Clinical Profile and Renal Survival of Anti-Glomerular Basement Membrane Disease Patients: A Retrospective Case Series from Northern India.

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is a rare organ-specific autoimmune disease. The overall and renal outcomes of patients have mostly been reported in small-sized cohorts. We aimed to study the clinical profile, overall survival, and renal survival of anti-glomerular basement membrane disease patients at our center. Methods: We conducted a retrospective analysis of the data regarding the clinical profile and renal survival of patients diagnosed with anti-GBM disease from October 2019 to March 2022, having a minimum follow-up of 12 months. Results: There were 15 patients in the study, with the mean age of presentation being 51.6 ± 13.7 years. The median duration of symptoms onset to the nephrologist opinion was 15 (10-23) days. The extrarenal manifestations were seen in the respiratory, otorhinolaryngological, and neurological systems. The mean serum anti-GBM titers were 154.5 (14.9-263.5) U/mL. Serum anti-GBM titers were present in 13/15 (86.6%) patients, and 12/13 (92.3%) patients had above the reference range. Anti-neutrophil cytoplasm antibody (ANCA) levels were assessed in 12/15 (80%) patients, and 9/12 (75%) had higher levels. Renal biopsy was available in 14 patients with more than 50% crescents. Along with crescents, necrotizing lesions, rupture of the Bowman's capsule, and granulomatous lesions were also seen. Among the initial therapies, the steroid pulse was given to 13 (86.6%) patients, whereas membrane plasmapheresis was given to 8 (53.3%) patients. Inj. cyclophosphamide and inj. rituximab were given to 8 (53.3%) and 4 (26.6%) patients, respectively. No difference was seen in clinical characteristics, renal biopsy features, treatment received, and outcomes with ANCA positivity except for age, where patients who were ANCA positive were older compared to patients who were ANCA negative. One-year renal and patient survival was seen in 4 (26.6%) and 6 (40%) patients, respectively. Conclusion: Most patients of anti-GBM disease have active sediments, raised creatinine, and non-specific symptomatology. There is poor renal and patient outcome as most patients present with advanced renal failure.

Outcome of Therapies for Membranous Glomerulonephritis During Three Waves of COVID Pandemic.

There is lack of clarity on immunosuppressive therapy in glomerular diseases and concomitant corona-virus infection. We retrospectively evaluated 36 patients with primary membranous nephropathy from January 2020 to December 2021 who had received immunosuppression during this period. Diagnosis of COVID-19 was made based on self-reported history of being COVID positive. History of hospitalization and oxygen therapy was noted. Four patients developed COVID-19 in this cohort, and all were infected only once. Two patients had asymptomatic disease and two were hospitalized for severe COVID-19 and had complete recovery. In immunocompromised patients, there is a high risk of infection. This observational study is an attempt to bridge the gap that immunosuppression can precipitate COVID-19 infection.

Bleeding risk assessment in immune thrombocytopenia.

The bleeding risk in immune thrombocytopenia (ITP) is related not only to low platelet count but also to the presence of platelet dysfunction. However, diagnosing a concomitant platelet dysfunction is challenging as most of the available platelet function assays (PFAs) require a platelet count of greater than 100,000/µL. Sonoclot coagulation and platelet function analyzer works on the principle of viscoelastometry, and results remain unaffected by the platelet counts. To assess the platelet function in adult acute ITP patients with the help of sonoclot coagulation and platelet function analyzer and correlate it with the risk of bleeding. Newly diagnosed acute ITP patients with a platelet count less than 20,000/µL were divided into two groups based on WHO bleeding grade: ITP non-bleeder (ITP-NB) group (WHO bleeding grade ≤1) and ITP bleeder (ITP-B) group (WHO bleeding grade ≥2). Platelet function was assessed by sonoclot in both groups. The patients without significant bleeding (ITP-NB) were followed up monthly for six months with the assessment of platelet function during each contact. Eighty patients (30 ITP-B and 50 ITP-NB) were prospectively included in this study. The median age of patients in the two groups was 37 years and 30 years, respectively. The female-to-male ratio was 4:1 and 1:1 in ITP-B and ITP-NB groups. The median platelet count in ITP-B and ITP-NB was 12000/µL (range 1000-19000/µL) and 8000/µL (range 1000-19000/µL), respectively. Mean platelet functions by sonoclot in both groups were lower than the normal cut-off (>1.6). However, the mean platelet function in the ITP-B group (0.2 + 0.17) was significantly lower than the ITP-NB group (1.2 ± 0.52) (p = 0.01). During the follow-up period of 6 months, patients in ITP-NB with a normal platelet function (>1.6) on sonoclot had lesser episodes (one episode) of clinically significant bleeding than patients with a low platelet function (4 episodes). Patients with acute severe thrombocytopenia and bleeding phenotype have a greater abnormality on platelet function by sonoclot than patients with non-bleeding phenotype. This information may help in taking therapeutic decisions in patients with acute ITP.

Pregnancy and long-term outcomes of female patients with chronic myeloid leukemia on tyrosine kinase inhibitors who experienced unplanned pregnancies.

PURPOSE: Despite the general recommendation to avoid Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML) during pregnancy, unplanned pregnancies still occur, particularly among female patients residing in low- and middle-income countries (LMICs). We aimed to investigate the outcomes of pregnancy, foetal development, and disease progression among female CML patients in chronic phase (CML-CP) undergoing TKI therapy who encountered unplanned pregnancies in a tertiary care hospital in northern India. METHODS: We conducted a retrospective analysis of all pregnancies in female CML-CP between January 2002 and December 2022 at our hospital. Patients were included if they had a confirmed diagnosis of CML-CP, were receiving TKI therapy during conception, and had available medical records. We analysed the data on pregnancy outcomes, foetal development, and disease progression through a review of medical records. RESULTS: We identified 36 pregnancies in female CML-CP patients on TKI therapy during the study period, with 33 (91.7%) being unplanned. Sixteen pregnancies (48.5%) were conceived at less than major molecular remission (MMR) status. Twelve pregnancies (36.4%) were electively terminated, 4 (12.1%) had miscarriages, and, 17 (51.5%) pregnancies resulted in childbirth. Out of the 17 childbirths, 10 were full-term deliveries, and 7 were preterm deliveries. Twin pregnancies had a high incidence (18.2%). Among the 21 pregnancies that were not electively terminated, TKI was stopped at the first pregnancy detection in 14 pregnancies, while imatinib was continued throughout 7 pregnancies. Patients who discontinued TKI had a higher but statistically non-significant incidence of adverse pregnancy outcomes compared to those who continued imatinib throughout pregnancy (64.2% vs. 28.6%, p = 0.18). Additionally, the risk of long-term disease progression among patients who discontinued TKI during pregnancy and those who continued imatinib throughout pregnancy was 21.4% and 16.7% (p = 0.9), respectively. The risk of long-term disease progression was significantly increased in those persistently at less than MMR pre- and post-gestation (p = 0.0002). CONCLUSION: Our findings suggest that continuing imatinib therapy during pregnancy, may be a reasonable option for CML patients residing in low- and middle-income countries to reduce the risk of disease progression and adverse pregnancy outcomes. Patients persistently at less than MMR levels pre- and post-gestation should be closely monitored for the risk of long-term disease progression. Further studies with larger sample sizes are needed to confirm these results.

Real-world experience of anti-D immunoglobulin in immune thrombocytopenia.

In developing countries, anti-D has been used in immune thrombocytopenia (ITP) as a cheaper alternative to human immunoglobulin. We aim to analyze the response and safety profile of anti-D in patients with severe ITP. A retrospective study was conducted at a tertiary care hospital in Northern India. Patients received a single intravenous infusion of 75 µg/kg anti-D. In total, 36 patients (20 females) were included in this study. The median duration from ITP diagnosis to anti-D therapy was 235 days (range 1-1613 days). Four (11.1%) patients received anti-D as an upfront treatment. The patients' platelet counts rose significantly by the end of day three and continued to be significantly high until day 30 of receiving anti-D (p ≤ 0.001). The overall response rate (ORR) by day seven was 88.89%. There was no effect of age, sex, duration of disease, prior therapy, and platelet count on the ORR. Patients were followed up for a median duration of 52 days (longest follow-up: 3080 days). Six (6/36, 16.67%) patients continued to be in remission till the last follow-up. The hemoglobin fall was statistically significant on day three and day seven (p < 0.001 and p = 0.001) and got normalized by day 30. We observed equally good ORR in mixed populations and different phases of ITP along with long-term sustained response. The study demonstrates a quick and high response rate along with good safety profile to anti-D in all forms of ITP.

Safety and efficacy of splenectomy in immune thrombocytopenia.

BACKGROUND: Immune Thrombocytopenia (ITP) is characterized by low platelet counts. Splenectomy has been in practice for the treatment of ITP since the early 20th century. We aimed to analyze the data of ITP patients from our hospital who underwent splenectomy and further present the long-term outcome and safety profile in these patients. METHOD: This study was a single-center, registry based study conducted at a tertiary care hospital in Northern India. Patients aged 18 years or more, who underwent splenectomy after at least one line of therapy, were included in the study. The primary outcome was the overall response rate (ORR) at one month after splenectomy. Secondary outcomes were sustained response, relapse-free survival, factors affecting the ORR, and adverse events after splenectomy. RESULTS: Forty-five patients of ITP were included in the study. Thirty-six patients underwent splenectomy in the first half (2001-2010), of the study period. The median age of the patients was 38 (19-56) years. The median duration from diagnosis to splenectomy was 1.76 (0.47-2.58) years. The median number of therapy received before splenectomy was 3 (1-6). The overall response rate (ORR) post-splenectomy at day 30 was 89.2% with 61.8% complete response (CR). The ORR was 88.5% at 1-year, with 48.8% CR. The relapse-free survival (RFS) at 5-years was 57.38% (95% Confidence Interval 40.59-71.02%), There was no effect of duration of disease, age, gender, and prior therapy received, on the ORR at one-month. At one year, the platelet response was significantly better in patients who had a CR at one-month than patients who had a partial response at one month. The relapse-free survival was better in patients who achieved CR after 1-month of splenectomy. During the median follow-up of 5.02 (1 month-20 years) years, there were five cases of overwhelming post-splenectomy infection (OPSI). There was no recorded incidence of perioperative mortality, deep vein thrombosis, or mesenteric thrombosis. DISCUSSION: Despite the variation in outcome from different studies, splenectomy gives the best possible long-term treatment-free remission amongst all the available second-line agents. It is also, one of the most financially affordable therapies. Despite advantages, the number of ITP patients undergoing splenectomy has been on the decline and largely attributable to the newer and more effective second-line therapies. There is no pre-surgery variable predicting the ORR after splenectomy. CONCLUSION: Splenectomy in ITP offers a long-term sustained response at an economical cost.

The clinical profile, management, and outcome of febrile neutropenia in acute myeloid leukemia from resource constraint settings.

INTRODUCTION: Acute myeloid leukemia (AML) is the commonest leukemia in adults. Mortality in thew first 30-days ranges from 6% to 43%, while infections account for 30-66% of early deaths. We aim to present our experience of infections in newly-diagnosed AML. METHOD: This prospective, observational study, was undertaken at a tertiary care hospital in Northern India. Patients with confirmed AML (bone marrow morphology and flow cytometry) and who had developed febrile neutropenia (FN), were included. RESULT: A total of fifty-five patients were included in the study. The median age of the patients was 47.1 years (12-71) and 28 (50.9%) were males. Fever (33, 60%) was the commonest presentation at the time of diagnosis. One or more comorbid conditions were present in 20 patients (36.36%). Infection at presentation was detected in 17 patients (30.9%). The mean duration to develop febrile neutropenia since the start of therapy was 11.24 days. With each ten-thousand increase in white blood cell (WBC) count, the mean number of days of FN development decreased by 0.35 days (p = 0.029). Clinical and/or radiological localization was possible in 23 patients (41.81%). Thirty-four blood samples (34/242, 14.04%) from 26 patients (26/55, 47.3%) isolated one or more organisms. Gram negative bacilli (GNB) were isolated in 24 (70.58%) samples. Burkholderia cepacia (8/34, 23.52%) was the commonest organism. The number of days required to develop febrile neutropenia was inversely associated with overall survival (OS). However, when compared, there was no statistically significant difference in OS between patients developing fever on day-10 and day-25 (p = 0.063). Thirteen patients (23.63%) died during the study period. DISCUSSION: Low percentage of blood culture positivity and high incidence of MDR organisms are a matter of concern. Days to develop febrile neutropenia were inversely associated with overall survival (OS), emphasizing the importance of preventive measures against infections. CONCLUSION: Infections continues to be a major cause of morbidity and mortality among AML patients.

Safety and efficacy of azathioprine in immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is a benign hematological disorder characterized by low platelet counts in peripheral blood and spectrum of various bleeding manifestations. Azathioprine is one of the effective, readily available, and affordable immunosupressants available for ITP management in developing countries. We aimed to study the efficacy and long-term safety profile of our patients with ITP who were treated with azathioprine. METHOD: This was a retrospective, single-center study conducted at a tertiary care hospital in Northern India. The patients who had received at least one line of therapy before receiving azathioprine were included in this study. All patients received oral azathioprine at a dose of 1 mg/kg/day (50 mg or 100 mg tablet formulations were used), which was increased up to 2 mg/kg/day depending upon the response and adverse effects. RESULT: Sixty-three patients were analyzed. Their median age was 28 years (range 15-68); 29/63 patients (46.03%) were females. The median duration from diagnosis to azathioprine initiation was 539 days (323 days-980.5 days). The patients included in the study had received a median of 3 (range 1-6) prior lines of therapies; 38/63 patients (60.32%) had received ≥3 prior therapies. Six patients (9.5%) had relapsed after splenectomy, and 16 patients (25.4%) had relapsed after receiving rituximab. The mean baseline platelet count was 10000/µL. The median time to response was 95 days (90 days-not reached) and the cumulative overall response rate (complete and partial response) at day 90 was 38.1%. Only one patient achieved complete response with azathioprine in our study. The cumulative rate of relapse at five years was 21.2%. Twenty-six patients stopped azathioprine after achieving some response (CR/PR) with Azathioprine for a median duration of 1067.5 days (range: 236 days-2465 days). They were followed up for a median of 870 days (range: 392 days-1928 days), and twelve of them relapsed. Twenty-six patients (26/63, 41.27%) reported one or more adverse events while on azathioprine. Leucopenia was the most frequent adverse event, followed by anemia and hepatobiliary laboratory abnormalities. Serious adverse events (grade ≥3 CTCAEv4) were noted in three patients (4.7%). One patient succumbed to severe sepsis multiorgan dysfunction while being on treatment. CONCLUSION: We conclude that azathioprine has a good response rate in chronic ITP patients. It is well-tolerated with minimal and manageable side effects.

Real-world Experience of Rituximab in Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is a relapsing-remitting disease often requiring more than one line of therapy. Rituximab is a recommended second-line therapy, but the real-world data on its efficacy and safety from resource constraint settings is limited. We aimed to analyze the safety and efficacy of rituximab in ITP. This is a single-center, retrospective study. This study was conducted at a tertiary care hospital in Northern India from 2005 to 2019. On audit of medical records, all patients of ITP (n-513) who had received rituximab (n-81) were screened for inclusion. Patients whose response assessment was not possible were excluded. Finally, 66 patients were analyzed using statistical packages of Python v3.7. The cumulative incidence of overall response on day 20 was 30.61%, and day 30 was 51.72%. The median time to response was 28 day (range 21-51 day). Cumulative incidence of complete response was 16.67%, and partial response 37.88%. After a median follow-up of 789 day (range 181-5260 day), the cumulative incidence of relapse was 30.32%, 36.12%, and 56.57% at 1, 2, and 5 years respectively. There was no effect of age, sex, duration of disease, lines of therapy received, and platelet count on either cumulative incidence of overall response or relapse. ANA positivity was significantly related to the better cumulative incidence of overall response (p = 0.012), but not with relapse. Infusion-related reactions were the commonest adverse event noted (n-4, grade ≥ 3 CTCAEv4). Rituximab and its generic version are safe and effective second line agent in ITP with a good overall response and sustained response.

Scrub typhus and lateral rectus palsy: an uncommon presentation of a common illness.

Scrub typhus is a zoonosis, which usually manifests as an acute febrile illness. It is caused by a rickettsia, Orientia tsutsugamushi, which is endemic in the Asian region. It can present with varied clinical manifestations, ranging from acute febrile illness to life-threatening multiorgan dysfunction syndrome. Central nervous system involvement in the form of altered sensorium and/or meningitis is frequently observed in scrub typhus. However, isolated cranial nerve involvement is uncommon and so far only a few such cases have been reported in the literature. We present a rare case of scrub typhus with fever and diplopia at presentation, which completely improved with doxycycline-based treatment.

Acute arthritis, skin rash and Lofgren's syndrome.

Sarcoidosis is an autoimmune multisystem granulomatous disorder of unknown aetiology, which mainly affects the adults in the age group of 20-39 years. The disease can affect any organ in the body but mainly presents as bilateral hilar lymphadenopathy, pulmonary infiltrates, cutaneous lesions, ocular manifestations and arthropathy. Lofgren's syndrome is an uncommon initial presentation of sarcoidosis which is recognised by the classical triad of acute arthritis, erythema nodosum and bilateral hilar lymphadenopathy. We describe a newly diagnosed case of sarcoidosis who presented as Lofgren's syndrome. Acute sarcoid arthritis should be kept as one of the differential diagnoses for patients presenting with acute arthritis and skin lesions; and chest X-ray should be considered to rule out bilateral hilar lymphadenopathy in these patients. Early suspicion and identification of classical clinical features are essential to establish early diagnosis.

Update on diagnosis and treatment of immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is a heterogeneous acquired disorder characterized by isolated thrombocytopenia whose exact pathogenesis is not yet clear. Depending upon the presence or absence of an underlying treatable cause, ITP can be categorized as primary or secondary. Primary ITP is a diagnosis of exclusion and there is no gold standard test for its confirmation. Recent drug intake, infections, lymphoproliferative disorders, and connective tissue disorders should be ruled out before labeling a patient as primary ITP. AREA COVERED: This review summarizes a comprehensive update on the diagnostic and therapeutic modalities for ITP. We reviewed the literature using GOOGLE SCHOLAR, PUBMED and ClinicalTrial.gov databases as needed to support the evidence. We searched the literature using the following keywords: 'immune thrombocytopenia,' 'idiopathic thrombocytopenic purpura,' 'thrombocytopenia,' 'immune thrombocytopenic purpura,' and 'isolated thrombocytopenia'. EXPERT OPINION: We believe that more detailed studies are required to understand the exact pathophysiology behind ITP. The first-line drugs like corticosteroids have both short-term and long-term adverse effects. This brings the need to explore effective alternative medications and to reconsider their role in ITP treatment algorithm if guidelines can be modified based on new studies.

Management of BK virus-associated haemorrhagic cystitis in allogeneic stem cell transplant recipients.

BK virus (BKV)-related haemorrhagic cystitis (HC) is an important cause of morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). The various risk factors include high-level BKV viruria and/or viremia, myeloablative conditioning, acute graft versus host disease (GVHD), cytomegalovirus viremia, and unrelated or HLA-mismatched donor. The presence of high plasma BK viral load and cytopenias have been implicated as important predictors for protracted disease course. These patients frequently require hospitalisation which may extend for several weeks. Supportive measures in the form of analgesics, intravenous hydration, bladder irrigation, and transfusion support remain the mainstay of management. Various drugs have been used with limited success in this setting. These include antiviral drugs, fluoroquinolones, leflunomide, growth factors, clotting factors, estrogens, and prostaglandins. The role of adoptive cellular immunotherapy has also been explored but lacks clinical validation. The strategies aimed at expediting urothelial repair like hyperbaric oxygen therapy (HBOT), intravesical fibrin glue and platelet-rich plasma (PRP) are emerging. Some patients with severe disease do require surgical intervention to relieve urinary obstruction. The frequent co-occurrence of acute GVHD and CMV disease further complicates the management in such patients. There is an unmet need for effective and evidence-based options for the prevention and management of this disease. Due to lack of robust data supported by randomised trials, the acceptability of the available guidelines to simplify the treatment is expected to be low. Despite the availability of various treatment options, the management of BKV-related HC in day-to-day practice continues to be a challenge. The aim of this article is to put forward an up-to-date review of the preventive and therapeutic strategies for BKV-related HC.

Real-world experience of eltrombopag in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is characterized by decreased platelet count in the peripheral circulation. The first-line therapy is corticosteroids with 53-80% overall response rate. Eltrombopag has been used as second-line therapy in ITP for over a decade now. The long-term efficacy and safety profile have been widely reported in the western world. However, the data from the resource-constraint settings of the developing world is scarce. We aim to present the real-life experience of efficacy and safety of eltrombopag from the resource-constraint settings. This was a retrospective, single-center study conducted at a tertiary care hospital in Northern India from 2012-2019. On audit of medical records, patients of ITP receiving eltrombopag were screened for inclusion. Patients whose treatment outcomes were not available were excluded. Finally, 53 patients were analyzed using statistical packages of Python v3.7. The patients' median age was 35 years (range 17-78), with 23 (43.4%) being female. The median time to response was 35 days (range 28-50 days) and the cumulative overall response rates (ORR) at day 30, day 60 and day 90 were 41.5%, 69.8%, and 81.1% respectively. A total of 10 patients on eltrombopag relapsed during follow up. The cumulative rate of relapse at one year, three years, and five years were 6.6%, 25.3%, and 47.7%, respectively. There was no significant difference in outcome (response rate or relapse) in any subgroups depending on age, sex, duration of disease, number of prior lines of treatment, splenectomy, or baseline platelet count. Six patients stopped eltrombopag after having a median sustained response for 796 days (range 658-1185), and after a median follow up of 624 days (range 92-1339), they continued to be in remission. Seventeen patients (17/53, 32%) reported one or more adverse events while on eltrombopag therapy. A total of 49 adverse events (n=4, grade ≥3 CTCAEv4) were noted. Anemia was the most frequent adverse event followed by hepatobiliary dysfunction as reflected by deranged AST/ALT or raised bilirubin. The use of eltrombopag among adult ITP patients in resource-constraint settings was well-tolerated and yielded excellent overall response. The benefit was found to be sustained on long-term follow up. However, events like anemia, hepatobiliary, and thrombotic complications merit closer follow up.

Paratrabecular myelofibrosis and occult mastocytosis are strong morphological clues to suspect FIP1L1-PDGFRA translocation in hypereosinophilia.

To study the clinico-haematological and histopathological characteristics of FIP1L1-PDGFRA rearranged hypereosinophilia/hypereosinophilic syndrome (F/P+ve HE/HES), a retrospective analysis of patients with F/P+ve HE diagnosed over a period of 43 months was performed. Peripheral blood smears, bone marrow aspirate (BMA) and biopsies (BMB) were reviewed in each case and; reticulin stain and immunohistochemistry for mast cell tryptase (MCT) and CD117 was performed. F/P+ve HE was diagnosed in a total of ten patients during study period. All patients were males with a median age of 36 years (23-44 years). The median duration of presenting complaints was 7 months (2 months-3 years) which included specific symptoms related to various organs (80% of cases). Anaemia, thrombocytopenia and splenomegaly were seen in 60%, 50% and 90% of the cases respectively. Mastocytosis was not obvious in BMA but identified by MCT on BMB in all cases. Myelofibrosis (grade ≥ 1) was seen in 80% of the cases and includes multifocal paratrabecular fibrosis in 50% of the biopsies. Our study shows that bone marrow mastocytosis and myelofibrosis are very useful morphological indicators to suspect F/P+ve HE and suggests the routine use of reticulin staining and MCT immunohistochemistry in all BMBs performed for the evaluation of HE/HES.