was evaluated. Pattern ERG n35, n95 and p50 waves were recorded and p50 wave amplitude was evaluated. The a-wave on flash and p50 on pattern waves represent retinal photoreceptor epithelium (RPE) photoreceptor response, which is mainly affected in beta-thalassemia. RESULTS: Ocular changes were detected in 38.3% and a significant correlation was noted with increase in age (p = 0.045) but not with serum ferritin, transfusion requirements or chelation therapy. Refractive errors were found in 14 cases (23%), such as myopia with astigmatism in 13 (21.7%) and only myopia in 6 subjects (10%). OCT abnormality was noted in 1 patient (1.7%) who had thinning of central retina; right eye 132 µm and left eye 146 µm (n > 200 µm). Abnormalities were noted in a-wave amplitude on flash ERG in 20% of cases, while reduced p50 amplitude on PERG was noted in 15%. CONCLUSIONS: A significant correlation was noted between ocular findings and increase in age, but not with serum ferritin, transfusion requirements or chelation therapy. ERG appears to be a promising tool for screening patients with beta-thalassemia and can serve as a follow-up test for evaluating retinal function.

Evaluation of carotid artery dynamics & correlation with cardiac & hepatic iron in ß-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 Young's elastic modulus (YEM) in ß-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 ß-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 ß-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.

Post Splenectomy Outcome in ß-Thalassemia.

OBJECTIVES: To evaluate changes in annual blood transfusion requirements and complications after splenectomy in patients with ß-thalassemia. METHODS: Forty post-splenectomy ß-thalassemic patients aged 8-33 y, receiving regular blood transfusions and chelation therapy were included and non transfusion dependant patients were excluded from this retrospective cross-sectional study. Details about their surgery, transfusion requirements, and platelet levels were recorded on a standard proforma. All patients underwent a B-mode and color-coded duplex sonography of the hepatoportal system during the study period. RESULTS: The average ferritin level in the year prior to the study was 4432 mcg/L (range 480-12,200 mcg/L). The annual blood transfusion requirement in the first year and 5 y post splenectomy [mean ± SD (138.41 ± 90.38 ml/kg/y); (116 ± 41.44 ml/kg/y)] were significantly different from requirements before splenectomy [(mean ± SD) 294.85 ± 226 ml/kg/y; p value <0.001]. There was a significant rise in platelet counts within 24 h post splenectomy with a mean rise of 4,51,000/mm(3) (p value < 0.001). During the follow up period, infections were noted in 50 % of patients, with malaria (18.75 %) being the most common. Doppler study of the portal system in one case showed portal vein thrombosis. CONCLUSIONS: A significant sustained fall in annual blood transfusion requirement and a rise in platelet counts occurred post-splenectomy. Increase in annual blood transfusion requirement should be investigated to find the cause.

X linked agammaglobulinemia: a single centre experience from India.

The authors report a series of seven cases of X-linked Agammaglobulinemia, diagnosed and receiving treatment at a tertiary care centre in Mumbai. The ages of the patients ranged from 15 mo to 15 y. After diagnosis at a mean age of 3 ½ y, all were advised intravenous immunoglobulin (IvIg) infusion therapy in doses of 400-600 mg/kg every 3-4 wk. They were followed up for an average duration of 9 y, throughout which the complications and overall response to immunoglobulin therapy have been observed. The clinical profiles of each of these cases were retrospectively analysed with respect to age at diagnosis, frequency and severity of infections before and after initiation of treatment, co-morbidities and response to therapy. The results demonstrate the importance of early diagnosis and its correlation with decreased complications.

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.

Effect of deferasirox chelation on liver iron and total body iron concentration.

OBJECTIVE: To determine efficacy of Deferasirox (DFX) on total body iron and liver iron concentration (LIC) as estimated by serum ferritin (SF) and liver MRI T2. METHODS: Thirty patients had baseline MRI T2 of the liver performed to determine LIC before starting DFX therapy and classified as normal >6.3 milliseconds (ms), mild 6.3-2.7 ms, moderate 2.7-1.4 ms and severe iron overload <1.4 ms. DFX was given 25-35 mg/kg/d. The serum ferritin (SF) level was estimated every 3 monthly. Liver iron is expressed as liver R2 = 1,000/T2. The primary end point of the study was to determine change in SF and liver MRI R2 values after 18 mo of therapy. RESULTS: All 30 patients had some degree of liver iron overload; 11 (36.6 %) had severe, 15 (50 %) had moderate while 4 (13.3 %) had mild overload. The pre-DFX therapy median SF of all was 3604.5 ng/mL (IQR 2357.0-5056.0) and median liver R2 was 574.71 Hz (IQR 411.3-770.8). After 18 mo, SF dropped significantly to a median of 2036.5 ng/mL (IQR 1700.0-3162.0) (p = 0.0011), while median liver R2 decreased from 574.71 to 568.18 Hz (IQR 393.4-803.2) which was not significant (p = 0.986). CONCLUSIONS: DFX monotherapy at the doses used decreases total body iron, but does not significantly decrease liver iron. It is well tolerated by Indian thalassemia patients, with observed side effects including rash, diarrhea, and transient albuminuria. MRI T2 (and derived R2) can serve as useful method in non invasive monitoring of LIC in thalassemia patient management.

XDR TB in a case of IL12Rß1 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.

Prevention on parent to child transmission of HIV - what is new?

Prevention of Mother-To-Child Transmission (PMTCT) of HIV has been at the forefront of research in the field of HIV/AIDS since the PACTG 076 proved successful in 1994. This was followed by many trials with single, dual, or triple Anti Retroviral Therapy (ART), with or without breast-feeding, with different modes of delivery. These trials aimed and promised to find a relatively simple, low-cost intervention that could virtually eliminate the risk of HIV transmission from mother to child, cutting across all geographic boundaries. However, translation of the findings from most of these research studies into successful national PMTCT programs and health policies has not been optimal. In the west, parent to child transmission of HIV has been virtually eliminated due to universal coverage, screening, planned conception wherever possible, thorough evaluation and appropriate antenatal, intranatal and postnatal interventions. In contrast, in resource limited settings where the magnitude of the problem is the greatest accounting for more than 95 % of all vertical transmissions of HIV, there is a constant struggle dealing with the birth of an infected infant every minute. It is time to make optimal choices to prevent the transmission of HIV from an infected mother to her child and virtually eliminate this largely preventable scourge in children.

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.

Evaluation of growth, puberty and endocrine dysfunctions in relation to iron overload in multi transfused Indian thalassemia patients.

OBJECTIVE: To determine the prevalence of growth abnormality and endocrine dysfunction in a group of multi transfused thalassemic children and to correlate these with their body iron stores. METHODS: This cross sectional study included 35 Thalassemia Major patients, aged 13 to 24 years. Growth and puberty were assessed clinically and the laboratory values of various hormone levels were stratified with their age and sexual maturity. RESULTS: 57.14% patients were short, 60% had not attained puberty, and 87.5% of the girls had primary amenorrhea. 14.29% had low FSH and 2.86% low LH levels. 89.47% of the boys had low free testosterone and 43.75% of the girls had low estradiol levels. While 20% had high TSH levels, 40% had high PTH levels, of which 92.8% had low levels of Vitamin D. Low levels of IGF-1 were noted in 51.43%. CONCLUSIONS: In this study analysis, short stature and hypogonadism were frequent findings. These results support the need for vigilant clinical evaluation of growth and puberty, as well as appropriate hormonal evaluation in poly transfused thalassemic children in order to detect and treat endocrine dysfunction early. The authors also recommend aggressive and adequate chelation from early life so that permanent damage to the endocrine glands can be prevented.

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.

Prevention of mother-to-child transmission of HIV--an overview.

With the human immunodeficiency virus (HIV) epidemic showing a shift towards women and young people, the increasing seroprevalence among women will result in an increase in the mother-to-child transmission of HIV. The vast majority of HIV-positive children worldwide acquire the infection through vertical transmission. The discovery of successful interventions that interrupt this transmission has been one of the greatest successes in AIDS research. The transmission of HIV from an infected mother to her child can be reduced to less than 2 peer cent by intensive interventions in the antenatal, intranatal and postnatal periods. To achieve this low rate, primary prevention of HIV infection in parents-to-be, early identification of seropositivity in pregnant women, prevention of unwanted pregnancies, prevention of mother-to-child transmission of HIV by appropriate antiretroviral therapy, special interventions in maternal management during labour, appropriate care and follow up of the newborn, all play an important role. However, these approaches are not always possible in developing countries wherein currently 95 per cent of vertical transmission occurs. Several questions and challenges remain. These include choice, availability, affordability, duration, long-term safety of optimal antiretroviral agents to be used during pregnancy and early neonatal life and the issue of transmission via breastfeeds in situations where alternatives to breastfeeding are not available. The challenge is to find the most cost-effective and feasible intervention to achieve zero per cent transmission of HIV from an infected mother to her child.