ED Management of the Bone Marrow Transplant Patient: Pearls & Pitfalls

Author: Rachel Ely, DO, MHA, NRP (EM Resident Physician at SAUSHEC) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Introduction

More than 40,000 hematopoietic cell transplants (HCTs) are performed globally each year, with 20,000 hematopoietic cell transplants occurring in the United States annually.^1–3 HCT is now performed with increasing frequency for a variety of malignant and non-malignant hematologic disease.⁴ Patients who have undergone HCT are increasing in numbers, and because their lifetime risk of complication is high, it is imperative that emergency physicians be familiar with complications specific to the post-HCT population and the general approach to management. The following cases and discussions highlight non-infectious gastrointestinal, neurologic, and pulmonary complications that are not widely seen in the general population, but must be considered when caring for the patient who has undergone hematopoietic cell transplant.

Case #1:

A 29-year-old male underwent allogeneic peripheral stem cell transplant two weeks ago for recurrent Hodgkin lymphoma. Over the past 48 hours, he has developed increasing abdominal pain and distention and has gained approximately five pounds. He has noticed that his eyes seem to have a yellow tint, and his family feel that his color seems ‘off’. He spoke with his oncologist at the academic center approximately an hour away, who advised him to come in to be evaluated in her office; however, the patient reports the pain was too severe to manage the hour-long car ride, and therefore he presents to your community emergency department for assistance.

 Gastrointestinal Complications

Presenting signs and symptoms indicating gastrointestinal complications of HCT are typically similar to GI disease in the general population. Common symptoms include jaundice, right upper quadrant pain associated with eating, vomiting, and diarrhea.⁵ The most common upper GI complaints after HCT are mucositis, vomiting, odynophagia, and abdominal pain.⁵ Lower GI complaints include diarrhea, bloody stool, and constipation.⁵ Important processes unique to HCT patients include oral mucositis, hepatic veno-occlusive disease, graft-versus-host disease, medication toxicity, infection or viral reactivation, and neutropenic enterocolitis. Important differential considerations in the hematopoietic cell transplant patient with GI complaints are summarized in Table 1, with further discussion of specific disease processes below.

GI Differential Considerations

• Acute or Chronic Graft Versus Host Disease (GVHD):
  • Background: Allogeneic grafts are typically not genetically identical to the recipient, creating the potential for graft immunity to recognize recipient tissue as foreign.⁶ Acute GVHD is historically defined as occurring within 100 days of transplant, and a more chronic manifestation is loosely defined as occurring outside of the 100 day mark or causing persistent symptoms.⁶
  • Presentation: GI manifestation of acute GVHD may include transaminitis, hyperbilirubinemia, or intestinal involvement resulting in profuse watery diarrhea.⁵ Often more than one organ system will be affected, and the majority of patients will have skin involvement.^5,7 Liver involvement is characterized by a gradual and parallel rise in serum bilirubin and alkaline phosphatase and AST and ALT elevation of up to 10 times the upper limit of normal.^7,8 Evidence of chronic GVHD may include dysphagia or aspiration as a result of esophageal webs and strictures.⁷ Chronic GVHD of the liver usually manifests with progressive elevation of alkaline phosphatase and gamma glutamyl transpeptidase, with hyperbilirubinemia having a later presentation.
  • Treatment: Mild aGVHD is often managed by adjusting prophylactic regimens such as cyclosporine or tacrolimus, thus making it important to obtain serum levels of these medications.⁶ For more severe disease, systemic immunosuppression with methylprednisolone 1-2 mg/kg/day may be required, and should be implanted after consultation with the patient’s oncologist.^6,7

• Hepatic Veno-Occlusive Disease:
  • Background: Hepatic veno-occlusive disease is thought to occur due to damage to the zone 3 sinusoidal endothelial cells, causing sinusoidal obstruction, with a resulting hypercoagulable state.^3,7,9,10
  • Presentation: Symptoms include rapid weight gain, ascites, painful hepatomegaly, elevated bilirubin, and jaundice.^9–12 Disease may range from mild symptoms to severe illness with multi-organ failure.⁹ Most cases present within the first three weeks after transplantation with unexplained weight gain as the most common initial symptom.^7,11 Twenty-five percent may require hemodialysis as a result of hepatorenal syndrome.⁷ Ultrasound of the liver may demonstrate reversal of portal or hepatic venous flow.⁷
  • Treatment: Approximately 70% of patients will recover spontaneously with supportive care, with goals including maintenance of appropriate intravascular volume and renal perfusion, sodium restriction, maintenance of hematocrit, avoidance of hepatotoxic medications, and hemodialysis as required.⁷ Therapeutic paracentesis may be required to minimize discomfort and to improve renal function.⁷ Defibrotide is an deoxyribonucleotide that acts at the vascular endothelium and has anti-thrombotic properties without significant effects on systemic coagulation.¹² It is FDA-approved for use in veno-occlusive disease, but should be started in consultation with the patient’s oncologist.¹¹

• Mucositis:
  • Background: Oral mucositis is one of the most common and best studied side effects of HCT, and may range from mild inflammation to extensive ulcerations that penetrate the submucosa.¹³ Mucositis may be a result of chemotherapeutic agents, infections (potentially CMV, HSV, VSV, or Candida) or may be an indicator of GVHD.⁷
  • Presentation: Despite its name, this mucosal inflammation may occur anywhere along the digestive tract.¹³ While these lesions can cause significant pain, poor oral intake, and impaired quality of life, the emergency physician should be aware of the risk for secondary infection as these lesions serve as a portal of entry for microorganisms into the bloodstream, specifically bacteremia secondary to viridans.^13,14
  • Treatment: Oral mucositis may be symptomatically managed with ice chips and oral rinses with saline, bicarbonate, aluminum hydroxide, lidocaine, or topical nystatin.⁷ Specific treatment is targeted at the underlying cause of mucositis, such as evaluating and treating for graft-versus host, managing infectious etiologies such as oral candidiasis, or discussing drug regimen modification with the patient’s hematologist/oncologist.⁷

• Neutropenic Enterocolitis (Typhlitis):
  • Background: The pathophysiology of neutropenic enterocolitis is not well understood, but is thought to be a result of inflammation and necrosis of the lymphoid-rich tissue of the ileocecum and carries a mortality between 75-100% if not aggressively managed.^15,16
  • Presentation: Symptoms include diarrhea, fever, melena or hematochezia, and abdominal pain.⁵ These symptoms often overlap with other potential abdominal complications, and imaging such as ultrasound or CT may be required to confirm the diagnosis, as well as to further identify complications such as bowel wall perforation.^5,16 Presence of severe neutropenia (ANC < 500/mL), bowel wall thickening >4mm, and lack of evidence of other pathology suggests diagnosis of neutropenic enterocolitis.¹⁶
  • Treatment: Treatment includes fluid resuscitation, bowel rest, broad spectrum antibiotics, and pain control.¹⁷ Surgical intervention is required in cases with evidence of bowel wall perforation, severe sepsis or clinical deterioration despite optimal medical management, or persistent GI bleeding.¹⁶

Pearls for the HCT Patient with GI Complaints

• While the usual suspects should remain on the differential, it is important to consider hepatic veno-occlusive disease, graft-versus-host disease, and neutropenic enterocolitis in post-HCT patients with GI symptoms.
• Oral mucositis, while seemingly benign, puts immunosuppressed patients at risk for bacteremia.
• Concurrent skin and GI symptoms should prompt suspicion for acute GvHD.
• Due to significant mortality risk, neutropenic patients with abdominal pain. should be empirically and aggressively treated for presumed typhlitis until proven otherwise.

Case #2:

A 13-year-old female who underwent allogeneic stem cell transplant 75 days ago presents to your emergency department with altered mental status. Her parents report that over the past twenty-four hours she has complained of headache. This morning she vomited twice, and shortly after vomiting she had a generalized seizure lasting three minutes, prompting her parents to call EMS. She has no seizure history, and parents report no fevers or trauma. Currently she is confused but her mentation is slowly improving. Her vital signs are heart rate 102, blood pressure 164/90, respirations 18 per minute, temperature 98.9 degrees orally, SpO2 99%, blood glucose 96 by finger stick.

Neurologic Complications

While neurologic symptoms after hematopoietic transplant are somewhat frequent, the vast majority of symptoms are related to vague changes in cognitive processing and executive function.¹⁸  Rarely, however, patients will suffer from more severe symptoms such as paresthesias, hallucinations, change in mental status, seizures, or coma.¹⁹  Besides the obvious risk of infectious neurologic insult, the post-HCT population has a unique susceptibility to non-infectious processes such as posterior reversible encephalopathy (PRES), thrombotic microangiopathy, and adverse effects of commonly used immunosuppressant medications.¹⁹  These conditions as well as progressive multifocal leukoencephalopathy (an uncommonly encountered viral process) are discussed below.^20,21 In general, post-HCT patients with changes in mental status who present to the emergency department should be evaluated as most others, with these few specific differential diagnoses in mind.

• Posterior Reversible Encephalopathy:
  • Background: The pathophysiology of PRES remains unclear, though theories typically include a hypothesis of blood-brain barrier dysfunction leading to fluid shifts resulting in cerebral vasogenic edema.²²
  • Presentation: PRES may present with seizures, headache, vomiting, visual disturbance, or altered mentation.²² Approximately 86% of incidences of PRES will occur within 100 days of hematopoietic transplant.¹⁹ Blood pressure may be normal or only slightly elevated.²²  Seizures are often initial manifestation of PRES, and may involve non-convulsive focal signs such as gaze deviation, visual hallucinations, and altered mentation.²² MRI is the imaging study of choice to identify PRES, which typically demonstrates predominantly parieto-occipital involvement.²² While CT is often the first study obtained in a neurologically altered patient, it is sometimes normal or nonspecific in the presence of PRES.²² EEG is important to evaluate for non-convulsive seizure or status epilepticus in the persistently altered patient.²² Rare but serious complications of PRES include cerebral hemorrhage, cerebellar herniation, and refractory status epilepticus.²²
  • Treatment: Management of PRES is primarily supportive, and includes standard management of seizure and status epilepticus if required. In the event of severe hypertension in PRES, after excluding cerebral infarction arterial pressure should be reduced by approximately 25% within the first hour and then more slowly, though specific pharmacologic agents have not been well studied.²² Symptoms typically improve within 1 week.²²

• Thrombotic Microangiopathy:
  • Background: Thrombotic microangiopathy is not well understood, but is thought to be related to an abnormality of vascular endothelium that contributes to platelet adhesion and aggregation.³ It is often precipitated by calcineurin inhibitors, infection, or acute GVHD.²³
  • Presentation: Identification of thrombotic microangiopathy is challenging due to the various potential clinical presentations, but the hallmark presentation includes thrombocytopenia as a result of platelet aggregation, fragmentation of erythrocytes resulting in anemia, and acute renal failure.²³ Other potential presentations include CNS impairment, GI bleeding, or multiorgan failure.^3,11 The median time of onset is 40 days after HCT.³ Evaluation of the patient suspected to have thrombotic microangiopathy should include CBC, renal function panel, LDH, peripheral smear to identify schistocytes, and a serum haptoglobin performed to aid in diagnosis.¹¹ Diagnosis is made based on the presence of thrombocytopenia and microangiopathic hemolytic anemia without other etiology.¹²
  • Treatment: Treatment primarily includes supportive care and stopping potential precipitating agents or disease states.^11,12  Plasma exchange, while historically cited as a potential treatment, has limited utility in treating thrombotic microangiopathy.

• Drug Toxicity:
  • Background: Many medications used in the early conditioning period, post-transplant maintenance period, and those used for microbial prophylaxis have a significant array of neurologic side effects at both toxic and occasionally therapeutic doses.¹⁹ Calcineurin inhibitors such as cyclosporine A, tacrolimus, and sirolimus are the most frequently cited offenders.^3,19
  • Presentation: Cyclosporine A and cisplatin can specifically cause hypomagnesemia contributing to vague neurologic complaints, and vincristine and cyclophosphamide can cause hyponatremia, contributing to seizure risk.³ The following table details the most common neurotoxic medications to cause various neurologic adverse effects.
  • Treatment: Adverse drug effects and toxicity should be managed by decreasing or discontinuing the offending agent in consultation with the patient’s hematologist/oncologist.

• Progressive Multifocal Leukoencephalopathy:
  • Background: PML is a demyelinating disease caused by the reactivation of the John Cunningham (JC) virus in a previously infected host or in those receiving an allogeneic hematopoietic graft.^24,25 JC virus activates as a result of impaired cellular immunity and destroys oligodendrocytes.²⁵
  • Presentation: Presentation is variable, as nearly any area of the brain may be affected.²¹ Up to half of patients have behavioral and cognitive changes, and many have motor weakness, changes in gait, vision deficits, and aphasia or dysarthria.²¹ CT may demonstrate hypodense lesions of the white matter, and MRI may show hyperintense lesions on T2-weighted images and possibly gadolinium enhancement.²¹ Fifty-five percent of patients will have elevated CSF protein levels.²¹ CSF should be tested for JC virus by PCR.²¹
  • Treatment: PML is almost universally fatal, and has historically been treated with antivirals, antimalarials, and chemotherapeutic agents.²⁴ Some patients may experience an improvement and even resolution of neurologic symptoms and improvement in viral load with the withdrawal of chronic steroid therapy.²⁵

Pearls for the HCT Patient with Neurologic Complaints

• The differential for encephalopathy in these patients should be broad and not limited to infectious causes.
• Many common medications given to transplant patients can have significant neurotoxicity and adverse effects even at therapeutic levels.
• The post-HCT patient with altered mental status requires a detailed, thorough history and evaluation, including:
  • Medication review
  • CBC and coagulation panel to evaluate for coagulopathy
  • Chemistries including magnesium level to rule out medication-related metabolic disturbance
  • LDH, haptoglobin, fractionated bilirubin, and peripheral smear to evaluate for intravascular hemolysis
  • Head CT, and potentially MRI
  • Likely lumbar puncture as guided by history, exam, and work-up, in coordination with the patient’s hematologist/oncologist

Case #3:

A 47-year-old female 120 days out from an allogeneic HCT for chronic myeloid leukemia presents to your emergency department with two weeks of slowly progressive shortness of breath. Initially her symptoms were only with exertion, but now she is dyspneic even at rest and complains of a dry, hacking cough and occasional audible wheezing. She denies fever, sputum production, sick contact, chest pain, or peripheral edema. Her vitals upon arrival are heart rate 114, blood pressure 132/74, respirations 26 per minute, SpO2 88% on room air, and temperature 98.4 orally. Her SpO2 improves to 94% on nasal cannula at 4 liters per minute. She has coarse wheezing on auscultation of all lung fields, no JVD, and a normal-appearing chest x-ray. You suspect an inflammatory process, but aren’t sure if you should treat with steroids, antibiotics, or both.

Pulmonary Complications

Forty to sixty percent of all HCT recipients will experience a pulmonary complication such as an inflammatory or infectious pulmonary infiltrate in their early post-transplant course.^4,26 Pulmonary infiltrate may contribute to up to 80% of transplant-related deaths.²⁶ Infectious infiltrates may be related to typical bacterial organisms, but less common etiologies such as CMV pneumonitis, tuberculosis, pneumocystis jirovecii, and aspergillosis must be considered.²⁶ Non-infectious etiologies include pneumonitis, pulmonary edema, alveolar hemorrhage, idiopathic pneumonia, bronchiolitis obliterans, and graft-versus host disease.^10,26 These non-infectious processes will be the focus of this review.

• Radiation pneumonitis:
  • Background: Pneumonitis that is severe enough to manifest symptoms occurs in approximately 7% of patients who have experienced total body irradiation as a conditioning measure.⁴
  • Presentation: Symptoms include shortness of breath, cough, and fever, with minimal findings on exam.⁴ Symptoms typically arise approximately 1-3 months after radiation exposure.⁴ Imaging may show focal haziness, or a dense infiltrate with a sharp non-anatomic border that follows the shape of the radiation treatment port.⁴
  • Treatment: Corticosteroids are the treatment of choice with an initial dose of 1-2 mg/kg.⁴

• Pulmonary edema and pleural effusions:
  • Background: Pulmonary edema after HCT is due to either increased capillary hydrostatic pressure or increased capillary permeability.⁴ Pleural effusions occur in approximately 16% of post-HCT patients, often as a result of aggressive hydration, blood product transfusion, cardiac or renal toxicity from chemotherapeutic agents, or total body irradiation.⁴
  • Presentation: Pulmonary edema may occur in the second or third week after HCT, presenting with acute dyspnea, hypoxia, weight gain, and bibasilar crackles.⁴
  • Treatment: Post-HCT pulmonary edema should be managed in the same manner as in the general population, including positive pressure ventilation and diuresis.⁴ Effusions are most commonly right-sided or bilateral, and frequently have no infectious etiology.⁴ Pleural effusion has been reported in up to 50% of HCT recipients with hepatic veno-occlusive disease, thus a right-sided pleural effusion with any other suggestion of hepatic dysfunction must be thoroughly evaluated.⁴

• Idiopathic pneumonia and Bronchiolitis Obliterans:
  • Background: Idiopathic pneumonia syndrome, bronchiolitis obliterans (BO), and bronchiolitis obliterans with organizing pneumonia (BOOP) are late-onset presentations of diffuse lung injury after HCT with no infectious etiology.^3,4 The etiology of these conditions is unclear, but is suspected to be a result of an auto-immune process against the bronchial trees, or perhaps a result of chronic graft-versus-host disease.⁴²⁷
  • Presentation: Presentation may involve dyspnea, dry cough, and hypoxemia, with patient experiencing anything from mild symptoms to ARDS.⁴ Imaging may demonstrate a chest x-ray unchanged from previous, or obvious interstitial infiltrates.⁴ CT of the chest can be helpful in identifying this process.³ Often, bronchoscopy and bronchoalveolar lavage is required to rule out presence of bacterial, viral, and infectious processes.²⁷
  • Treatment: Treatment is primarily supportive in the emergency department.⁴ High-dose corticosteroids are typically used although evidence of its mortality benefit is lacking.^3,4 Some patients receiving cyclosporine or IVIG for GVHD prophylaxis have been observed to have reduced severity of disease.⁴

• Diffuse Alveolar Hemorrhage:
  • Background: DAH is more frequently observed in autologous HCT recipients, with an incidence of 2-21% and a high mortality rate.^3,4,12 DAH is typically seen at approximately 2-3 weeks post-transplant and is a result of endothelial swelling and thrombi in the pulmonary microvasculature.^4,10
  • Presentation: Symptoms include dyspnea, dry cough, fever, and hypoxemia; interestingly, hemoptysis is rare.⁴ If DAH is suspected in the emergency department, CBC and coagulation panel should be obtained and abnormalities corrected.³ Chest x-ray may show mild interstitial or alveolar infiltrates early in the process, but may quickly progress to a severe alveolar pattern.⁴ Diagnosis is made by bronchoscopy.
  • Treatment: High-dose corticosteroids improve mortality and may help to avoid progression to respiratory failure.⁴ Fresh frozen plasma transfusion and plasmapheresis have been studied with inconclusive results.¹² While agents such as TXA have not been thoroughly investigated, a case series reports good results when used locally during bronchoscopy.^12,28 Sixty-day survival from onset of symptoms is approximately 16% in DAH and 32% in those found to have an infectious-related DAH, with overall mortality of DAH secondary to HCT at 80%.^10,12

• Graft-Versus-Host Disease:
  • Background: While pulmonary complications of acute GvHD are minimal, they are common with chronic GvHD and also contribute to increased risk of developing other non-infectious pulmonary complications.⁴
  • Presentation: On average, symptoms typically arise near the five month mark post-transplant.⁴ Common respiratory symptoms of cGvHD are shortness of breath, dry cough, crackles or wheezes on pulmonary exam.⁴ Chest x-ray may range from completely normal to diffuse bilateral infiltrates.⁴
  • Treatment: As with other forms of GvHD, pulmonary symptoms are managed with high-dose steroid therapy such as prednisone 1 mg/kg/day as well as other immunosuppressive medications such as cyclosporine in consultation with the patient’s hematologist-oncologist.^4,6

Pearls for the HCT Patient with Pulmonary Complaints

• The exact etiology of a patient’s respiratory syndrome may be difficult to discriminate in the Emergency Department and often requires invasive testing such as bronchoscopy and biopsy for definitive diagnosis.
• Advanced imaging such as CT of the chest is often required to aid in guiding therapy.
• Initial treatment should be supportive with supplemental oxygen, positive pressure, beta agonists, and systemic steroid therapy as guided by the history and exam, with evidence of infectious etiology aggressively treated with early antibiotics.

References/Further Reading

1         Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2015;21:1863–9. doi:10.1016/j.bbmt.2015.07.032.

2         Appelbaum FR. Hematopoietic-Cell Transplantation at 50. N Engl J Med 2007;357:1472–5. doi:10.1056/NEJMp078166.

3         Munchel A, Chen A, Symons H. Emergent Complications in the Pediatric Hematopoietic Stem Cell Transplant Patient. Clin Pediatr Emerg Med 2011;12:233–244. doi:10.1016/j.cpem.2011.07.005.

4         Khurshid I, Anderson L. Non-infectious pulmonary complications after bone marrow transplantation. Postgrad Med J 2002;78:257–62. doi:10.1136/pmj.78.919.257.

5         Barker CC, Anderson RA, Sauve RS, Butzner JD. GI complications in pediatric patients post-BMT. Bone Marrow Transplant 2005;36:51–8. doi:10.1038/sj.bmt.1705004.

6         Funke VAM, Rodrigues Moreira MC, Vigorito AC. Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. Rev Assoc Med Bras 2016;62:44–50.

7         Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 2012;18:1851–60. doi:10.3748/wjg.v18.i16.1851.

8         El-Sayed MH, El-Haddad A, Fahmy OA, Salama II, Mahmoud HK. Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation. Eur J Gastroenterol Hepatol 2004;16:1347–54.

9         Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepatic Veno-Occlusive Disease following Stem Cell Transplantation: Incidence, Clinical Course, and Outcome. Biol Blood Marrow Transplant 2010;16:157–68. doi:10.1016/j.bbmt.2009.08.024.

10       Y. N, B. B. Hemorrhagic and thrombotic complications in bone marrow transplant recipients. Thromb Res 2007;120:S92–8.

11       Miano M, Faraci M, Dini G, Bordigoni P. Early complications following haematopoietic SCT in children. Bone Marrow Transplant 2008;41 Suppl 2:S39–42. doi:10.1038/bmt.2008.53.

12       Nadir Y, Brenner B. Thrombotic complications associated with stem cell transplantation. Blood Rev 2012;26:183–7. doi:10.1016/j.blre.2012.05.001.

13       Haverman TM, Raber-Durlacher JE, Rademacher WMH, Vokurka S, Epstein JB, Huisman C, et al. Oral complications in hematopoietic stem cell recipients: The role of inflammation. Mediators Inflamm 2014;2014. doi:10.1155/2014/378281.

14       Margaix-Munoz M, Bagan J V., Jimenez Y, Sarrion MG, Poveda-Roda R. Graft-versus-host disease affecting oral cavity. A review. J Clin Exp Dent 2015;7:e138–45. doi:10.4317/jced.51975.

15       Sachak T, Arnold MA, Naini B V, Graham RP, Shah SS, Cruise M, et al. Neutropenic Enterocolitis 2015;0:1–8. doi:10.1097/PAS.0000000000000517.

16       Nesher L, Rolston KVI. Neutropenic enterocolitis, a growing concern in the era of widespread use of aggressive chemotherapy. Clin Infect Dis 2013;56:711–7. doi:10.1093/cid/cis998.

17       Mickley M, Gutierrez C, Carney M. Oncologic and Hematologic Emergencies in Children. In: Tintinalli J, Stapczynski J, Ma O, Yealy D, Meckler G, Cline D, editors. Tintinalli’s Emerg. Med. A Compr. Study Guid. 8th ed., New York, NY: McGraw-Hill; 2016.

18       Syrjala KL, Martin PJ, Lee SJ. Delivering care to long-term adult survivors of hematopoietic cell transplantation. J Clin Oncol 2012;30:3746–51. doi:10.1200/JCO.2012.42.3038.

19       Pruitt  a. a., Graus F, Rosenfeld MR. Neurological Complications of Transplantation: Part I: Hematopoietic Cell Transplantation. The Neurohospitalist 2012;3:24–38. doi:10.1177/1941874412455338.

20       Lin R, Liu Q. Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation. J Hematol Oncol 2013;6:94. doi:10.1186/1756-8722-6-94.

21       Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic criteria: Consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430–8. doi:10.1212/WNL.0b013e31828c2fa1.

22       Masetti R, Cordelli DM, Zama D, Vendemini F, Biagi C, Franzoni E, et al. PRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ Transplantation. Pediatrics 2015;135:890–901. doi:10.1542/peds.2014-2325.

23       Krishnappa V, Gupta M, Manu G, Kwatra S, Owusu OT, Raina R. Acute kidney injury in hematopoietic stem cell transplantation: A review. Int J Nephrol 2016;2016. doi:10.1155/2016/5163789.

24       Avivi I, Wittmann T, Henig I, Kra-Oz Z, Szwarcwort Cohen M, Zuckerman T, et al. Development of multifocal leukoencephalopathy in patients undergoing allogeneic stem cell transplantation-can preemptive detection of John Cunningham virus be useful? Int J Infect Dis 2014;26:107–9. doi:10.1016/j.ijid.2014.03.1381.

25       Kawan L, Kentouche K, Beck JF, Gruhn B. Progressive multifocal leukoencephalopathy after allogeneic bone marrow transplantation. Infection 2009;37:60.

26       Wang J-Y, Chang Y-L, Lee L-N, Chen J-H, Tang J-L, Yang P-C, et al. Diffuse pulmonary infiltrates after bone marrow transplantation: the role of open lung biopsy. Ann Thorac Surg 2004;78:267–72. doi:10.1016/j.athoracsur.2004.03.002.

27       Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;28:425–34. doi:10.1038/sj.bmt.1703142.

28       Solomonov A, O F, T Z, B B, M Y. Pulmonary hemorrhage: a novel mode of therapy. Respir Med 2009;103:1196–200.