Lallindra Gooneratne

Sarcoidosis and haematological malignancies: is there an association?

Sarcoidosis is a multi-system granulomatous disorder commonly affecting young adults frequently presenting with bilateral hilar lymphadenopathy, pulmonary infiltrates, skin and/or eye lesions(Reich, 2006). Although the aetiology of sarcoidosis is unknown, it is thought to result from a T-cell mediated immunological response against an environmental trigger in a susceptible host. It has been postulated that T-cell dysregulation may predispose patients with sarcoidosis in the development of the malignant disease. However, the association between sarcoidosis and malignancies remains controversial (Brincker, 1989; Reich, 2006). We performed a retrospective review of all haemato-oncology patients treated at our centre over a 15-year period. Case records from 3016 patients with haematological malignancies were reviewed and 10 patients were identified with concurrent sarcoidosis. Patient characteristics are detailed in Table I. The median age at diagnosis of the haematological malignancy was 52 years (range: 35–59 years), with a median follow-up period of 66 months (range: 1Æ4–358 months). In contrast, the median age at diagnosis of sarcoidosis was 44Æ5 years (range: 30–53 years). Haemato-oncological diagnoses were determined according to the World Health Organization classification criteria (Jaffe et al, 2001). Of the five patients with a lymphoid malignancy, all had evidence of pulmonary sarcoidosis or peri-hilar lymphadenopathy that was distinct from the site of the lymphoid malignancy. The diagnoses of the lymphoid malignancies were confirmed by immunohistochemical staining, while the diagnosis of sarcoidosis was based on histological and radiological findings, as well as elevated angiotensin converting enzyme levels. All biopsies of the non-caseating granulomatous lesions were negative for microbiological culture and gram-stain. In addition, Ziehl-Neelsen staining was negative for Mycobacteria and Periodic acid-Schiff stain was negative for fungi samples. Sarcoidosis was observed in the lungs of seven patients, skin of six patients, liver of one patient and eyes of two patients. Sarcoidosis predated the haematological malignancy in eight (80%) patients by a median of 78 months (range: 11– 349 months) and followed the diagnosis of haematological malignancy in two patients. Two patients had active sarcoid that required treatment at the time of diagnosis of the haematological disease as detailed in Table II. Five patients had advanced stage haematological malignancies, defined as acute myeloid leukaemia (AML)>first complete remission; myelodysplastic syndrome (MDS)>refractory anaemia with excess blasts (RAEB) I; chronic myeloid leukaemia>first chronic phase; non-Hodgkin Lymphoma (NHL)/Hodgkin lymphoma (HL): Stage III/IV. There was no clear correlation between the severity of sarcoidosis and stage of malignancy. Three patients (30%) had an additional nonhaematological malignancy (breast carcinoma = 1, squamous cell carcinoma of skin = 1, testicular seminoma = 1); two of these three patients had received chemotherapy or radiotherapy for their haematological disorder prior to development of the secondary lesion. Patient 3 had been treated with chlorambucil for NHL 12 years prior to development of breast cancer. Patient 5 had received six courses of CLOPP (bleomycin, etoposide, doxorubicin, cyclophosphomide) chemotherapy 14 years prior to the development of squamous cell carcinoma, which was surgically excised later. Patient 6 had a testicular seminoma, which was treated with orchidectomy and extended field radiotherapy and developed MDS RAEB after 3 years. Only one patient (Patient 5) had a detectable karyotypic abnormality with complex cytogenetics [45 XY, -5, del (7) (q21.q36)]. In addition, one of the patients with a second malignancy (Patient 3) also developed immune thrombocytopaenic purpura at the same time as NHL was diagnosed. A review of the literature shows evidence both for and against an association between sarcoidosis and malignancies. Seersholm et al (1997) analysed a cohort of 254 patients with sarcoidosis followed up for a median duration of 25 years, with only 33 patients developing a malignancy. There was only one case of leukaemia, and this study did not support an association between sarcoidosis and haematological malignancies. In contrast, post-mortem findings on 131 patients with sarcoidosis and a malignancy revealed HL in 23 patients and NHL in 30 patients (Brincker, 1972). In addition, various other forms of haematological malignancies, including AML, chronic monomyelocytic leukaemia, multiple myeloma and hairy cell leukaemia have been reported to coexist with sarcoidosis. Kings College Hospital is a tertiary centre with a wide referral base extending out of London. It is difficult to accurately estimate the referral population of our centre, which limits the ability to perform formal epidemiological analysis of the association between haematological malignancy and sarcoidosis. In our cohort, sarcoidosis occurred in 10 out of 3016 patients (0Æ33%). In contrast, the annual incidence of sarcoidosis in the South London population has been estimated at 1Æ5–16Æ8/100 000/year (Edmondstone & Wilson, correspondence

Dapsone for primary immune thrombocytopenia in adults and children: an evidence‐based review

Primary immune thrombocytopenia is a potentially life‐threatening condition. Approximately two‐thirds of adult patients do not have a sustained response to steroids (first‐line therapy). For these patients, a number of other treatment options exist, such as rituximab, splenectomy, immunosuppressants, and thrombopoietin receptor agonists, but they are costly and have side effects. Dapsone is an inexpensive drug with a well‐established safety profile. Unfortunately, this treatment option has not been explored adequately. This review is aimed at analyzing the currently available evidence for the use of dapsone as second‐line or third‐line therapy in primary immune thrombocytopenia.

Sarcoidosis as an unusual cause of hepatic dysfunction following reduced intensity conditioned allogeneic stem cell transplantation

Sarcoidosis as an unusual cause of hepatic dysfunction following reduced intensity conditioned allogeneic stem cell transplantation

ATG vs thiotepa with busulfan and cyclophosphamide in matched-related bone marrow transplantation for thalassemia

Matched-related bone marrow transplantation (BMT) may cure >80% of low-risk children with severe thalassemia (ST). Very long-term follow-up studies have shown how the standard busulfan-cyclophosphamide (BuCy) regimen may be associated with normalization of health-related quality of life, no second malignancies in the absence of chronic graft-versus-host disease, and fertility preservation in many patients. However, because BuCy may be associated with high rejection rates, some centers incorporate thiotepa (Tt) in busulfan- or treosulfan-based regimens, a combination that may increase the risk of permanent infertility. This study retrospectively compares matched-related BMT outcomes in 2 groups of low-risk ST patients conditioned with either Tt or anti-thymocyte globulin (ATG) in addition to BuCy. A total of 81 consecutive first BMTs were performed in 5 collaborating startup BMT centers in the Indian subcontinent between January 2009 and January 2016; 30 patients were transplanted after conditioning with Tt-BuCy between January 2009 and July 2013, whereas between August 2013 and January 2016, 51 patients received ATG-BuCy. All patients were <15 years and had no hepatomegaly (liver ≤2 cm from costal margin). Actuarial overall survival in the Tt-BuCy and ATG-BuCy groups was 87% and 94% and thalassemia-free survival was 80% and 85% at a median follow-up of 37 and 17 months, respectively, with no significant differences by log-rank statistics. Substituting Tt with ATG in the standard BuCy context seems safe and effective and may decrease transplant-related mortality. Higher fertility rates are expected for patients who received ATG-BuCy.

Rituximab in the treatment of autoimmune haemolytic anaemia

Rituximab is a B‐cell depleting monoclonal antibody that is gaining popularity as an effective therapy for many autoimmune cytopenias. This article systematically evaluates its therapeutic efficacy in the treatment of different types of autoimmune haemolytic anaemia. We conclude that there is sufficient evidence to recommend it as a second line therapy for warm autoimmune haemolytic anaemia (wAIHA) either as monotherapy or combined therapy. Evidence from a single randomized controlled trial suggests that it may also be more efficacious as first line therapy in combination with steroids than steroids alone. A fewer number of studies have assessed its role in cold autoimmune haemolytic anaemia (cAIHA) and cold agglutinin disease (CAD) with success rates varying from 45–66%. In the absence of alternative definitive therapy, rituximab should be considered for patients with symptomatic CAD and significant haemolysis. Case reports of its efficacy in mixed autoimmune haemolytic anaemias are available but evidence from case series or larger cohorts are nonexistent.

Slow platelet recovery pattern during the 2011 dengue outbreak: a preliminary report

During the 2011 dengue outbreak, health care providers in Colombo, Sri Lanka noticed a slow rise in platelet counts in patients recovering from dengue fever when compared to the 2010 outbreak. This study was carried out to confirm this observation. The platelet recovery rates of two groups of patients from 2010 and 2011 (n=28 and n=25 respectively) were computed and compared. The platelet recovery rates, of patients from the 2011 outbreak were found to be slower than the platelet recovery rates of patients from the 2010 outbreak (p value=0.0089).

Aplastic anaemia and PNH transformation with deposition of liver iron

A 37-year-old man was diagnosed with very severe aplastic anaemia (AA) with a normal paroxysmal nocturnal haemoglobinuria (PNH) screen. He had no initial response to antithymocyte globulin (ATG) and ciclosporin, but blood counts recovered following a second course of ATG and oxymetholone. Ten years later he developed ‘red urine’ and an elevated lactate dehydrogenase (LDH). Flow cytometry with FLAER (fluorescent labelled aerolysin) confirmed a large PNH clone (left). He required regular blood transfusions. He developed Budd-Chiari syndrome and intra-hepatic tissue plasminogen activator (TPA) was administered followed by long-term warfarin. He developed further hepatic vein thrombosis, and eculizumab was started. Transfusion requirements initially reduced but later increased. However, his urine colour and LDH remained normal. Direct Coombs test was positive (IgG-negative, C3d3) and C3d-positive extravascular haemolysis was diagnosed. Erythropoietin was given and blood transfusions were continued. Serum ferritin was 2400 lg/l and magnetic resonance image-based measurement of liver iron concentration (FerriScan) confirmed parenchymatous iron deposition (right) with an average liver iron concentration of >43 mg/g dry tissue (normal range 0·17 –1·8). He is clinically stable requiring two to three transfusions every 3 months, on eculizumab, warfarin and erythropoietin. Approximately 10% of AA patients treated with ATG progress to haemolytic PNH. Diagnosis of PNH requires demonstration of reduction/absence of glycosyl phosphatidyl inositol (GPI)-linked proteins in at least two cell lines. FLAER specifically binds to the GPI anchor, and has become the most useful reagent for detecting white cell PNH clones (left). Most patients with haemolytic PNH are iron-depleted due to intravascular haemolysis and loss via the kidneys. Complement blockade at C5 by eculizumab results in increased C3 levels upstream in the complement cascade, resulting in extravascular haemolysis. This, together with the multiple blood transfusions he received for over 10 years and heterozygosity for the H63D mutation would have contributed to iron overload. FerriScan is a non-invasive, measurement of liver iron concentration, which can be done as an outpatient and obviates the need for liver biopsy.

Klippel-Trenaunay syndrome presenting with acanthocytosis and splenic and retroperitoneal lymphangioma: a case report

IntroductionKlippel-Trenaunay syndrome is a rare congenital mesodermal abnormality characterized by bone and soft tissue hypertrophy, extensive hemangioma and venous abnormalities. We report the case of a patient with two additional rare clinical manifestations in the background of Klippel-Trenaunay syndrome, namely, acanthocytosis and splenic and retroperitoneal lymphangioma.Case presentationA 24-year-old Sri Lankan man from North Central Province in Sri Lanka presented to our general medical unit with symptomatic anaemia. He had been diagnosed with Klippel-Trenaunay syndrome at the age of six years, with hemihypertrophy of his right lower limb and strawberry naevi over both lower limbs. His blood film results were positive for acanthocytes, which accounted for more than 20% of the red blood cell population. He was also found to have extensive splenic lymphangiomas and a large retroperitoneal lymphangioma encasing the mesentric vessels in the right para-aortic region. An extensive battery of tests to identify a secondary cause for the acanthocytosis failed to show any positive results.ConclusionsRetroperitoneal lymphangioma has been reported in association with Klippel-Trenaunay syndrome once before, but an association with acanthocytosis has never been reported. Given the rarity of all three conditions this is not surprising. The cause of acanthocytosis in this setting is currently unresolved. It is plausible that this may be a primary association with Klippel-Trenaunay syndrome, as an alternative aetiology was not found.

Can findings on peripheral blood smear differentiate leptospirosis from other infections? A preliminary comparative study

Background Blood smear changes have never been investigated as a potential tool to aid in the diagnosis of leptospirosis. Methods Blood smears prepared from patients with leptospirosis, dengue and sepsis within the first 5 days of illness were reported by haematologists blinded to the diagnosis. Results A total of 20, 28 and 22 patients with leptospirosis, dengue and sepsis, respectively, were analysed. Neutrophil leucocytosis, toxic changes in neutrophils, left shift, reactive lymphocytes, target cells and thrombocytopaenia were seen in 60%, 70%, 40%, 70%, 50% and 65% of the leptospirosis patients, respectively. The combination of reactive lymphocytes with toxic neutrophils or neutrophil leucocytosis was highly suggestive of leptospirosis. Conclusions Peripheral blood smear findings may be helpful in differentiating leptospirosis from other common acute febrile illnesses.

Pregnancy outcomes of antiphospholipid syndrome: In a low resource South Asian setting.

Problem Antiphospholipid syndrome is associated with recurrent pregnancy loss, and specific treatment improves pregnancy outcome. Laboratory diagnosis is limited in South Asia. We assessed management outcomes of definite/probable antiphospholipid syndrome treated at a tertiary centre in Sri Lanka. Method Descriptive cross-sectional study of pregnancy outcomes with heparin and aspirin therapy. Outcome measures: miscarriage, intrauterine death and live birth when compared to previous untreated pregnancies. Results Of 646 gestations in 145 women, 146 (22.6%) received specific treatment. In the preceding pregnancies without specific treatment, the rates of miscarriage, late fetal loss, stillbirth and live birth were 60%, 26%, 8% and 7%, respectively. Following specific treatment with low-dose aspirin ± low-molecular weight heparin in 146 pregnancies (145 women), the rates of miscarriage, late fetal loss, stillbirth and live birth were 14%, 10%, 3% and 74%, respectively. Mean birth weight was 2.54 ± 0.62 kg, preterm births complicated 32 (29.6%) with a mean gestational age at delivery 33.7 ± 2.6 weeks, with three neonatal deaths. Maternal complications were: pre-eclampsia 16 (10.9%), gestational diabetes 28 (19.2%), antepartum haemorrhage in 1 patient. Only 73/145 (50.3%) women had laboratory confirmation of antiphospholipid syndrome, while others were treated empirically. Live births in diagnosed vs. empiric treatment – 80.8% vs. 67.1%. Conclusion Pregnant women with clinical antiphospholipid syndrome when treated with low-dose aspirin and heparin, the live birth rate of 7% in the previous pregnancy resulted in live births of 74% in a resource limited South Asian setting.