Depression among adolescents is a significant public Hematopoietic Stem Cell Transplantation (HSCT) stands as a pivotal milestone in the realm of medical science, offering a beacon of hope for children grappling with an array of life-threatening hematological and immunological disorders.[1] The concept of replenishing a patient's hematopoietic and immune system by infusing stem cells from a compatible donor, be it a closely matched family member or an unrelated individual, has transformed the treatment landscape for conditions that were once deemed untreatable or refractory to conventional therapies. 

Allogeneic HSCT, in particular, has emerged as a potent curative strategy with the potential to confer long-term disease control and even complete remission. A`llogeneic haematopoietic stem cell transplantation (allo-HSCT) is needed to cure a subpopulation of children with de novo and relapsed acute lymphoblastic leukaemia (ALL). [2]

Despite its remarkable promise, the path to recovery for pediatric patients undergoing allogeneic HSCT is fraught with complexities and beset by a multifaceted spectrum of early complications that can have profound implications for the patient's overall health and transplant outcomes.[3] These complications encompass a wide range of clinical challenges, spanning from infections and the insidious graft-versushost disease (GVHD) to hematological anomalies and organ toxicities.[4] It is within this crucible of post-transplantation complications that the resilience of both pediatric patients and their healthcare providers is put to the test.

However, allo-HSCT is associated with significant transplant-related mortality, ranging from 5 to 24%, due to serious infections or acute or chronic graft-vs.-host disease (GvHD), while secondary malignancies, organ dysfunction and compromised quality of life may pose additional problems (1–3). Despite advances in the HSCT procedure and refinements in supportive care strategies over the last 20 years, infections remain an important cause of morbidity and mortality after HSCT (4).

Understanding the incidence, nature, and determinants of these early complications is an imperative task in the realm of pediatric HSCT. Not only does this knowledge play a pivotal role in enhancing the quality of care offered to these young patients, but it also contributes to the refinement of existing protocols and informs the development of more effective treatment strategies. The setting in which this exploration takes place is of particular significance in this study: a Tertiary Care Government Hospital. This choice of setting brings with it its own unique dimensions, including considerations of resource availability, healthcare infrastructure, and the demographics of patients served.

This paper embarks on a comprehensive examination of early complications following allogeneic HSCT in pediatric patients within the context of a Tertiary Care Government Hospital. Through a meticulous review of the medical records of these patients, this research endeavors to elucidate the prevalence, types, and potential determinants of these complications in this specific healthcare environment. The insights garnered from this study are instrumental, not only for the optimal management of individual cases but also for the collective advancement of pediatric HSCT care.

Aims & Objectives

To study the infectious complications following allogeneic HSCT in pediatric patients in a tertiary care government hospital.

Objectives

Primary objective:

• To study the complications occurring in first 100 days after bone marrow transplant in children.

Secondary objective:

• To recognize the risk factors associated with these complications.

This retrospective observational study was conducted at the Bone Marrow Transplant Unit, M.Y. and Superspeciality Hospital, Indore (M.P.), over one year following Institutional Ethics Committee approval. Data was collected from medical records of pediatric patients (<18 years) who underwent HSCT between 2018 and 2023, with a total sample size of 65 patients. Incomplete or absent records were excluded.

Methodology

Clinical data was collected prospectively from medical records, transplant registries, and laboratory reports. The data was gathered at regular intervals: pre-transplant, immediately post-transplant, and during the first 100 days following HSCT. Key variables recorded included:

1. Demographic Information: Age, sex, underlying condition (e.g., thalassemia, aplastic anemia), and transplant type (matched sibling donor, haploidentical, unrelated).
2. Transplantation Details: Type of HSCT (bone marrow, peripheral blood stem cells), conditioning regimen, and immunosuppressive therapy.
3. Infection Data: Types and timing of infections (bacterial, viral, fungal), cultures, and microbial organisms identified.
4. Immunosuppressive Therapy: Use of cyclosporine A (CSA), granulocyte colony-stimulating factor (G-CSF), and other immunosuppressive agents.
5. Sepsis Data: Presence of clinical sepsis, including signs and symptoms, and diagnostic test results (blood cultures, bacterial/viral identification).

Diagnostic Criteria for Infections

Infections were diagnosed using clinical signs and symptoms in combination with laboratory investigations. The following diagnostic criteria were used:

1. Bacterial Infections: Diagnosis confirmed by positive blood cultures, culture from infection site, or radiological findings suggestive of bacterial infection.
2. Viral Infections: Detection of viral DNA or RNA via PCR testing, antigen detection, or serology (CMV, VZV).
3. Fungal Infections: Positive fungal cultures, antigen detection (e.g., galactomannan), or imaging findings consistent with fungal infections.

 Statistical Analysis

Data was extracted using a customized proforma and analyzed in IBM SPSS Version 22. Descriptive statistics were presented as numbers and percentages, while associations between non-parametric variables were assessed using the Pearson Chi-square test (p < 0.05 considered significant).

The study was conducted in a state government hospital, where treatment is provided free of cost, incurring no additional financial burden. Ethical approval was obtained, and patient confidentiality was strictly maintained.

Demographic and diagnostic characteristics: A higher proportion of male participants (64.6%) compared to female participants (35.4%). The majority of the participants were in the younger age categories, with 38.5% aged between 0-6 years and 43.1% in the 6-12 year range. The mean age of the participants was 8.11 ± 4.28 years. The table further highlights that thalassemia major was the most prevalent diagnosis, affecting 67.7% of participants, followed by aplastic anemia (18.5%) and sickle cell anemia (6.2%). Other conditions, though present, represented a smaller proportion of the sample.

[Table 1]

Table 1: Clinicodemographic profile of study participants

Donor characteristics and profile: Majority of donors were relatively young, with 52.3% of them being under 10 years of age and 35.4% falling within the 11-20 year range. The mean age of donors was 12.71 ± 9.63 years, and a slight majority were female (53.8%). Regarding histocompatibility, 89.2% of donors were identified as identical matches, while 10.8% were haploidentical matches. The table also provides information on CMV and VZV status, with 89.2% of donors testing positive for CMV IgG and 61.5% testing negative for VZV IgG. The source of stem cells was predominantly bone marrow (83.1%). [Table 2]

Table 2: Donor Profile and Characteristics

Post-transplant characteristics and infection-related data: The findings show that 55.4% of patients received cyclosporine A (CSA) as part of their immunosuppressive regimen, and 78.5% were administered granulocyte colony-stimulating factor (G-CSF) following the transplant. Clinical sepsis was observed in 50% of patients, with bacterial cultures testing positive in the same proportion. The most commonly isolated bacterial organisms included coagulase-negative staphylococci (CONS) (21.4%), Klebsiella species (21.4%), and Burkholderia species (17.9%). Antibiotic treatment predominantly involved meropenem (71.4%) and vancomycin (32.1%), with multidrug resistance observed in 25% of cases. Fungal prophylaxis was also administered, with voriconazole being the most frequently used agent (41.5%). [Table 3]

Table 3: Post-transplant Characteristics and Infections

Infective complications: 

The study found no significant association between bacterial infection and various parameters in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Specifically, sex (p = 0.273), age groups (p = 0.991), diagnosis (p = 0.087), stem cell source (p = 0.658), and type of match (p = 0.426) were not statistically linked to bacterial infection. Regarding clinical sepsis, it was observed in 50% of children, with an equal distribution between clinical and culture-positive cases. Antibiotic duration for bacterial infection varied, with most children (64.3%) receiving antibiotics for over 21 days, whereas for clinical sepsis, 42.9% of children received antibiotics for 15-21 days, and 39.3% for more than 21 days

Table No. 4. Association between various parameters and Bacterial infection (n=28)

Pearson Chi-square test applied. A p value of <0.05 was considered as statistically significant

The study found no statistically significant association between fungal infection and various parameters in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Specifically, sex (p = 0.374), age groups (p = 0.686), diagnosis (p = 0.975), stem cell source (p = 0.849), type of match (p = 0.262), and the type of antifungal prophylaxis (p = 0.490) were not significantly linked to fungal infection risk. These findings suggest that these factors do not play a significant role in the occurrence of fungal infections in the study population.

Table No. 5. Association between various parameters and Fungal infection (n=9)

Pearson Chi-square test applied. A p value of <0.05 was considered as statistically significant

The analysis indicates no statistically significant associations between protozoal infection and various parameters in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Specifically, sex (p = 0.421), age groups (p = 0.961), diagnosis type (p = 0.136), stem cell source (p = 0.137), and type of match (p = 0.125) do not show significant relationships with protozoal infection risk. These findings suggest that these factors are not significantly associated with the occurrence of protozoal infections in the study population.

Table 6: Association between various parameters and Protozoal infection (n=15)

Pearson Chi-square test applied. A p value of <0.05 was considered as statistically significant

Association of various parameters with CMV reactivation (n=15): The analysis shows no statistically significant associations between various parameters and CMV reactivation in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Specifically, sex (p = 0.421), age (p = 0.268), diagnosis type (p = 0.947), stem cell source (p = 0.470), type of match (p = 0.559), donor CMV status (p = 0.125), and post-transplant immunosuppression (p = 0.604) do not show significant relationships with CMV reactivation. These findings suggest that these factors are not significantly associated with the risk of CMV reactivation in this population.

Table 7. Association of various parameters with CMV reactivation (n=15)

Pearson Chi-square test applied. A p value of <0.05 was considered as statistically significant

Outcome parameters: Disease free survival was seen in 51 (78.4%) children, rejection in 5 (7.7%) children, and total deaths in 11 (16.9%) children.

Table 8. Distribution of children according to various outcome parameters)

There were 11 deaths in the study. Among them, 6 (54.5%) children died due to bacterial infection; 1 (9.1%) due to fungal infection. Whereas 4 (36.4%) deaths were caused due to non-infectious diseases.

Table 9. Distribution of children according to cause of death due to infectious diseases%

Hematopoietic Stem Cell Transplantation (HSCT) plays a crucial role in treating pediatric patients with severe hematological and immunological disorders. Particularly, allogeneic HSCT offers the potential to achieve disease remission and long-term disease control by replacing a patient's immune and hematopoietic systems with those from a compatible donor. Despite its life-changing potential, pediatric patients undergoing allogeneic HSCT face several challenges, particularly in the early posttransplantation period. These complications include infectious risks, graft-versus-host disease (GVHD), hematological abnormalities, and organ toxicities, which can significantly impact recovery and longterm outcomes. A thorough understanding of these complications' incidence, characteristics, and predictors is essential, especially in the context of a Tertiary Care Government Hospital.

This study focused on 65 pediatric patients who underwent allogeneic HSCT. The cohort consisted of 35.4% females and 64.6% males, showing a male predominance (male:female ratio of 1.82:1), consistent with other studies, such as Hierlmeier et al. (2018)[9], which reported 54.1% males and 45.9% females among 229 pediatric patients, and Zajac-Spychala et al. (2016), with 54.1% males in their study of 308 children. The age distribution in this cohort revealed that 38.5% were aged 0-6 years, 43.1% were between 6-12 years, and 18.5% were aged 12-18 years. The majority were in the 612 years group, with a median age of 8 years, aligning with studies by Hierlmeier et al. (2018)[9] and Zajac-Spychala et al. (2016), who both reported a median age of 7 years. A study by Lee et al. (2023)[10], which included 227 pediatric patients, showed a slightly higher male representation.

Thalassemia major was the most common condition treated with HSCT in this cohort, accounting for 67.7% of the cases, followed by aplastic anemia (18.5%), sickle cell anemia (6.2%), and rare conditions like Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), B-cell Acute Lymphoblastic Leukemia (ALL), and T-cell ALL, each accounting for 1.5%. This distribution contrasts with Hierlmeier et al. (2018)[9], where leukemia, lymphoma, solid tumors, and CNS tumors were common indications. Zidan et al. [11] reported 20% of patients with T-cell ALL, 15% with B-cell ALL, and 65% with AML. Rafiee et al.'s systematic review indicated that 33% had AML, 16% had ALL, and 12% had lymphoma.

Regarding donor characteristics, 52.3% of the donors were aged 10 years or younger, 35.4% were between 11-20 years old, and 12.3% were over 20 years old. The mean donor age was 12.71 ± 9.63 years, with the youngest being 2 years old and the oldest 50 years. Female donors made up 53.8%, and male donors 46.2%, with most being siblings (90.8%), followed by parents (9.2%). These findings are consistent with trends observed in other studies, confirming that sibling donors are the most common source, followed by parents.

In terms of matching, 89.2% of patients received identical donor matches, while 10.8% underwent haploidentical matching. This distribution contrasts with the study by Koh et al. (2010)[12], where a smaller proportion of patients (9) received mismatched related donor transplants, while 60 received matched donors, and 133 received transplants from unrelated donors. CMV IgG positivity was observed in 93.8% of both patients and donors, while 41.5% of patients tested positive for Varicella Zoster Virus (VZV), which is higher than in Zidan et al.'s study, where only 15.8% had elevated CMV antibody titers. This suggests a higher risk of CMV reactivation.

The study's stem cell sources included 83.1% bone marrow, 1.5% a combination of bone marrow and cord blood, and 15.4% peripheral blood stem cells (PBSC). The stem cell dose varied across patients:

6.2% received ≤2 million cells/kg, 32.3% received 2-5 million cells/kg, 29.2% received 5-10 million cells/kg, and 32.3% received more than 10 million cells/kg.

Post-transplant immunosuppression regimens were diverse, with 55.4% of patients receiving cyclosporine (CSA) alone, 6.2% receiving CSA plus mycophenolate mofetil (MMF), 35.4% receiving CSA plus methotrexate (MTX), and 1.5% receiving CSA, MTX, and MMF. CSA alone and the combination of CSA+MTX were the most commonly used regimens. Granulocyte colony-stimulating factor (G-CSF) was administered to 78.5% of patients to stimulate stem cell mobilization.

Fungal prophylaxis treatments included voriconazole (41.5%), fluconazole (32.3%), posaconazole (10.8%), micafungin (7.7%), amphotericin-B (6.2%), and caspofungin (1.5%), with voriconazole, fluconazole, and posaconazole being the most frequently prescribed antifungal medications. Zidan et al. [11] also highlighted the importance of prophylactic antimicrobials, including both antibacterial and antifungal treatments, in preventing infections in HSCT recipients.

Regarding infectious complications, our study found no significant association between sex, age, diagnosis, stem cell source, or type of match and the occurrence of bacterial infections. This finding is in line with Zajac-Spychala et al. (2016)[13], who reported 237 bacterial infection episodes among pediatric HSCT recipients, showing a lower incidence of invasive bacterial infections in matched donor recipients compared to mismatched unrelated donors. Similarly, no significant relation was found between sex, age, diagnosis, stem cell source, fungal prophylaxis, and fungal infections, which mirrors the study by Koldehoff and Zakrzewski et al. [14], where invasive fungal infections occurred in 1026% of HSCT recipients.

For protozoal infections, no significant associations were found, consistent with the lack of identified predictors in previous studies. Regarding CMV reactivation, no significant relationships were observed between the infection and sex, age, diagnosis, stem cell source, type of match, donor CMV status, or post-transplant immunosuppression. This contrasts with studies suggesting that CMV reactivation is a significant post-transplant concern.

Outcomes in the study revealed that 78.4% (n=51) of patients were discharged disease-free, 7.7% (n=5) experienced graft failure, and 18.5% (n=12) succumbed to post-transplant complications. These findings align with Zaidman et al. (2022), which reported an overall survival rate of 44%, with neurological complications contributing to one-third of mortalities. Olson et al. (2023) reported higher survival rates of 89%, highlighting variability across different centers. In our study, infections were the primary cause of death within the first 100 days, with bacterial infections contributing 54.5% and fungal infections 9.1%. Other causes of death included bleeding, veno-occlusive disease (VOD), bone marrow aplasia, and graft rejection, each contributing 9.1%. Zaidman et al. (2022)[15] identified older age, the use of alemtuzumab, and neurological sequelae as risk factors for mortality, while Olson et al. (2023)emphasized GVHD, infections, and infection control as crucial factors influencing survival. Kang et al. (2015)[16] similarly identified neurological sequelae and chronic GVHD as significant mortality risk factors.

In conclusion, this study aimed to examine the infectious complications following allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients, focusing on bacterial, fungal, protozoal infections, and CMV reactivation. The results indicate that various parameters, including sex, age, diagnosis, stem cell source, type of match, and post-transplant immunosuppression, did not show statistically significant associations with the occurrence of these infections. Despite the lack of significant relationships between these factors and infection outcomes, it is crucial to continue monitoring and managing infections closely in pediatric HSCT recipients, as they remain at high risk for infectious complications. Further studies with larger sample sizes may help identify potential risk factors or trends that could guide preventive and therapeutic strategies for improving patient outcomes in this vulnerable population.

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