key: cord-0060617-5f7qy6z5
authors: Mirgh, Sumeet; Khattry, Navin
title: Acute Complications in Stem Cell Transplantation
date: 2021-01-29
journal: Contemporary Bone Marrow Transplantation
DOI: 10.1007/978-3-030-36358-1_6
sha: c447198b24e5ea189994d260b29cd166835cb027
doc_id: 60617
cord_uid: 5f7qy6z5

Hematopoietic stem cell transplantation (HSCT) remains an effective method for treating a multitude of malignant or nonmalignant disorders. While in autologous HSCT, patients receive their own stem cells after myeloablation, allogeneic HSCT implies using stem cells derived from a donor. It is often a last curative option, however, associated with a considerable risk of early and long-term complications. Acute complications determine the future course of illness, have a bearing on chronic complications, and overall quality of life. Similar to acute graft-versus-host disease, complications till day+100 posttransplant are included under acute complications. These include endothelial pathologies like engraftment syndrome (ES), transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease of liver (VOD), capillary leak syndrome, and others which include noninfectious pulmonary complications, posterior reversible encephalopathy syndrome (PRES), infections (bacterial/fungal/viral), acute graft-versus-host disease (aGVHD), mucositis, and graft failure. It is important to recognize these complications at the earliest, for implementing suitable interventions, salvaging the graft and to prevent any disease relapse.

complications till day+100 posttransplant are included under acute complications. These include endothelial pathologies like engraftment syndrome (ES), transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease of liver (VOD), capillary leak syndrome, and others which include noninfectious pulmonary complications, posterior reversible encephalopathy syndrome (PRES), infections (bacterial/fungal/viral), acute graftversus-host disease (aGVHD), mucositis, and graft failure. It is important to recognize these complications at the earliest, for implementing suitable interventions, salvaging the graft and to prevent any disease relapse.

Hematopoietic stem cell transplant · Engraftment syndrome · Steroids · Capillary leak · Thrombotic microangiopathy · Sinusoidal obstruction syndrome · Venoocclusive disease · Idiopathic pulmonary syndrome · Diffuse alveolar hemorrhage · Posterior reversible encephalopathy syndrome · Mucositis · Graft failure · Chimerism · G-CSF 

Hematopoietic stem cell transplant, first pioneered in the 1970s, is now an established therapy. In India, the first bone marrow transplant was done in a 9-year-old girl for acute myeloid leukemia (AML) in 1983 at Tata Memorial Hospital, Mumbai. The recipient survived for 22 years without any GVHD or relapse. Since then, it has expanded to nearly 100 transplant centers across the country (Saikia 2020) . Most common indications for allogeneic transplants include leukemias, hemoglobinopathies, and bone marrow failure, whereas myeloma and relapsed/refractory lymphoma constitute the main indications of autologous transplants (Kulkarni and George 2019) . Transplant physicians should be well versed with both acute and chronic complications posttransplant. In this chapter, acute complications seen after HSCT will be discussed, with the exclusion of infections and graft-versus-host disease.

For simplicity of understanding, acute complications posttransplant have been divided into endothelial, infective, acute GVHD, and others (Table 1) .

A group of complications sharing many common characteristics occur after transplant:

• Early after HSCT (between day 0 and day +100).

• Diagnosis is usually based on the presence of overlapping clinical manifestations ("Syndromes"). • Pathophysiologically, they begin at the capillary level in a systemic way or in one or more affected organs. • If not properly treated, they can evolve into an irreversible multiorgan dysfunction/failure (MODS/MOF). Adapted from Carreras et al. (2019) There is a complex interplay between the "pro-inflammatory" and "pro-thrombotic" state secondary to endothelial damage. Hence, all are clubbed together in one group. "Idiopathic pneumonia syndrome" was formerly included in this group. There is increasing evidence that GVHD is also consequent to endothelial dysfunction. Hence, GVHD might be incorporated in this group in the near future (Carreras et al. 2019) . Table 1 summarizes the endothelial complications. The organ-specific complications, however, begin in a single organ, but affect systemically.

Engraftment syndrome is defined as the development of a noninfectious fever in combination with diarrhea, rash, or pulmonary infiltrates within 24 h of engraftment (Cornell et al. 2015) . This syndrome has various synonyms: CLS of the engraftment, autoaggression syndrome, respiratory distress of the engraftment, aseptic-septic shock, and some label it as "autologous GVHD" (Carreras et al. 2019 ).

Pathophysiologically, ES is a result of a systemic endothelial damage, both due to the conditioning regimen (Spitzer 2015) and due to massive release of pro-inflammatory cytokines (due to recruitment of activated leukocytes concomitant with granulocyte recovery) (mainly IL-2, TNF-α, IFN-γ, IL-6), products of degranulation and oxidative metabolism of neutrophils (Carreras et al. 2019) . These subsequently cause vascular leak, organ dysfunction, and constitutional symptoms such as fever. Unfortunately, this pathogenesis overlaps with that of acute GVHD and there is no pattern of cytokines specific for ES (Spitzer 2015) . The contribution of concomitant administration of G-CSF, a potent endothelial toxicant, to the development of ES is speculative (Carreras et al. 2019 ).

ES is classically observed after autologous HSCT. However, it has also been described after NMA (nonmyeloablative) Allo-SCT and CBT (cord blood transplant). The incidence ranges between 5% and 50%, depending on the study population and criteria for diagnosis (Carreras et al. 2019) . Risk factors for development of ES include:

• Diseases: Breast cancer, lymphomas other than Hodgkin lymphoma, POEMS, multiple sclerosis (Spitzer 2015 ). • Female gender (possible) (Cornell et al. 2015; Gorak et al. 2005; Sheth et al. 2018 ). • Growth factors (GM-CSF > GCSF) (possible) (Cornell et al. 2015) . • Phenotype of CD34+ donor cells ( expression of GATA-2, CD130, CXCR4).

• Chemotherapy (Cornell et al. 2015) .

MM (Multiple Myeloma): Previous exposure to Bortezomib/Lenalidomide. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, skin changes): Prior cyclophosphamide exposure associated with reduced risk of ES.

In general, less aggressive chemotherapy associated with increased risk of ES • Intensity of the conditioning (NMA < MEL < BEAM < CY/TBI) (Carreras et al. 2019) .

Although the incidence of ES is similar irrespective of age (both children and adults), there may be considerably more NRM in children compared with adults (Spitzer 2015) . ES in Allo-SCT has been variably reported between 10% and 22% in adults, and 17-48% in children. Gorak et al. reported older recipient age, female gender, and treatment with amphotericin-B, as factors associated with development of ES. In contrast to Auto-HSCT, NRM was significantly higher among Allo-SCT patients with ES (Gorak et al. 2005) . As per one study in 217 adult Allo-SCT recipients, there was a strong association in the development of acute GVHD before day 28, in patients who developed ES (Omer et al. 2014 ). However, due to lack of standard definitions of ES, there is no clear data to prove that ES impacts the DFS or OS (Spitzer 2015) .

The first description of ES was in 1995 by Lee et al., when they retrospectively analyzed 248 patients of Auto-SCT and observed the development of noninfectious fever and rash, at a median of 7 days post stem cell infusion (Lee et al. 1995) . The clinical manifestations typically include fever, i.e., high grade, but importantly well tolerated, without any clinical/microbiological documentation or improvement with antimicrobial therapy. This fever accompanies rash (maculopapular rash mimicking GVHD) and signs of vascular leak (hypotension, Noncardiogenic pulmonary edema, pleural effusions, ascites, weight gain, edema), with/without any organ dysfunction (CNS, liver, pulmonary, renal) (Carreras et al. 2019; Cornell et al. 2015; Spitzer 2015) . Hence, the diagnosis of ES relies on clinical criteria as outlined in Table 2. A syndrome mimicking ES, termed preengraftment syndrome (PES), has been described after umbilical cord blood transplantation and RIC transplants. It occurs at a median of 7 days, but can precede as early as 3 days, following a transplant and 4-15 days before marrow recovery. A role for granulocytes is unclear, as it usually precedes their recovery >1 week. Similar to ES, PES is also steroid responsive, which may explain an underlying immune mechanism (Spitzer 2015) . Another entity is the peri-engraftment respiratory distress syndrome (PERDS). This is defined as fever >38.3°C + evidence of pulmonary injury in the form of hypoxia and/or pulmonary infiltrates on chest radiographs (CXRs) in the absence of clinical cardiac dysfunction that has to occur within 5 days of neutrophil engraftment (Capizzi et al. 2001) .

There have been no head-to-head comparisons of both criteria. However, as per literature (including an Indian study), there is evidence that Maiolino criteria are more sensitive, than Spitzer (Sheth et al. 2018; Carreras et al. 2010) . In fact, Sheth et al. proposed a modified Maiolino criteria (Maiolino criteria with time laxity) for diagnosis of all patients with possible ES (Sheth et al. 2018) . Similarly, Dispenzieri et al. observed more than 50% incidence in POEMS patients undergoing Auto-SCT, and proposed maintaining the Spitzer and Maiolino criteria but uncoupling the timing between the neutrophil recovery and clinical manifestations. Although there is no significant difference in the patterns of ES among various disorders, there is an unusually high frequency of ES in POEMS patients. This might be due to Table 2 Spitzer and Maiolino criteria for diagnosis of engraftment syndrome (Carreras et al. 2019; Spitzer 2015) Around the day when engraftment starts (i.e., first day of ANC > 500/uL) Spitzer criteria (2001 All three major criteria or two major criteria and one or more minor criterion, within 96 h of engraftment Comments More complex but specific Less specific, but simple an aberrant cytokine milieu in them (VEGF, TNF-α), possibly exaggerated by ASCT (Dispenzieri et al. 2008) . The skin rash associated with ES has been reported more frequently reported in patients with breast cancer undergoing ASCT, compared to those with lymphoma. On the other hand, ASCT use for autoimmune disorders, since corticosteroids are regularly used as a maintenance therapy in these patients, may prophylactically reduce the risk of ES (Spitzer 2015) . There are other events, similar to ES, which must be differentiated from it (refer Table 3 ).

Considering the inadequacy of the clinical criteria and possible progression to MODS (in absence of timely intervention), it would be ideal to identify biomarkers which would help us to take a decision preemptively. However, data regarding the same is scarce. A recent study identified PCT (procalcitonin) <2 ng/ml as an adjunctive biomarker for identification of patients suffering from noninfectious fever associated ES post-ASCT (Knoll et al. 2019) . Similarly, Elafin has been identified as an IHC stain and a new biomarker for pre-engraftment syndrome (Chacon et al. 2013 ). However, the former is an expensive test in a resource-limited setting, while the latter is not easily available. An Indian study showed WBC/ CRP ratio >0.056, as an important inexpensive bedside tool with high specificity to identify engraftment fever from an infectious etiology (Punatar et al. 2015) .

Finally, one may believe that ES may trigger a graft-versus-tumor effect in ASCT, and consequently, lead to increased survival. However, a review of nearly 600 patients failed to show any effect of ES on relapse and survival (Cornell et al. 2013) . Further studies on the pathogenesis and biomarkers which will help differentiate the ever-lasting dilemma of the relation between ES and acute GVHD are required (Fig. 1 ).

Idiopathic systemic capillary syndrome (also known as Clarkson disease) was initially described in healthy people who manifested with episodic crisis of hypotension, hypoalbuminemia, and severe anasarca (Carreras et al. 2019) . It has been defined as weight gain>3% in 24 h and positive intake balance despite furosemide administration (Nurnberger et al. 1997 ). Subsequently, it has been described after administration of cytokines (IL-2, IL-4, TNF, G-CSF) and post-HSCT. Pathophysiologically, the inclusion of CLS in this group points to an underlying endothelial damage as the cause. This might be secondary to high levels of VEGF and angiopoietin-2 in such patients (Carreras et al. 2019 ).

The incidence varies between 5.4% and 21% (Lucchini et al. 2016; Nurnberger et al. 1997) and it is predominantly observed in children (Carreras et al. 2019) . venules and capillaries, versus acute GVHD which shows interface dermatitis (vacuolization of the basal layer of the epidermis and a lymphocytic infiltrate in the superficial dermis) and epidermal apoptotic keratinocytes (Nishio et al. 2009 ). # Brain natriuretic peptide significant and dramatic response to Bevacizumab, thereby pointing the role of an underlying pathogenesis secondary to VEGF (Yabe et al. 2010) . Importantly, CLS patients have significant high risk of developing acute GVHD at day +30. The prognosis of patients with CLS remains dismal. As per Lucchini et al. two-third patients needed admission to ICU and nearly half required invasive mechanical ventilation. The TRM in patients with CLS is eightfold than those without CLS (43% versus 5%) (Lucchini et al. 2016) . We need future studies that will delineate the biological relation between sepsis, GvHD, and CLS development in terms of cytokine release and endothelial damage.

Microangiopathy (TA-TMA) Introduction TMAs (thrombotic microangiopathies) comprise a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia and thrombocytopenia due to platelet clumping in the microcirculation leading to ischemic organ dysfunction. In order to standardize this phenomenon, a consensus has been recently proposed by an International Working Group (as below): 

The incidence is highly variable and ranges between 0.5% and 76%. This is due to the variability of manifestations and absence of a single, uniformly accepted diagnostic criteria. Moreover, the presence of other causes of anemia, thrombocytopenia, and renal dysfunction in post-HSCT setting further confounds the picture (Jodele et al. 2015; Elemary et al. 2019 ).

The gold standard for diagnosis of microangiopathy would be an organ biopsy. However, it is not always feasible in a post-transplant immunosuppressed patient with severe thrombocytopenia. Moreover, presence of clinical and lab markers which would serve as a surrogate for evidence of microangiopathy, question the necessity of an invasive procedure. The criteria used for diagnosis are summarized in Table 4 . Importantly, coagulation parameters (PT, aPTT) in all these criteria are normal, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity is <10% (Carreras et al. 2019) (Refer Fig. 2 ). The criteria above explore the clinical and lab markers for diagnosis of TA-TMA. The BMT-CTN criteria (2005) pay more attention on the pathogenesis of microangiopathy (schistocytes, elevated LDH, ruling out immune hemolysis by a negative Coombs' test) and systemic involvement (renal/CNS) other than hematological system, whereas IWG criteria include the focus mainly on hematological parameters with inclusion of cytopenias. The overall TMA criteria (2010) were more broad as they included both cytopenias (of IWG criteria) and microangiopathy markers (both IWG and BMT-CTN), albeit, without renal/ CNS involvement (Carreras et al. 2019; Jodele et al. 2015; Elemary et al. 2019 ). Jodele et al., as per their experience, showed three important aspects of TA-TMA. Firstly, creatinine alone is a very poor marker for AKI in TMA. Hence, the inclusion of proteinuria and hypertension (disproportionate to that expected from use of steroids and CNIs) as early markers of kidney injury. Moreover, CNS symptoms develop much later, as a part of severe multivisceral TMA. Lastly, they pointed out that schistocytes are evident later in the course of the disease. The description of cases with histopathological evidence of TMA, without any schistocytes on smear, refutes the norm that they are sine-qua-non in TMA (Wirtschafter et al. 2018; Murphree et al. 2019 ). It has been hypothesized that this might be due to increased vascular permeability and extravasation of RBCs into tissues. Hence, an acute elevation of LDH, with proteinuria and severe hypertension, were preemptive of impending TA-TMA (occurring nearly 10-14 days before diagnosis of TMA). They also included markers of complement activation, thereby giving weightage on the "second-hit" component of TA-TMA. Importantly, it has been shown that patients with proteinuria (>30 mg/dl) and markers of complement activation (elevated C5b-9 levels) have a dismal prognosis, with an 84% NRM (nonrelapse mortality) at 1 year (Jodele et al. 2015 ). This will not only help us in prognostication but also enable us to switch gears to an aggressive management, when either of these markers is deranged.

Stop CNIs (cyclosporine)/sirolimus. Treat concomitant infections, GVHD (which might be further triggers for TA-TMA), and renal replacement therapy for renal dysfunction. Watch for flare of GVHD after discontinuation of CNIs. Substitute it with MMF and/or steroids. 2. Specific therapy.

a. TPE (therapeutic plasma exchange) Although initial descriptions of TPE suggested a limited benefit in hardly one-third cases with 80% mortality, recent data have suggested 59-64% CR rates. TPE was more beneficial in patients who initiated it early after diagnosis (within first 2 weeks), and those with factor H autoantibodies. Importantly, TPE use in TA-TMA is for at least 2-3 weeks, after which it can be tapered off (unlike TTP/aHUS where it is tapered off after 5 days), if there is clinical improvement. This is important as premature discontinuation can result in a flare (Carreras et al. 2019; Elemary et al. 2019 ). Even after initial improvement, TPE has to be tapered slowly over 3-4 weeks (Khosla et al. 2018 ). Defibrotide is a polydeoxyribonucleotide salt has been used in VOD posttransplant with variable CR rates between 30% and 60%. It is an endothelial protector that blocks action of plasminogen-activator inhibitor-1 and attenuates the effects of TNF. It has antithrombotic, anti-inflammatory, thrombolytic, and fibrinolytic properties (Carreras et al. 2019; Khosla et al. 2018) . The response rate with defibrotide has been 55%, either as monotherapy or in combination. The dosing in TA-TMA is extrapolated from that of VOD, i.e., 6.25 mg/kg every 6 h (Jodele et al. 2015) . However, Defibrotide is not available in India. It has to be imported and its prohibitive cost limits its usage. Interestingly, it has been used at low doses <10 mg/kg/day as monotherapy, i.e., one-third of the approved dose and still effective (Devadas et al. 2017) . This efficacy at a reduced dosage with the safety and ease of administration of Defibrotide makes it a productive option for transplant physicians. d. Eculizumab

As per the understanding of complement activation in the pathogenesis of TA-TMA, terminal complement inhibitors such as Eculizumab, a C5 inhibitor, have come up as a promising new therapy in these patients. Responses have been documented in 67-92% patients. Dosing is similar to that of PNH, i.e., 900 mg every 2 weeks, with dose modulation as per monitoring of CH50 levels. Importantly, antimeningococcal prophylaxis should be used from the initiation of therapy until 8 weeks after completion of therapy or till CH50 becomes normal. Compared with aHUS, eculizumab for TA-TMA typically requires a longer induction time with at least 4-6 weeks of therapy. However, it can be discontinued after TA-TMA resolution without disease relapse, and lifelong treatment is not required. It is recommended to use eculizumab as monotherapyas concurrent use of TPE would remove eculizumab from the blood as well as replenish C5 available for activation. Intriguingly, concurrent use of eculizumab and rituximab may affect rituximab activity as the latter medication depends in part on complement activity. Other newer drugs available for the same with limited literature include interleukin-2 receptor (CD25) antibodies (basiliximab, daclizumab), NO donors (eicosapentaenoic acid, statins, transdermal isosorbide tape), TNF-α inhibitors (Infliximab), prostacyclin analogs, and bosentan (Khosla et al. 2018 ).

Jodele et al. recently reported that protein-uria⩾30 mg/dL and elevated serum C5b-C9 levels (evidence of terminal complement activation) are associated with worse prognosis, with a survival rate of <20%. These patients deserve early intervention with eculizumab (Khosla et al. 2018) . Some authors believe that there are two forms of TA-TMA. One, associated with CNI (calcineurin inhibitor) and the other, unrelated to it. Whereas the former has a good prognosis, the latter has a bad prognosis and needs specific treatment (Carreras et al. 2019) . In their excellent review, Khosla et al. have proposed that TMA index (LDH/platelets ratio) ⩾20, schistocyte count >5-10/hpf, elevated serum creatinine, adult >18 years, and unrelated/ haplo donors have a bad prognosis (Khosla et al. 2018 ). An Indian study recently showed that 5-year OS in patients with TA-TMA was nearly half of that for patients without TA-TMA (29% vs. 51%) (Kalantri et al. 2019 ).

Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease of the liver (VOD), is the term used to designate the symptoms and signs that appear early after HSCT because of conditioning regimen-related hepatic toxicity. It is characterized by jaundice, fluid retention, and tender hepatomegaly appearing in the early (first 35-40 days) after HSCT (Carreras et al. 2019) . It is a multisystem disease with an overall mortality >80%. Historically, it was initially published in veterinary literature, back in the 1920s. Subsequently, in the 1950s, it was diagnosed in humans, after bush-tea ingestion (due to pyrrolizidine alkaloids) and secondary to chemotherapy. The first evidence in the field of HSCT came in 1982 from a series of 29 patients treated with high dose mitomycin-C and autologous bone marrow transplant (Cairo et al. 2020 ).

Incidence as per two prospective studies, for autologous HSCT varies between 3% and 6%, and for allogeneic HSCT varies between 9% and 14% (Carreras et al. 2019) (Fig. 3 and Table 5 ).

Development of diagnostic criteria is important to enable clinicians to identify this disease entity, make the correct diagnosis promptly, and intervene appropriately. Two of these criteria have been in long use since more than two decades (Table 6) (1993) Baltimore criteria (1987) Development of two or more of the following events within 20 days of HCT (and without an obvious, alternative medical explanation):

Serum bilirubin >2 mg/l within 21 days of HCT, Plus at least two of the following:

Serum total bilirubin concentration > 2 mg/l (>34·2 micromoles/l)

Hepatomegaly or right upper quadrant pain Ascites Sudden weight gain due to fluid accumulation (>2% of baseline body weight) Weight gain >5% from pre-HCT weight (without an alternative medical explanation) (iii) Recent clinical descriptions that are different from those described 25 years ago. (iv) Development of newer imaging capabilities which may be more sensitive to specific indicators of SOS/VOD.

The European Society for Blood and Marrow Transplantation (EBMT) has proposed a revised differential diagnostic criteria (below) for both children and adults, which incorporates both clinical and radiological criteria for early diagnosis of this entity. However, it should be borne in mind that anicteric VOD and refractory thrombocytopenia are typical of pediatric VOD (Cairo et al. 2020 ).

Any two of the following criteria following HCT:

• Elevated bilirubin (!2 mg/l) (!34.2 μmoles/l) or greater than upper institutional limits †. 

• Any one of the following criteria following HCT.

• Hepatic biopsy consistent with SOS/VOD.

• Unexplained elevated portal venous wedge pressure (Cairo et al. 2020 ).

After diagnosis of VOD, it is imperative to grade the severity in order to prognosticate the patient in terms of outcomes. The original SOS/VOD grading classification was developed by McDonald et al. in 1993 (Cairo et al. 2020 ).

• No adverse effects of liver disease.

• No treatment of fluid retention.

• No analgesic treatment of enlarged liver.

• Complete reversal of signs, symptoms, and abnormal laboratory values secondary to VOD.

MODERATE (one or more)

• Adverse effects of liver disease secondary to VOD. • Treatment of fluid retention (Diuretic, fluid restriction, and/or Na + restriction). • Complete resolution of signs, symptoms, and abnormal laboratory values secondary to VOD.

• Adverse effects of liver disease secondary to VOD. • Signs, symptoms, and abnormal laboratory values secondary to VOD that did not all normalize by Day +100 posttransplant. • Death due to VOD.

Recently, EBMT proposed a system (Table 7) for early prognostication, which included kinetics of symptom development/bilirubin, renal function, in addition to liver functions (bilirubin, transaminases), and weight gain. However, this is for VOD in adults.

The pediatric criteria utilized the same adult criteria (as above), with the addition of ascites, coagulation abnormalities (refractory thrombocytopenia and unresponsiveness of INR [International Normalized ratio] to correct to vitamin K), pulmonary dysfunction, and central nervous system injury (Carreras et al. 2019; Cairo et al. 2020 ). However, the above criteria focus primarily on liver and do not include other organ involvement. Moreover, the widely used McDonald criteria are more than two decades old, and the recent ones have not been validated in clinical studies. As a consequence, Cairo et al. recently proposed the use of NCI CTCAEv5.0 (National Cancer Institute Common Terminology Criteria for Adverse Events) grading system for VOD. CTCAEv5.0 system uses hepatic, fluid retention, renal, pulmonary, cardiac, and CNS manifestations in their grading (Cairo et al. 2020 ).

A. Prevention/Prophylaxis 1. Avoid modifiable risk factors • Avoid the use of hepatotoxins during conditioning (e.g., azoles, acetaminophen).

• Identify drug-drug interactions in preparative regimens and modify as appropriate.

• Risk-adjust preparative regimen intensity according to hematopoietic cell transplantation-comorbidity index (HCT-CI). UDCA is a hydrophobic bile acid, i.e., nontoxic to hepatocytes (unlike hydrophilic bile acids). It protects the liver by modulating release of cytokines and its immunomodulatory effects. It is recommended by EBMT and BSBMT (Carreras et al. 2019; Cairo et al. 2020) . Hence, it is recommended at the start of conditioning until day 90 after transplant (Mohty et al. 2020 ).

Recommended for use in high-risk pediatric transplants, at a dose of 25 mg/kg/day. In one RCT, when used at the above dose from first day of conditioning till day +30 post-HCT, the incidence of VOD was 12% versus 20% in those who did not receive defibrotide prophylaxis (Carreras et al. 2019; Cairo et al. 2020 ). 

Supportive care remains an important cornerstone of therapy. The most important aspect is to minimize extracellular fluid overload without compromising intravascular volume and renal perfusion, while maintaining weight < 5% of baseline. Hence, a hawk-eye approach to fluid intake, salt load, urine output, and daily weights remains the mainstay of supportive care. Some patients develop ascites with or without pleural effusion, or pulmonary infiltrates in the absence of ascites and become hypoxemic. Patients may require serial small volume paracentesis (to maintain renal perfusion and adequate lung volumes in children) for ascites, which is associated with discomfort or pulmonary compromise. Hemodialysis or hemofiltration may be required for patients who experience renal failure or need more invasive methods to control fluid balance during the evolution of SOS/VOD (Carreras et al. 2019; Cairo et al. 2020) . In order to avoid any hepatotoxic drugs, azoles should be replaced by echinocandins, if feasible (Mohty et al. 2020 ).

Defibrotide is approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adults and children with SOS/VOD following HCT with renal or pulmonary dysfunction and "severe" SOS/VOD. On comparison with best supportive care, Defibrotide leads to a statistically significant improvement in day+100 survival (38% vs. 25%). It is used at a dose of 6.25 mg/kg every 6 hourly, and duration as per response (Cairo et al. 2020) . No dose adjustments are needed in renal failure, while corrected body weight is needed in obese patients. Duration of Defibrotide therapy is for 14-21 days, until the resolution of all clinical features of VOD.

However, it can be stopped earlier if there is a complete response. Importantly, although it is approved for severe VOD, there are recommendations for an earlier preemptive use of Defibrotide in moderate SOS/VOD. The most important adverse event associated with Defibrotide is bleeding, followed by a small risk of anaphylaxis. Some experts recommend to keep a higher platelet cut-off of 30,000 for patients on Defibrotide. Similarly, if planning any intervention, it should be withheld at least 2 h before and after the procedure (Mohty et al. 2020 ).

It is recommended by some authors. However, its role is debatable, and no there is no defined dose (Carreras et al. 2019) . Considering the increased infectious risk associated with methylprednisolone, recommendations are against its primary use in SOS (Mohty et al. 2020 ).

A small retrospective study analyzed the benefit of t-PA + heparin combination, in 42 HSCT patients. Responses occurred in 29% patients, however, at the cost of bleeding in 88% patients. Hence, it is no longer recommended due to the excessive risk of bleeding (Dalle and Giralt 2016) .

Lastly, orthotopic liver transplantation and transjugular, intrahepatic, portosystemic shunts have been successfully performed in small numbers of patients with SOS/VOD (Cairo et al. 2020 ).

Patients with mild to moderate VOD without any evidence of multiorgan dysfunction (associated renal or pulmonary dysfunction) have a favorable prognosis. However, prognosis for patients with severe disease (accompanied by multiorgan dysfunction) is guarded. Recently, the prognosis has improved due to better supportive care and new treatment options (Cairo et al. 2020) . With respect to grading, the OS and day 100 survival rate were significantly lower in patients with very severe SOS as compared to other three groups (58% vs. 89%). Similarly, day100 TRM (transplantrelated mortality) was significantly high (more than one-third) in the very severe SOS group (36.7%) versus others (2-8%) (Mohty et al. 2020 ).

We live in an era of biomarkers. Recently, markers have been identified for prognostic value, both at day 0 (L-Ficolin, HA, VCAM-1) and at diagnosis of VOD (ST2, ANG2, L-Ficolin, HA, VCAM-1) (Carreras et al. 2019) . Future studies will be needed to delineate the prognostic value of these markers. Similarly, novel imaging methods like Doppler ultrasound with shear wave elastography and contrastenhanced ultrasound may serve as innovative modalities for diagnosis of VOD (Dietrich et al. 2018).

Lung injury has been observed in 25-55% of patients post-HSCT, and this contributes to the morbidity and mortality in post-HSCT period. Due to more rampant and preemptive use of antibiotics, infectious complications have decreased, and the immune complications continue to predominate. These complications can be subdivided on the basis of their localization (Carreras et al. 2019 ). 

Fortunately, due to increased use of RIC, incidence of IPS has decreased from >20% two decades back to <10% (8% after MAC, 2% after RIC) (Carreras et al. 2019 ). Its incidence after autologous HSCT has been reported around 5.7% (Kantrow et al. 1997 ).

• Older age.

• Karnofsky index <90.

• Higher "diagnosis-HSCT" interval.

• MAC/conditioning incorporating BCNU or TBI (!12 Gy). • HLA disparity.

• GVHD prophylaxis with MTX.

• Acute GVHD.

• Previous viral infection. • Other malignancies than leukemia (Carreras et al. 2019 ).

• Prior HCT. 

The usual presentation occurs before 120 days, most commonly between day+18 and day+21. This is, in contrast, to the commonly noticed risk period of day+40 to +50, approximately two decades back (Vande Vusse and Madtes 2017). In contrast, IPS in autologous HCT usually presents around day+63 (range: 7-336 days) (Cheng and Madtes 2017) .

As expected from its name, clinical features include symptoms and signs of pneumonia: fever, dry cough, breathlessness, tachypnea, crackles/rales on chest auscultation. This is accompanied by multilobar infiltrates on chest CT, increased alveolar-arterial diffusion of oxygen, and restrictive abnormality on pulmonary function tests (Carreras et al. 2019 ).

Importantly, IPS remains an entity with poor prognosis with 60-80% mortality. If mechanical ventilation is required, >90% patients succumb to the illness (Carreras et al. 2019) . Hence, in the field of HSCT, IPS remains an important complication with dire need for biomarkers which can preempt early use of steroids and newer therapies.

Supportive therapy (Carreras et al. 2019) • Airway.

Mechanical ventilation (invasive or not [high-flow nasal O2, CPAP]) • Breathing.

Supplemental O 2 therapy • Circulation.

Strict control of fluids balance/hemofiltration • Others.

Empiric broad-spectrum antimicrobials (Fig. 5) . Definitive Therapy

Consistent with the pathogenesis, due to the marked inflammatory cytokine storm in the lungs, steroids are recommended. Methylprednisolone 2 mg/kg/day, administered early in the course of illness, should be considered as early as possible (Carreras et al. 2019) . Doses more than 2 mg/kg/day have been tried and not been shown to improve any response versus doses lesser than that (Fukuda et al. 2003 ).

Preclinical data has shown the significance of TNFα in pathobiology of IPS. Hence, Etanercept 0.4 mg/kg twice weekly (maximum of eight doses) was tried in combination with systemic steroids (2 mg/kg/day). Importantly, Yanik et al. published a randomized study of combination (etanercept + steroids) versus steroids + placebo. Although it was terminated prematurely due to slow accrual, there were no significant differences in response rates at day +28 (Yanik et al. 2014 ). On the other hand, the same group conducted a phase II trial in pediatric patients; more than two-third achieved a CR (71%) with a 1-year survival of 63% (Yanik et al. 2015) . This combination has also been shown to be effective in exceptional cases of late IPS with 42% CR rate, and a 2-year survival of 62% among the responders (Thompson et al. 2017) . 

Tocilizumab (anti IL-6) and Brodalumab (anti IL-17) are experimental agents which can be tried (Carreras et al. 2019 

Detailed immunological evaluations have shown CD4 + T h 17 cells playing an important role in IPS and GVHD (Mauermann et al. 2008) . Novel therapies targeting them, i.e., Halofuginone may represent an important paradigm (Sundrud et al. 2009 

DAH is higher in patients after TBI and highdose Cy (Carreras et al. 2019 ) recipients with inherited metabolic storage disease, especially mucopolysaccharidosis (Kharbanda et al. 2006) . Surprisingly, the frequency of DAH is similar among both MAC and RIC conditioning regimens, and it does not appear to have any co-relation with platelet counts (Carreras et al. 2019) .

It usually presents within the first month after SCT (median 23 days), particularly during the pre-engraftment phase. However, more than one-third cases (nearly 42%) present later in the course of posttransplant period. The clinical presentation is similar to IPS, with the exception of hemoptysis (in DAH) (Carreras et al. 2019 ). On imaging, these patients present with diffuse alveolar and interstitial infiltrates, primarily in central and basilar distribution (Vande Vusse and Madtes 2017). However, in order to differentiate it from IPS, Bronchoscopy with BAL becomes the most important modality. It is defined by the presence of (any of the following):

• Minimum 20% hemosiderin laden macrophages (may take 72 h to appear). • Minimum 30% alveoli showing blood.

• Progressive bloodier return of BAL fluid aliquots, in at least three segmental bronchi (as a surrogate for blood in alveoli).

However, it is very difficult to differentiate infectious from noninfectious DAH, in the absence of a pathogen. Hence, infectious workup as usual should be sent during a BAL (Carreras et al. 2019, Vande Vusse and .

Methylprednisolone remains the mainstay of therapy for DAH. There have been two studies at different doses, however, with contrasting results. Wanko et al. showed that high-dose steroids (>4 mg/kg/day of methyprednisolone or equivalent) decrease mortality with better efficacy, along with addition of amino-caproic acid (ACA) (Wanko et al. 2006 ). On the other hand, Rathi et al. demonstrated that addition of ACA did not make a difference, irrespective of dose of methylprednisolone (Rathi et al. 2015) . Hence, the best treatment is to use low-dose steroids (Methylprednisolone 250 mg/day) AE ACA (Carreras et al. 2019) . Similarly, addition of rVIIa has not been shown to alter time to resolution of alveolar hemorrhage, duration of mechanical ventilation, duration of oxygen supplementation, or hospital mortality. Unfortunately, it led to thrombotic events in 9% patients (Elinoff et al. 2014) . Along with steroids, maintaining adequate oxygenation with supplemental oxygen is necessary. Mechanical ventilation should be avoided, if possible, and noninvasive ventilation (CPAP, BiPAP) be administered (Carreras et al. 2019 ).

Unfortunately, the prognosis of DAH remains dismal. As per one study, mortality is as high as 85% by day+100. Importantly, mortality is higher in patients with multiorgan dysfunction (>60%) and in patients who develop DAH late post-allo-SCT (70%) (Carreras et al. 2019 ).

Syndrome). D. Delayed Pulmonary Toxicity Syndrome (DPTS). Delayed pulmonary toxicity syndrome is a specific pulmonary complication, exclusive to autologous HCT. It is characterized by the presence of interstitial pneumonitis and fibrosis, which may delay for months to years (Carreras et al. 2019 ). Incidence of DPTS varies between 29% and 64% in auto-SCT recipients who receive conditioning regimens containing cyclophosphamide, cisplatin, etoposide, and bischloroethylnitrosurea (BCNU). Median time to onset is 45 days (range: 21-149 days) (Wilczynski et al. 1998) . Symptoms are nonspecific and include exertional dyspnea, dry cough, and fever. Pulmonary function testing reveals a restrictive pattern with a marked reduction in the diffusion capacity (Soubani and Pandya 2010) . Imaging reveals bilateral interstitial infiltrates and ground-glass opacities (Wilczynski et al. 1998) . This syndrome has a favorable prognosis and response to steroids (1 mg/kg) has been noted in >90% cases. In responders, steroids are tapered over a period of 2 months (Soubani and Pandya 2010) .

This is an unusual pulmonary complication, with an unknown etiology. It is usually seen in children with GVHD, at a median time of 72 days post-HCT. Intriguingly, it presents with fever and peripheral pulmonary nodules on chest CT. Surgical lung biopsy shows necrotic, basophilic thromboembolism with entrapped monocytes. Interestingly, clinical presentations improve over 2 weeks, and radiographic findings clear over weeks (CengizSeval et al. 2018) . Since this is a rare and under-reported entity, there is no proven treatment. Woodard et al. showed the benefit with 1-2 mg/kg prednisolone till resolution of primary symptoms (typically 2 weeks), followed by a taper over 2-4 weeks, with a 3-year OS 71% (Woodard et al. 2000) .

PAP is characterized by the presence of PAS-positive lipoproteins in terminal bronchioles and alveoli, due to macrophage dysfunction. Similar to congenital and autoimmune PAP, with deficiency of GM-CSF either congenitally or due to antibody respectively, secondary PAP can occur post HCT, either due to macrophage depletion or anti-GM-CSF alloantibody. Diagnosis is clinched by the presence of milky/opaque BAL fluid yielding PAS-positive material and after excluding infectious pathologies. However, lung biopsy is needed for definitive diagnosis (Vande Vusse and Madtes 2017). PAP may be self-limited but can progress to fatal respiratory failure. Importantly, the prognosis of PAP remains poor, and value of inhaled GM-CSF in these patients is questionable (Soubani and Pandya 2010) (Tables 8 and 9 ).

This entity was first described in 1996, as a syndrome with typical neurological features and imaging findings, by Hinchey et al. (1996) . PRES (Posterior reversible encephalopathy syndrome) is a rare but serious complication postallogeneic SCT. Apart from allo-SCT, it has been reported in patients with severe hypertension, eclampsia, autoimmune disorders, renal failure, sepsis (Schmidt et al. 2016; Gaziev et al. 2017) , chemotherapy (Methotrexate, L-asparaginase, Adriamycin, Cyclophosphamide, Cytarabine, Vincristine), and immunosuppressants (Steroids, Cyclosporine, Tacrolimus, Rituximab, Interferon, Antithymocyte globulin (ATG), Fludarabine, Sirolimus) (Kapoor et al. 2018) . Pathophysiologically, it has been hypothesized to occur due to disturbance of cerebral autoregulation or secondary to cerebral vasoconstriction. In the former, sudden development of hypertension which overwhelms cerebral autoregulation results in loss of endothelial integrity and transudation of fluid, leading to vasogenic edema. On the other hand, there is cerebral vasoconstriction leading to perfusion deficit and ischemic changes in the latter (Schmidt et al. 2016; Gaziev et al. 2017 ). The incidence varies from 1.6% to 7.2% (Carreras et al. 2019) . Two retrospective Indian studies in pediatric patients have described its incidence to be 8.4% and 17%, respectively (Kapoor et al. 2018; Doval et al. 2019 ). In contrast to its name, it is not always reversible. If not recognized early, it can lead to permanent neurodeficits, as a result of status epilepticus, intracranial bleed, or ischemic infarcts (Schmidt et al. 2016) . Many factors predispose to development of PRES in any patient. Underlying disorders (hemoglobinopathies especially sickle cell > thalassemia) (Schmidt et al. 2016; Gaziev et al. 2017) , hematological malignancies (Allo-SCT for myeloma) (Bartynski et al. 2005) , conditioning (MAC, TBI-containing regimens), unrelated donor transplant (Schmidt et al. 2016) , presence of concomitant acute GVHD/ steroid therapy, and CNI as GVHD prophylaxis (Bhunia et al. 2019) . Typical clinical features include headache with a surge in blood pressure, visual disturbance, seizures, focal neurodeficit with possible renal dysfunction. Although vasogenic edema may be seen in CT in some patients, MRI is more sensitive. T2w-MRI sequences show bilateral multifocal areas of hyperintensity in white matter of parietooccipital regions. This MRI feature has to be differentiated from acute toxic encephalopathy, which has similar changes. Whereas subcortical white matter is involved in PRES, periventricular white matter is predominantly affected in acute toxic encephalopathy. (Carreras et al. 2019) . Hence, MRI with FLAIR sequence is the imaging modality of choice in all patients suspected of having PRES (Kapoor et al. 2018 ).

There is enough evidence to show that CNI-induced PRES need not always have supratherapeutic levels. Hence, irrespective of drug levels, CNI should be discontinued (Schmidt et al. 2016) . It has been shown that after discontinuation of CNI, neurological symptoms resolve within 3-8 days. However, the possibility of worsening/leading to de novo GVHD, after CNI discontinuation is an unsolved issue. Unfortunately, there are no guidelines for the same (Gaziev et al. 2017) . Majority of experts recommend shifting to MMF AE Steroids for GVHD prophylaxis. However, there is evidence to say that this is inadequate, and shifting to mTOR inhibitors (Everolimus, Sirolimus) as a CNI-free GVHD prophylaxis would be better (Schmidt et al. 2016; Schleuning et al. 2009 ). As per Schmidt et al., switching to Everolimus was well tolerated, without any seizures/hypertension, with survival similar to that of patients without PRES (Schmidt et al. 2016) . Substituting with an alternate CNI, or restarting same CNI after resolution of symptoms, has shown to lead to recurrence of seizures (Gaziev et al. 2017 ).

For BP control, in the first 2 hours, not >20-25% reduction should be attempted, as overzealous faster correction could hamper cerebral perfusion. IV Labetolol and IV sodium nitroprusside are two easily available parenteral medications. Other medications include Nicardipine and Fenoldopam. Labetolol has been found to be safe and effective (Kapoor et al. 2018) . Clinical resolution has been shown in 2-5 days of blood pressure control (Schmidt et al. 2016) . Resolution of MRI features take 2-4 weeks. 3. Antiepileptics.

Antiseizure medications have to be started as per institution policy. Although any of the followingfosphenytoin, phenobarbitone, levetiracetamcan be given, latter (levetiracetam) is preferred due to relative paucity of drug interactions (Schmidt et al. 2016; Kapoor et al. 2018) . Oral valproate has been proven to be ineffective in prevention of seizures (Gaziev et al. 2017) . 4. Complement inhibition.

Similar to its role in TA-TMA, Eculizumab has been shown to be useful in patients with PRES, refractory to conventional therapies (Bhunia et al. 2019 ). Gaziev et al. showed that patients with PRES had significantly lower survival, as compared to patients without PRES. This difference was highly detrimental to the cohort of patients with sickle-cell disease (Gaziev et al. 2017 ). On the other hand, studies have shown no difference in survival, irrespective of PRES (especially when Everolimus-based regimen was used as GVHD prophyalxis) (Schmidt et al. 2016) , including a recent publication on haplo-SCT patients (Chen et al. 2020) . It is important to recognize that permanent neurodeficits can occur in 12% patients of PRES, if not recognized early (Burnett et al. 2010 ).

Graft failure and poor graft function are related, but very important terms, in the field of transplant. As per definition, after SCT, Engraftment is coined when recipient achieves an absolute neutrophil count > 500 cells/liter [(ANC) > 0.5 Â 10 9 /L)], on the first day of three consecutive days. Similarly, platelet recovery is defined as a platelet count >20,000cells/liter [(PLT) > 20 Â 10 9 /L] on the first day of seven consecutive days without transfusion support. Primary graft failure is characterized by nonachievement of engraftment [peripheral blood ANC < 0.5 Â 10 9 /L by day + 28 after allo-HSCT, in the absence of relapse] and absence of initial donor cell chimerism (donor cells <95%). For umbilical cord blood transplant, the cut-off is relaxed to day+42 for the same definition. In contrast, secondary graft failure is characterized by loss of donor cells after initial engraftment and recurrent ANC < 0.5 Â 10 9 /L. On the other hand, poor graft function is defined as at least two severe cytopenias AE transfusion dependency in the presence of a hypoplastic/aplastic bone marrow, in absence of severe GVHD/relapse, with full donor chimerism. While incidence of graft failure ranges between 3.8% and 5.6%, poor graft function ranges from 5% to 27%. It is imperative to remember that graft failure rates vary as per transplant settings (Ozdemir and CivrizBozdağ 2018) (Fig. 6 ). Similar to graft failure, is another term called 'Graft Rejection', which is an immune mediated rejection of donor cells by the host. However, the prognosis of primary and secondary graft failure is dismal, with 5-year OS <20% (Carreras et al. 2019) (Tables 10 and 11 ).

Donor-specific antibodies are preformed/preexisting donor-specific anti-HLA antibodies in the recipient. They occur due to previous transfusions, or prior pregnancy, and increase the risk of graft failure two-tenfold, irrespective of the stem cell source and conditioning regimen. The specificity of these DSAs is important. Those against class I (HLA-A, and HLA-B) and class II (HLA-DRB1) are detrimental versus those antibodies against HLA-DPB1 and HLA-DQB1, which have an uncertain role (Brand et al. 2013) . The overall prevalence of DSAs in haploidentical HSCT is 10-20%. The frequency is higher in multiparous females and patients who have received may allogeneic blood products. In general, antibody-mediated graft failure is due to either ADCC (antibody-mediated cellular cytotoxicity) or CDC (complement-dependent cytotoxicity) (Ciurea et al. 2018) .

It is imperative for the transplant physician to detect these DSAs prior to transplant. The methods used for detecting these DSAs are either cell-based assays or solid-phase immunoassays. In cell-based cross-matched assays, donor WBCs are incubated with recipient serum. If patient's serum contains DSA, antibody will be its corresponding target antigen on donor lymphocytes, and give a positive result. Problems associated with this test include need for greater number of viable donor lymphocytes, detection of non-HLA antibodies (clinical relevance questionable), and its inability to find out specificity of antibodies. On the other hand, solid-phase immunoassays (SPI) utilize solid matrix-bound solubilized HLA molecules, against the patient's serum, to detect a reaction. This solid matrix can be either microtiter plate (enzyme-linked immunosorbent assay; ELISA) or polystyrene beads (multiplexed multianalyte bead arrays) performed on a conventional flow cytometer or a fluoroanalyzer (Luminex). The Luminex SAB (single antigen bead) array enables us to detect antibodies with HLA specificity. The latter are more sensitive, as they can detect even low-level anti-HLA antibodies in patient's serum. SPIs are now preferred for detection and monitoring of DSA in HSCT. In case the patient is found to be positive on SPI, further modified techniques like C4d or C1q are done to detect complement-fixing antibodies, which are associated with poor graft survival. A positive test for DSA is considered when MFI (mean fluorescence intensity) is >1000. Importantly, although rejection can occur at any level beyond 1000 MFI, >5000 MFI are associated with high levels of primary graft failure (Ciurea et al. 2018 ).

There is no specific standard of care for DSA positive recipients. The same concepts and drugs are used in various combinations. a. Antibody removal: by Plasmapheresis (most common desensitization method). It is done for 1-4 procedure days between days 10 and 17, and even posttransplant. b. Inhibition of antibody production: Rituximab 375 mg/m 2 or Bortezomib (proteasome inhibitor) prior to conditioning. c. Antibody neutralization: IVIg donor platelets or "buffy coat" (white blood cells) infusion. a. G-CSF: Bittencourt et al., in their retrospective study, showed that 95% patients responded to administration of G-CSF. Of these, nearly three-fourth responses were well-sustained even after G-CSF discontinuation. Importantly, they showed that patients whose WBC count increased to >0.1 Â 10 9 /L within 3 days of G-CSF support were more likely to have a sustained response (Bittencourt et al. 2005) . Boost -DLI could be recommended if decreasing levels of donor chimerism are observed. On the other hand, CD34 boost without prior conditioning can be given for patients with poor graft function, i.e., persistent for 2 months after its onset (Carreras et al. 2019 ).

The outcome of a patient with graft failure is dismal. Hence, second transplant remains the only option at times, in conditions of despair. Regarding donor choice, unless there is significant delay, different donor should be chosen. Haploidentical donors can be considered. Conditioning before second transplant is required. Ferra et al. showed in their study that Fludarabine/ATG (antithymocyte globulin) and Cyclophosphamide/ATG conditioning regimens with a high CD34 dose could achieve engraftment with low toxicity. Peripheral blood is the preferred graft, with posttransplant immunosuppression with calcineurin inhibitor-based regimens. Ex-vivo T-cell depletion should be avoided, especially if there was previous immune graft rejection (Carreras et al. 2019 ).

Mucositis refers to mucosal damage secondary to chemotherapy. It can occur in the oral cavity; pharyngeal, laryngeal, esophageal regions; and other areas of the gastrointestinal tract. Mucositis occurs in approximately 20-40% of patients receiving conventional chemotherapy, but its frequency is up to 80% in patients receiving highdose chemotherapy as conditioning for HSCT (Lalla et al. 2014 ). All patients undergoing myeloablative conditioning, methotrexate based GVHD prophylaxis, prior radiotherapy of headneck region, are at high risk of development of mucositis. Symptoms of mouth and throat pain typically begin within 7-10 days, after the start of conditioning regimen. This may persist for 2-3 weeks. Importantly, mucositis typically affects nonkeratinized portions of buccal and labial mucosa, latero-ventral surface of tongue, and soft palate. Lesions begin as erythema followed by welldefined smooth membranes. When ulcerations affect keratinized surfaces (gingiva, tongue dorsum, hard palate), it is most likely due to HSV reactivation (Treister 2013) . The pathobiology of mucositis includes direct damage from chemotherapy/radiotherapy, reactive oxygen species, proinflammatory cytokines, and metabolic byproducts of colonizing microorganisms. Mucositis leads to a significant financial impact, including possibility of secondary infection, nutrition support, analgesia, and hospital stay (Lalla et al. 2014) .

Patients should be evaluated daily for oral pain, and examined for mucosal changes. There are multiple severity assessment scales (Table 12) to guide management (Treister 2013) .

At the earliest indication of oral symptoms, the patient should be given a soft, bland diet to prevent irritation and injury to oral mucosa. If it progresses, patients may need a liquid diet with or without supplemental IV nutrition. In severe cases, one may need TPN (Total parenteral nutrition). Patients should be instructed to keep oral cavity clean and free from any secondary infection. Topical analgesics (swish and spit) can help control symptoms. These include viscous lidocaine, "magic mouth wash" (equal portions of lidocaine, diphenhydramine, Maalox), and morphine solution. Some patients may need opioids for pain relief (Treister 2013) . Patientcontrolled analgesia with morphine or transdermal fentanyl patch can be used to treat pain due to mucositis (Lalla et al. 2014) .

MASCC-ISOO (Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology) recommends oral cryotherapy, palifermin (human keratinocyte growth factor-1), low-level laser therapy, and benzydamine mouth wash, as measures to prevent mucositis. Among these, palifermin and laser therapy are the two modalities used in the field of HSCT. Palifermin is the only FDA approved agent for mucositis prevention. It is given at a dose of 60 μg/kg/day for 3 days prior to conditioning and 3 days after transplant, in patients receiving TBI-based conditioning in context of an autologous HSCT. On the other hand, low-level laser therapy (wavelength 650 nm, power 40 mW, and each square centimeter treated with required time to a tissue energy dose of 2 J/ cm 2 ) can be used, irrespective of whether TBI was used in conditioning or not. Oral cryotherapy would be of benefit to patients receiving highdose melphalan, with or without TBI for conditioning. On the other hand, panel recommended against the use of sucralfate mouth wash, chlorhexidine mouthwash, GM-CSF mouthwash, systemic pilocarpine for prevention (Lalla et al. 2014 ). Caphosol, a neutral, supersaturated, Ca(2+)/PO(4)(3-) mouth rinse, has been shown to reduce the severity of mucositis, duration of analgesia, and days to engraftment (Papas et al. 2003) . The same was reiterated by Quinn (2013), when he reviewed the data from 24 studies (Quinn 2013) .

A pharmacokinetic-pharmacodynamic study from India showed that Curcumin decreased the levels of inflammatory cytokines in patients receiving high dose melphalan for ASCT. This could be further explored in the clinical setting (Khattry et al. 2012) . Similarly, a second study from the same center explored the combination of resveratrol-copper 48 hours prior till 21 days after melphalan infusion. They showed that it reduced the levels of serum IFNγ and salivary IL-1β, TNF-α with a significant reduction of oral mucositis (Agarwal et al. 2020) . Another study from India observed that supersaturated calcium phosphate was ineffective for prevention and treatment of mucositis (Bhatt et al. 2017) . To reiterate the above finding, as per recent abstract at European Hematology Association 2020, a randomized trial between cryotherapy and supersaturated calcium phosphate did not find any difference between the two for prevention of oral mucositis (Belloumi et al. 2020 ).

A broad spectrum of acute complications posttransplant contributes to morbidity and mortality. It is imperative that transplant physicians are cognizant of these syndromes for early diagnosis and 

EP1392: a pro-oxidant combination of resveratrol and copper to reduce post-transplant toxicity in patients with multiple myeloma receiving high dose melphalan: results of an exploratory study (RESCU001)

Variable incidence of cyclosporine and FK-506 neurotoxicity in hematopoietic malignancies and marrow conditions after allogeneic bone marrow transplantation

EP1422: cryotherapy vs supersaturated calcium phosphate rinses in multiple myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized clinical trial

Supersaturated calcium phosphate rinse in prevention and treatment of Mucositis in patients undergoing hematopoietic stem cell transplant

Successful treatment with eculizumab for posterior reversible encephalopathy syndrome due to underlying transplant-associated thrombotic microangiopathy in patients transplanted for sickle cell disease

Granulocyte colonystimulating factor for poor graft function after allogeneic stem cell transplantation: 3 days of G-CSF identifies long-term responders

Endothelial dysfunction in sepsis

On the role of HLA antibodies in hematopoietic stem cell transplantation

Presentation of reversible posterior leukoencephalopathy syndrome in patients on calcineurin inhibitors

Modified diagnostic criteria, grading classification and newlyelucidated pathophysiology of hepatic SOS/ VOD afterhaematopoietic cell transplantation

Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation

Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center

Current approach to non-infectious pulmonary complications of hematopoietic stem cell transplantation

Elafin: a possible new biomarker and immunohistochemical stain for pre-engraftment syndrome

Posterior reversible encephalopathy syndrome (PRES) after haploidenticalhaematopoietic stem cell transplantation: incidence, risk factors and outcomes

Hematologic abnormalities and acute lung syndromes

An update on pulmonary complications of hematopoietic stem cell transplantation

Validation of recently proposed con-sensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation

The European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines for the detection and treatment of donor-specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation

Divergent effects of novel immunomodulatory agents and cyclophosphamide on the risk of engraftment syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma

Engraftment syndrome following autologous stem cell transplantation -an update unifying the definition and management approach

Hepatic Veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment

Life-threatening capillary leak syndrome after G-CSF mobilization and collection of peripheral blood progenitor cells for allogeneic transplantation

Granulocyte colony-stimulating factor-induced capillary leak syndrome confirmed by extravascular lung water measurements

Successful treatment of transplant associated thrombotic Microangiopathy (TA-TMA) with low dose defibrotide

Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome

Posterior reversible encephalopathy syndrome in HSCT for Hemoglobinopathies

Transplant-associated thrombotic microangiopathy: diagnostic challenges and management strategies

Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation

Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation

Posterior reversible encephalopathy syndrome after hematopoietic cell transplantation in children with hemoglobinopathies

Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival

A reversible posterior leukoencephalopathy syndrome

Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation

Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial

Erythropoietin therapy after allogeneic hematopoietic cell transplantation has no impact on long-term survival

Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multisystem endothelial injury

Pre-transplant use of tyrosine kinase inhibitors increases risk of transplant associated thrombotic microangiopathy -a single centre analysis of incidence, risk factors and outcomes

Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation

PRES in pediatric HSCT: a single-center experience

Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders

Curcumin decreases cytokine levels involved in Mucositis in autologous transplant setting: a pharmacokineticpharmacodynamic study

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

Procalcitonin as a biomarker to differentiate bacterial infections from engraftment syndrome following autologous hematopoietic stem cell transplantation for multiple myeloma

Access to hematopoietic stem-cell transplantation in India

MASCC-ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy

Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation

Epidemiology, risk factors, and prognosis of capillary leak syndrome in pediatric recipients of stem cell transplants: a retrospective single-center cohort study

Interferon-gamma regulates idiopathic pneumonia syndrome, a Th171CD41 T-cell-mediated graftversus-host disease

Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/venoocclusive disease in adult patients: a position statement from an international expert group

Biopsy-proven thrombotic microangiopathy without schistocytosis on peripheral blood smear: a cautionary tale

Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children

Risk factors for capillary leakage syndrome after bone marrow transplantation

Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults

Graft failure after allogeneic hematopoietic stem cell transplantation

A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation

Ratio of total leucocyte count to C-reactive protein: does it help differentiate engraftment fever from infective fever in patients undergoing autologous stem cell transplant?

Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: a review of current data

Low-, medium-and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage

Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group

Blood and bone marrow transplantation in India. Past, present, and future

Risk factor analysis of idiopathic pneumonia syndrome after allogeneic hematopoietic SCT in children

Humanbiomarker discovery and predictive models fordisease progression for idiopathic pneumoniasyndrome following allogeneic stem cell transplantation

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolatemofetil and ATG in Allo-SCT for leukemia with high relapse risk: an observational cohort study

Clinical management of posterior reversible encephalopathy syndrome after allogeneic hematopoietic stem cell transplantation: a case series and review of the literature

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies

Engraftment syndrome: clinical features and predictive factors in autologous stem cell transplant

Blood transfusions and pulmonary complications after hematopoietic cell transplantation

The spectrum of noninfectious pulmonary complications following hematopoietic stem cell transplantation

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Halofuginone inhibits Th17 cell differentiation by activating the amino acid starvation response

Effects of total body irradiation on the vascular endothelium

Etanercept and corticosteroid therapy for the treatment of late-onset idiopathic pneumonia syndrome

Oral health in stem cell transplantation

National Institutes of Health, National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE) Version 5

Early onset noninfectious pulmonary syndromes after hematopoietic cell transplantation

The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation

Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid

Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

Pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation

Rapid improvement of life-threatening capillary leak syndrome after stem cell transplantation by bevacizumab

Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint pediatric consortium and children's oncology group study (ASCT0521)

Eltrombopag for treating thrombocytopenia after allogeneic stem cell transplantation