Volume 26, Issue 8 e14378

COMPREHENSIVE REVIEW

Open Access

Neutropenia in pediatric solid organ transplant

Lyndsay A. Harshman,

Lyndsay A. Harshman

Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

Search for more papers by this author

Robin Williams,

Robin Williams

Division of Pediatric Hematology/Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA

Search for more papers by this author

Rachel M. Engen,

Corresponding Author

Rachel M. Engen

[email protected]

orcid.org/0000-0002-0584-7951

Division of Nephrology, Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA

Correspondence

Rachel M Engen, Division of Nephrology, Department of Pediatrics, University of Wisconsin Madison, Madison, WI, USA.

Email: [email protected]

Search for more papers by this author

Lyndsay A. Harshman,

Lyndsay A. Harshman

Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

Search for more papers by this author

Robin Williams,

Robin Williams

Division of Pediatric Hematology/Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA

Search for more papers by this author

Rachel M. Engen,

Corresponding Author

Rachel M. Engen

[email protected]

orcid.org/0000-0002-0584-7951

Division of Nephrology, Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA

Correspondence

Rachel M Engen, Division of Nephrology, Department of Pediatrics, University of Wisconsin Madison, Madison, WI, USA.

Email: [email protected]

Search for more papers by this author

First published: 20 August 2022

https://doi.org/10.1111/petr.14378

All authors contributed equally to the drafting and writing of this manuscript.

Share a link

Email
Wechat
Bluesky

Abstract

Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm³ and occurs in up to 25%–30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.

Abbreviations

ANC: absolute neutrophil count
aHR: adjusted hazard ratio
ATG: antithymocyte globulin
CBC: complete blood count
CMV: cytomegalovirus
EBV: Epstein–Barr Virus
G-CSF: granulocyte-colony-stimulating Factor
HR: hazard ratio
NGAL: neutrophil gelatinase-associated lipocalin
PTLD: posttransplant lymphoproliferative disorder
RR: relative risk
SOT: solid organ transplant

1 THE NEUTROPHIL

Neutrophils, or polymorphonuclear leukocytes, are the most abundant white blood cells in circulation and play a key role in antimicrobial defense. Neutrophils develop from pluripotent stem cells in the bone marrow. During differentiation, the developing neutrophils undergo a number of intermediate stages, including acquisition of granules containing an array of toxins, specifically myeloperoxidase, defensins, protease 3, neutrophil gelatinase associated lipocalin (NGAL), lysozyme, and metalloproteases.¹ Once fully mature, only 3%–5% of neutrophils are released from the bone marrow into circulation, where they survive anywhere from 5 to 135 h. The majority of neutrophils remain in the bone marrow, held in reserve in the “storage pool.”² This means that readily quantifiable neutrophils in the peripheral blood represent only a fraction of the body's total reserve, and that the body can respond quickly to infections by mobilizing neutrophils from the bone marrow.

Neutropenia is generally defined as an absolute neutrophil count (ANC) in the circulation of less than 1500/mm³ (or 1500/μl or 1.5 × 10⁹/L). Severity of neutropenia may be further classified as mild (1000/mm³ to 1499/mm³), moderate (500/mm³ to 1000/mm³), or severe (<500/mm³)³ or, alternatively by National Cancer Institute Common Terminology Criteria for Adverse events grade (Table 1).⁴ An absolute neutrophil count of <100/mm³ is defined as agranulocytosis. The clinical implications of neutropenia are related to the status of the bone marrow reserve pool. In situations where the bone marrow reserve is intact, there is no association between degree of neutropenia and risk of infection. The bone marrow in these patients can rapidly provide an adequate number of neutrophils in the setting of infection; however, if the bone marrow reserve is depleted, then grade or stage of neutropenia will correlate with infection risk.⁵

TABLE 1. Classification of severity of neutropenia

Absolute neutrophil count	Grade	NCI stage	Risk of infection
>1500/mm³	Normal	1	Baseline
1000–1499/mm³	Mild	2	No significant increased risk
500–999/mm³	Moderate	3	Some increased risk
<500/mm³	Severe	4	Significant risk; typical infectious symptoms may be absent

Abbreviation: NCI, National Cancer Institute.

2 EPIDEMIOLOGY AND ETIOLOGY OF NEUTROPENIA AFTER SOLID ORGAN TRANSPLANTATION

Neutropenia is estimated to occur in approximately 25%–30% of solid organ transplant recipients in the first-year posttransplant. Table 2 shows the incidence of neutropenia within the first year following solid organ transplant as reported among both adult and pediatric solid organ transplant recipients by organ system.

TABLE 2. Incidence of neutropenia within the first-year posttransplant reported in adult and pediatric solid organ transplant recipients, by organ

Transplanted organ	Incidence of neutropenia
Transplanted organ	Pediatric	Adult
Heart	54.2%⁶⁰	30%–53.6%^{45, 57, 85}
Kidney	54.8%^{56, 75}	28%–47.5%^{13, 58, 74, 86, 87}
Lung	Not reported	42.1%⁷³
Liver	39%⁵⁶	24%–57%^{14, 23, 58}

2.1 Drug-induced neutropenia

Most epidemiologic studies after solid organ transplantation (SOT) attribute neutropenia to requirement for immunosuppressive medications. However, data on the incidence of neutropenia due to individual medications are largely limited to initial premarketing clinical trials; real-world reports are often complicated by polypharmacy. Here, we will review the incidence, etiology, and management of neutropenia associated with common and well-studied transplant-associated medications; however, neutropenia can also occur with a variety of medications beyond those discussed in detail here (Table 3).

TABLE 3. Common transplant medications associated with neutropenia

Common transplant medications associated with neutropenia
Immunosuppressives
Tacrolimus
Mycophenolate mofetil
Azathioprine
Antithymocyte globulin
Rituximab
Antihypertensives
Angiotensin-converting enzyme inhibitors
Propranolol
Furosemide
Anti-infectives
Trimethoprim-Sulfamethoxazole
Ganciclovir/Valganciclovir
Dapsone
Leflunomide
Semisynthetic penicillins
Vancomycin
Cephalosporins
Acyclovir
Oseltamivir

Tacrolimus is the most commonly used posttransplant maintenance immunosuppression medication in the United States, prescribed to over 70% of intestine and pediatric liver and over 90% of pediatric heart, lung, and kidney recipients.^6-10 It inhibits calcineurin by binding to FK506-binding protein, thereby blocking calcium-dependent events, including interleukin-2 gene transcription required for T-cell activation.¹¹ Tacrolimus also inhibits glucuronidation of mycophenolic acid, leading to increased blood levels,¹² which is the presumed mechanism by which it causes neutropenia. Zafrani et al.¹³ showed that the combination of tacrolimus and mycophenolate mofetil was an independent risk factor for neutropenia in kidney transplant recipients, and Alraddadi et al also showed that tacrolimus trough level was an independent predictor of neutropenia in liver transplant recipients.¹⁴ Cyclosporine does not have similar effects on mycophenolic acid levels, and a three-year study of 125 pediatric kidney transplant recipients reported a neutropenia incidence-rate of 0.064/patient-year with tacrolimus compared with 0.014/patient-year with cyclosporine.¹⁵ Multiple case reports of presumed tacrolimus-associated neutropenia report resolution with conversion of tacrolimus to cyclosporine^16-18; however, in many of these cases, the neutropenia persisted after mycophenolate mofetil was initially discontinued, resolving only once tacrolimus was stopped. Therefore, it remains unclear if tacrolimus affects neutrophil counts by additional mechanisms.

Mycophenolate mofetil and mycophenolic acid are among the most commonly used maintenance immunosuppressive medications, prescribed to over 90% of pediatric heart, lung, and kidney transplant recipients, 35% of intestine recipients, and over 40% of pediatric liver recipients in the United States.^6-10 Mycophenolic acid and its prodrug, mycophenolate mofetil, inhibit lymphocyte proliferation by blocking inosine monophosphate dehydrogenase, an enzyme involved in the synthesis of guanosine nucleotides. Mycophenolic acid has a stronger affinity for the type II isoform of the enzyme, which is found primarily in lymphocytes, than the type I isoform present in most other cells, thus contributing to its specificity as an immunosuppressive agent.¹⁹ The method by which mycophenolic acid causes neutropenia is less clear, but mouse models suggest that it may suppress T cells that produce interleukin-17, a cytokine that drives the production of granulocyte colony-stimulating factor, which is critical for neutrophil production.²⁰

Mycophenolate mofetil has been associated with neutropenia in 2%–22%^{21, 22} of individuals, with higher rates reported with concomitant valganciclovir use. Ferrer-Machin et al reported that neutropenia occurred in 56% of 57 adult liver transplant recipients prescribed mycophenolate mofetil and valganciclovir, compared with 37% of the 87 recipients prescribed mycophenolate mofetil alone.²³ Individuals with higher mycophenolic acid area under the curve (AUC) may be at higher risk of hematologic toxicities, but this has not been replicated in all studies. A target AUC_0–12h of 30–60 mg-h/L has been recommended for pediatric kidney and adult liver transplant recipients, but data in heart and lung recipients are limited.²⁴

Reduction in dose or discontinuation of mycophenolic acid can quickly improve the neutrophil count but is associated with an increased risk of acute rejection.²⁵ Brar et al.²⁶ reported that adult kidney transplant recipients whose mycophenolic acid was reduced or discontinued due to neutropenia doubled their risk of acute rejection, while Zafrani et al.¹³ reported an odds ratio for acute rejection of 1.11 per day off the medication. Due to the high incidence of neutropenia in SOT patients concomitantly receiving MMF and valganciclovir, and equally concerning acute rejection episodes when MMF is reduced or discontinued, alternative immunosuppressive medications have been considered. However, a Cochrane review did not find any difference in the incidence of hematologic side effects between mycophenolic acid and azathioprine.²⁷

Antithymocyte globulin (ATG) is comprised of rabbit-derived polyclonal anti-T-cell antibodies and may be used as induction immunosuppression or treatment of rejection in transplantation. Targets for ATG include multiple molecules that are present on the neutrophil cell surface, including LFA-1, ICAM-1, CCR7, and CD16.^{28, 29} Data on the risk of neutropenia are limited. Büchler et al reported an ANC <1500/mm³ in 13% and an ANC <800/mm³ in 2.5% in renal transplant recipients within 14 days of initiation of therapy; all patients discontinued ATG with resolution of neutropenia. ATG was identified as an independent risk factor for neutropenia in a USRDA study of 6043 kidney transplant recipients with neutropenia.^{30, 31} Leukopenia is reported in 24.6%–33.5% of patients treated with ATG, but studies often do not differentiate if this is due to lymphopenia or neutropenia.^{32, 33} If a patient develops neutropenia while receiving a course of thymoglobulin, dose reduction is recommended.³⁴

Rituximab is a humanized monoclonal antibody that targets CD20, which leads to binding and depletion of B cells. It may be used pretransplant, for ABO incompatible and highly sensitized patients, and posttransplant, for antibody-mediated rejection and CD20(+) posttransplant lymphoproliferative disease (PTLD). Late-onset neutropenia, occurring four or more weeks after rituximab infusion, has been reported in 4%–27.3% of patients.^{33, 35} The incidence may be higher in some solid organ recipients. Kabei et al.³⁶ reported late-onset neutropenia in 48% of ABO incompatible heart transplant recipients at 2–12 months after rituximab treatment; 41.6% of those with late-onset neutropenia developed acute rejection. Similarly, Ahmadi et al reported neutropenia in four of six kidney transplant recipients at 35–93 days after treatment with rituximab. One of these patients died secondary to endocarditis.³⁷ The reason for late-onset neutropenia and increased rejection risk is unknown. It has been hypothesized that depletion of immunoregulatory B cells leads to increased levels of B-cell-activating factor (BAFF) or other cytokines or competition between B-cell lymphopoiesis and granulopoiesis.^{36, 37} Granulocyte-colony-stimulating factor (G-CSF) has been reported as a possible treatment for rituximab-associated neutropenia.³⁸

Trimethoprim-sulfamethoxazole is commonly used for prophylaxis against Pneumocystis jarovecii in immunocompromised patients. It inhibits thymidine synthesis by inhibiting folic acid synthesis and is associated with neutropenia in 34%–35% of children treated with trimethoprim-sulfamethoxazole for otitis media, often as early as 10 days of initiating treatment. Principi et al. showed that this incidence could be reduced to 17.5% with co-administration of folic acid.^{39, 40} Leukopenia, anemia, and thrombocytopenia have also been reported.³³ If trimethoprim-sulfamethoxazole toxicity is suspected, the drug can be substituted with pentamidine, atovaquone, or dapsone, although dapsone is also associated with a rare and idiosyncratic but serious neutropenia risk.^{41, 42}

Valganciclovir, a prodrug of ganciclovir, may be used for cytomegalovirus prophylaxis or treatment after solid organ transplant. Ganciclovir triphosphate accumulation in cells is associated with a decrease in neutrophil count within the first 3 months of treatment,⁴³ where it is hypothesized to inhibit DNA polymerase.⁴⁴ Kidney transplant recipients with a polymorphism in ABCC4, a multidrug efflux transporter, have been shown to be at risk of a decline in neutrophil count during valganciclovir treatment.⁴⁴ Valganciclovir has been associated with neutropenia in 40%–77.3% of solid organ transplant recipients,^{45, 46} with several studies associating neutropenia with valganciclovir ‘overexposure’.^{47, 48} Incidence of neutropenia may be higher in pediatric than adult patients.⁴⁹ Dose reduction in valganciclovir is not recommended due to the risk of development of resistant cytomegalovirus⁵⁰; discontinuation of the drug with increased cytomegalovirus screening is an alternative for patients with significant toxicities.

2.2 Infection-induced neutropenia

Numerous common childhood infections can cause transient neutropenia, including respiratory syncytial virus, influenza, parvovirus, human herpes virus 6, measles, rubella, varicella, malaria, and shigella. Less common infectious causes include typhoid fever, brucellosis, tularemia, tuberculosis, kala-azar, and Rocky Mountain spotted fever. In most cases, the neutropenia is related to viral suppression of the bone marrow or viral-induced autoimmunity.⁵¹ The degree of neutropenia in these settings is typically mild-to-moderate and will resolve within days to weeks, depending on the pathogen. However, of particular concern to pediatric SOT patients is neutropenia related to Epstein–Barr virus and cytomegalovirus.

Epstein–Barr virus (EBV) is a member of the herpesvirus family that is acquired by 90% of children in developing countries prior to age 5 years.⁵² However, in the United States, 47%–60% of pediatric solid organ transplant recipients are EBV-naïve prior at the time of transplantation.^6-9 Mild neutropenia occurs in 40% of immunocompetent children early in the course of infectious mononucleosis, and severe neutropenia has been reported.⁵³ Data from transplant recipients are more limited, but Hyun et al.⁵⁴ reported neutropenia in one of eight pediatric kidney transplant recipients with EBV DNAemia, while Hadou et al reported severe neutropenia in one of 18 pediatric kidney recipients with EBV DNAemia.⁵⁵

Cytomegalovirus (CMV) is another human herpesvirus with a seroprevalence rate of 30%–97% worldwide.⁵⁰ However, data from the United States show that 61%–71% of pediatric solid organ transplant recipients are CMV-naïve at the time of transplant.^7-10 CMV does not typically cause neutropenia in immunocompetent individuals but is a component of the CMV syndrome that includes fever, malaise, atypical lymphocytosis, leukopenia, thrombocytopenia, and/or elevated hepatic transaminases as well as symptomatic end-organ disease.^{14, 50} High-risk CMV serostatus has been associated with risk of neutropenia in a cohort of 100 pediatric kidney and liver transplant recipients⁵⁶ as well as large cohorts of adult liver, kidney, and heart recipients,^{30, 57, 58} although it can be difficult to separate the effects of CMV serostatus from those of prophylactic valganciclovir.

2.3 Autoimmune neutropenia

Antineutrophil antibodies can develop in the setting of infection, autoimmune disorders, ABO incompatible transplants, passenger lymphocyte syndrome, and immune system dysregulation related to immunosuppression. The antibodies target circulating neutrophils, usually the NA1 antigen, for destruction but generally do not affect bone marrow reserves. In a single-center cohort of 764 pediatric solid organ transplant recipients, Schoettler et al.⁵⁹ reported autoimmune neutropenia in 0.3% of patients; all cases resolved after switching tacrolimus to either cyclosporine or sirolimus. In a cohort of 77 pediatric heart recipients with neutropenia, Rose-Felker et al.⁶⁰ reported identifying antineutrophil antibodies in six of fourteen patients who were tested. Most children with autoimmune neutropenia will have spontaneous remission of disease in 7–24 months although serious infections occur in approximately 10%.⁶¹ Corticosteroids, intravenous immunoglobulin, and G-CSF have bene proposed as potential treatments for autoimmune neutropenia,⁵¹ but their usefulness is questionable given the low infection rate and normal bone marrow reserve.

Chronic benign neutropenia is thought to overlap autoimmune neutropenia in phenotype and typically presents in infants and children less than 3 years old with spontaneous resolution in two to three years; conversely, chronic idiopathic neutropenia tends to present in older children and does not remit. Both disorders are associated with normal bone marrow reserves and are not associated with increased infections.⁶²

2.4 Neutropenia associated with nutritional deficiencies

Deficiencies in folate, vitamin B12, and copper may cause neutropenia due to decreased granulopoiesis and are often associated with macrocytosis and pancytopenia.⁶³ While these nutritional deficiencies are uncommon in healthy children, they may be a consideration in chronically ill children with poor oral intake or malabsorption syndromes. Serum testing for folate and vitamin B12 levels may serve as an initial screen, while copper deficiency can be diagnosed by checking ceruloplasmin levels. Treatment is with supplementation of the deficient nutrient.

2.5 Other causes of neutropenia

There are a variety of reasons for a child to have neutropenia independent of SOT status. Benign familial neutropenia is a condition resulting in lower than “normal” absolute neutrophil counts and has been reported to be more common in African Americans (4.5%), South African blacks, West Indians, and Arab Jordanians.^{64, 65} It is hypothesized to be secondary to a defect in release of mature neutrophils from the bone marrow to the circulation; bone marrow neutrophil reserves are normal, and there is no increased infection risk.^{66, 67} In some cases, there may be an associated single nucleotide polymorphism in the Duffy antigen/receptor chemokine gene, a receptor for pro-inflammatory cytokines, that is protective against malaria.^68-70 Examination of pretransplant blood counts should help make this diagnosis.

Hypersplenism can result in neutrophil trapping and neutropenia but does not affect bone marrow reserve. Infections are uncommon. G-CSF treatment is contraindicated in hypersplenism as it has been associated with splenic rupture.⁷¹ A variety of congenital disorders cause neutropenia including cyclic neutropenia, severe congenital neutropenia, Chediak-Higashi syndrome, and Shwachman-Diamond-Oski syndrome; the majority of these would be expected to be diagnosed early in life.⁷² Finally, bone marrow disorders, including leukemia, can present with neutropenia, but generally as part of a broader suppression of bone marrow cell lines.

3 OUTCOMES OF NEUTROPENIA IN SOLID ORGAN TRANSPLANT RECIPIENTS

Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Chow et al and Rose-Felker et al reported no increase in infection, acute rejection, or death among pediatric or adult heart transplant recipients with an ANC <1000/mm³.^{57, 60} Conversely, severe neutropenia among adult lung recipients was associated with a higher risk of mortality when compared with recipients with no neutropenia (aHR 2.97, p = .04) but with no difference in rejection or CMV infection. Gram-negative bacterial infection incidence was higher among those with moderate or severe neutropenia, but gram-positive infections were more common only among those with severe neutropenia.⁷³

An analysis of 41 705 adult kidney transplant recipients in the US Renal Data System reported that neutropenia was associated with an increased risk of graft loss (aHR 1.59, p < .001), death (aHR 1.74, p < .001), and infectious causes of death (aHR 1.8, p < .001), and similar results have been reported in multiple smaller studies.^{26, 58, 74} Among pediatric kidney recipients, Jarasvaraparn et al.⁵⁶ reported a higher risk of hospitalization (RR 2.7, p < .001) and infection (RR 1.8, p = .04) but not acute rejection, and Becker-Cohen et al.⁷⁵ reported that those with an ANC <1500/mm³ maintained stable graft function during the neutropenic episodes.

Reported outcomes for neutropenic liver transplant recipients are similarly mixed. Alraddadi et al reported that an ANC <1000/mm³ was an independent predictor of mortality among adult liver recipients (HR 3.76, p < .001),¹⁴ but Perez et al reported no infections among liver recipients with an ANC <900/mm³.⁴⁶ Among pediatric liver recipients, Jarasvaraparn et al.⁵⁶ reported no increased risk of hospitalization or infection among those with neutropenia.

4 EVALUATION AND MANAGEMENT OF NEUTROPENIA

Initial evaluation of the neutropenic transplant recipient begins with an assessment of the severity of neutropenia and risk of infection. Patients with an ANC <500/mm³ are at highest infection risk and require counseling on strict hand washing, avoidance of sick contacts, and prompt medical evaluation of any fever. Patients should be screened for infectious symptoms, especially gingivitis, periodontitis, skin infections, and pneumonia symptoms.⁷⁶ Evaluation of the cause of neutropenia includes review of the patient's medication list and testing for EBV and CMV DNAemia. Children should be assessed for signs or symptoms of other viral infections that can cause neutropenia. In patients with increased risk of nutritional issues (e.g., malabsorption or short-gut syndrome), vitamin B12, methylmalonic acid, homocysteine, copper, ceruloplasmin, and folate levels should be quantified to evaluate for micronutrient deficiencies that may be easily corrected.

Laboratory follow-up of neutropenia often occurs at least weekly in severe neutropenia and every 2–4 weeks in more moderate cases. If neutropenia is persistent without a clear underlying cause, further evaluation should include testing for antineutrophil antibodies and consideration to bone marrow examination as the most direct assessment of neutrophil reserve. Patients with neutropenia secondary to low bone marrow reserve will be at highest risk of infection, but those with normal marrow reserve, such as in chronic benign neutropenia and hypersplenism, will generally not be at increased risk.⁵¹ Hematology consultation should be initiated by the transplant clinician for patients with neutropenia in the setting of other cytopenias (anemia and/or thrombocytopenia), as this may be a symptom of a lymphoproliferative infiltrate or a broader bone marrow failure syndrome.

Management of neutropenia should begin by addressing the underlying cause, including reducing or removing bone marrow suppressing medications when appropriate, treating infections, and addressing nutrient deficiencies. A sample, single-center algorithm for the approach to management of neutropenia is shown in Figure 1. Providers should be cautious about reducing doses of antibiotics and antivirals due to the risk selecting for drug-resistant pathogens.⁵⁰ Reduction in immunosuppressive medications carries an increased risk of allograft rejection. An alternative proposed therapy is G-CSF, a cytokine that stimulates production of neutrophil colonies and speeds their maturation and release into the circulation.⁷⁷ It is most highly studied in children treated with chemotherapy, where meta-analytic data showed a modest reduction in the duration of hospitalization by 1.42 days (95% CI 0.62–2.22 days) for children receiving G-CSF compared to placebo.⁷⁸ Reported side effects include fever, headache, skeletal pain, rash, nosebleed, diarrhea, anemia, and hair loss.³⁴

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer PowerPoint

A sample algorithm for the management of neutropenia after pediatric kidney transplantation is shown

Among adult solid organ transplant recipients, G-CSF use has been shown to increase white blood cell counts^79-82 but its impact on clinical outcomes remains unclear. In a randomized control trial that treated liver transplant recipients with G-CSF for 21 days posttransplant, Winston et al found no beneficial impact for prevention of infection or death.⁸³ A study using data from 41 705 US Medicare patients showed a decreased risk of death in unadjusted analysis, but this finding was no longer significant after adjustment in multivariable models.³⁰ Among 228 lung transplant recipients, G-CSF use was associated with a higher risk of chronic allograft dysfunction in those with mild neutropenia but decreased risk of death in those with severe neutropenia (aHR 0.24).⁷³

Turgeon et al reported that 8% of 50 kidney or liver recipients who were treated with G-CSF developed acute rejection within 2 months of G-CSF therapy.⁷⁹ Similarly, Schneider et al.⁸² reported a trend toward increased rejection among 12 kidney recipients treated with G-CSF, and Nguyen et al reported an incidence rate of acute rejection of 0.067 episodes/month among heart transplant recipients treated with G-CSF compared with 0.011 episodes/month in the untreated group.⁷⁷ Conversely, Hamel et al.⁸¹ found no rejection within one-month G-CSF treatment among 36 kidney transplant recipients. The mechanism of rejection following receipt of G-CSF is unclear and may conceivably be a result of immunosuppression reduction as a first-line response prior to use of G-CSF.

There are two cohort studies examining G-CSF use in pediatric kidney transplant recipients. Becker-Cohen et al.⁷⁵ reported 46 neutropenic children, 16 of whom had an ANC <500/mm³. All patients with moderate-to-severe neutropenia also had discontinuation of oral valganciclovir and trimethoprim-sulfamethoxazole, a dose decrease in their antimetabolite immunosuppression, and discontinuation of the antimetabolite if ANC did not improve. Eight patients with severe neutropenia were treated with G-CSF at a dose of 5 mcg/kg/day for 1–4 doses. Patients were selected for treatment either due to infection (n = 5) or persistent severe neutropenia despite medication changes (n = 3). Neutrophil counts returned to the normal range within 3–10 days of treatment. In a multicenter cohort study, Engen et al reported 341 neutropenic patients, of whom 83 were treated with G-CSF at a median dose of 5 mcg/kg/dose for 2–7 doses. G-CSF was more commonly prescribed to patients with a lower ANC (median 310/mm³) compared with the untreated group (895/mm³). G-CSF treatment was associated with decreased incidence of hospitalization but no change in total duration of neutropenia, bacterial infections, rejection, or posttransplant lymphoproliferative disease in an adjusted analysis. Recurrence of neutropenia was more common in the G-CSF-treated group, likely related to the short (3.5 h) half-life of the medication.⁸⁴ Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with severe or recurrent infections associated with severe neutropenia.

5 CONCLUSION

Neutropenia is a common complication after SOT related to multiple, often interacting variables. While drug-induced neutropenia is common, a broad differential is necessary. Management of drug-induced neutropenia is a matter of trial and error, reducing various medication doses until ANC improves. Consultation with a pediatric hematologist is warranted, particularly where neutropenia is persistent and/or G-CSF use is being considered. G-CSF appears to be safe in the pediatric solid organ transplant population and may be helpful for those with severe neutropenia complicated by severe or recurrent infections. The clinical and allograft outcomes in this population are mixed and emphasize the need for more detailed longitudinal studies to assess the best management strategies associated with neutropenia after SOT.

CONFLICT OF INTEREST

Authors have no Conflict of Interest to disclose.

Open Research

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

REFERENCES

1Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012; 30: 459-489. doi:10.1146/annurev-immunol-020711-074942
10.1146/annurev-immunol-020711-074942
CAS PubMed Web of Science® Google Scholar
2Frater J, How L. I investigate neutropenia. Int J Lab Hematol. 2020; 42: 121-132.
10.1111/ijlh.13210
PubMed Web of Science® Google Scholar
3 Neutropenia–Hematology and Oncology–Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/hematology-and-oncology/leukopenias/neutropenia
Google Scholar
4 Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Components and Organization CATEGORY. 2006.
Google Scholar
5Palmblad J, Dufour C, Papadaki HA. How we diagnose neutropenia in the adult and elderly patient. Haematologica. 2014; 99: 1130-1133.
10.3324/haematol.2014.110288
PubMed Web of Science® Google Scholar
6Horslen SP, Smith JM, Weaver T, Cafarella M, Foutz J. OPTN/SRTR 2020 annual data report: intestine. Am J Transplant. 2022; 22: 310-349.
10.1111/ajt.16992
PubMed Web of Science® Google Scholar
7Kwong AJ, Ebel NH, Kim WR, et al. OPTN/SRTR 2020 annual data report: liver. Am J Transplant. 2022; 22: 204-309.
10.1111/ajt.16978
PubMed Web of Science® Google Scholar
8Lentine KL, Smith JM, Hart A, et al. OPTN/SRTR 2020 annual data report: kidney. Am J Transplant. 2022; 22: 21-136.
10.1111/ajt.16982
PubMed Web of Science® Google Scholar
9Colvin M, Smith JM, Ahn Y, et al. OPTN/SRTR 2020 annual data report: heart. Am J Transplant. 2022; 22: 350-437.
10.1111/ajt.16977
PubMed Web of Science® Google Scholar
10Valapour M, Lehr CJ, Skeans MA, et al. OPTN/SRTR 2020 annual data report: lung. Am J Transplant. 2022; 22: 438-518.
10.1111/ajt.16991
PubMed Web of Science® Google Scholar
11Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995; 17: 584-591.
10.1097/00007691-199512000-00007
CAS PubMed Web of Science® Google Scholar
12Zucker K, Tsaroucha A, Olson L, Esquenazi V, Tzakis A, Miller J. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit. 1999; 21: 35-43.
10.1097/00007691-199902000-00006
CAS PubMed Web of Science® Google Scholar
13Zafrani L, Truffaut L, Kreis H, et al. Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study. Am J Transplant. 2009; 9: 1816-1825.
10.1111/j.1600-6143.2009.02699.x
CAS PubMed Web of Science® Google Scholar
14Alraddadi B et al. Characteristics and outcomes of neutropenia after orthotopic liver transplantation. Liver Transpl. 2016; 22: 217-225.
10.1002/lt.24332
PubMed Web of Science® Google Scholar
15Lancia P, Aurich B, Ha P, Maisin A, Baudouin V, Jacqz-Aigrain E. Adverse events under tacrolimus and cyclosporine in the first 3 years post-renal transplantation in children. Clin Drug Investig. 2018; 38: 157-171.
10.1007/s40261-017-0594-0
CAS PubMed Web of Science® Google Scholar
16De Rycke A, Dierickx D, Kuypers DR. Tacrolimus-induced neutropenia in renal transplant recipients. Clin J Am Soc Nephrol. 2011; 6: 690-694.
10.2215/CJN.07320810
PubMed Web of Science® Google Scholar
17Amorim J, Costa E, Teixeira A, Rebocho MJ, Loureiro M, Barbot J. Tacrolimus-induced neutropenia in a cardiac transplant patient. Pediatr Transplant. 2014; 18: 120-121.
10.1111/petr.12188
CAS PubMed Web of Science® Google Scholar
18Clément J, Taton B, Merville P, et al. Two cases of tacrolimus-induced neutropenia: a probably under-diagnosed cause of neutropenia after solid-organ transplantation. Clin Transpl. 2018; 32:e13295.
10.1111/ctr.13295
Web of Science® Google Scholar
19Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000; 47: 85-118.
10.1016/S0162-3109(00)00188-0
CAS PubMed Web of Science® Google Scholar
20Von Vietinghoff S, Ouyang H, Ley K. Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production. Kidney Int. 2010; 78: 79-88.
10.1038/ki.2010.84
CAS PubMed Web of Science® Google Scholar
21 fda. CellCept® (mycophenolate mofetil capsules) (mycophenolate mofetil tablets) CellCept® Oral Suspension (mycophenolate mofetil for oral suspension) CellCept® Intravenous (mycophenolate mofetil hydrochloride for injection).
Google Scholar
22Nogueras F, Espinosa MD, Mansilla A, Torres JT, Cabrera MA, Martín-Vivaldi R. Mycophenolate mofetil-induced neutropenia in liver transplantation. Transplant Proc. 2005; 37: 1509-1511.
10.1016/j.transproceed.2005.02.038
CAS PubMed Web of Science® Google Scholar
23Ferrer-Machín A et al. Evaluation of neutropenia secondary to mycophenolate mofetil associated with valganciclovir in liver transplant patients. Farm Hosp. 2021; 45: 77-81.
PubMed Web of Science® Google Scholar
24Bergan S, Brunet M, Hesselink DA, et al. Personalized therapy for mycophenolate: consensus report by the international association of therapeutic drug monitoring and clinical toxicology. Ther Drug Monit. 2021; 43: 150-200.
10.1097/FTD.0000000000000871
CAS PubMed Web of Science® Google Scholar
25Vanhove T, Kuypers D, Claes KJ, et al. Reasons for dose reduction of mycophenolate mofetil during the first year after renal transplantation and its impact on graft outcome. Transpl Int. 2013; 26: 813-821.
10.1111/tri.12133
CAS PubMed Web of Science® Google Scholar
26Brar S et al. Outcomes among CMV-mismatched and highly sensitized kidney transplants recipients who develop neutropenia. Clin Transpl. 2022; 36:e14583.
10.1111/ctr.14583
CAS PubMed Web of Science® Google Scholar
27Wagner M et al. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2015; 12:CD007746.
Google Scholar
28Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007; 217(21): 1387-1394.
10.1038/sj.leu.2404683
Web of Science® Google Scholar
29 A Guide to Neutrophil Markers | Biocompare: The Buyer's Guide for Life Scientists. https://www.biocompare.com/Editorial-Articles/577944-A-Guide-to-Neutrophil-Markers/
Google Scholar
30Hurst FP, Belur P, Nee R, et al. Poor outcomes associated with neutropenia after kidney transplantation: analysis of united states renal data system. Transplantation. 2011; 92: 36-40.
10.1097/TP.0b013e31821c1e70
PubMed Web of Science® Google Scholar
31Büchler M, Ligny BH, Madec C, Lebranchu Y, The French Thymoglobuline Pharmacovigilance Study Group. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transpl. 2003; 17: 539-545.
10.1046/j.1399-0012.2003.00102.x
CAS PubMed Web of Science® Google Scholar
32Jafari A, Najivash P, Khatami M-R, Dashti-Khavidaki S. Cytopenia occurrence in kidney transplant recipients within early post-transplant period. J Res Pharm Pract. 2017; 6: 31.
10.4103/2279-042X.200983
CAS PubMed Web of Science® Google Scholar
33Khalil MAM, Khalil MAU, Khan TFT, Tan J. Drug-induced hematological cytopenia in kidney transplantation and the challenges it poses for kidney transplant physicians. J Transp Secur. 2018; 2018: 1-22.
Google Scholar
34 Highlights of Prescribing Information. These highlights do not include all the information needed to use THYMOGLOBULIN® safely and effectively. See full prescribing information for THYMOGLOBULIN. THYMOGLOBULIN® (anti-thymocyte globulin [rabbit]) for injection, for intravenous use.
Google Scholar
35Mitsuhata N, Fujita R, Ito S, Mannami M, Keimei K. Delayed-onset neutropenia in a patient receiving rituximab as treatment for refractory kidney transplantation. Transplantation. 2005; 80: 1355.
10.1097/01.tp.0000184275.81396.45
PubMed Web of Science® Google Scholar
36Kabei K, Uchida J, Iwai T, et al. Late-onset neutropenia and acute rejection in ABO-incompatible kidney transplant recipients receiving rituximab and mycophenolate mofetil. Transpl Immunol. 2014; 31: 92-97.
10.1016/j.trim.2014.06.001
CAS PubMed Web of Science® Google Scholar
37Ahmadi F et al. Rituximab-related late-onset neutropenia in kidney transplant recipients treated for antibody-mediated acute rejection. Exp Clin Transplant. 2017; 15: 414-419.
PubMed Web of Science® Google Scholar
38Jia C, Jingwen W. Clinical analysis of late-onset neutropenia following rituximab. Advers Drug React J. 2018; 20: 210-215.
Google Scholar
39Principi N, Marchisio P, Biasini A, Villa AD, Biasini G. Early and late neutropenia in children treated with cotrimoxazole (Trimethoprim-Sulfamethoxazole). Acta Paediatr. 1984; 73: 763-767.
10.1111/j.1651-2227.1984.tb17772.x
CAS PubMed Web of Science® Google Scholar
40Asmar BI, Maqbool S, Dajani AS. Hematologic abnormalities after oral trimethoprim-sulfamethoxazole therapy in children. Am J Dis Child. 1981; 135: 1100-1103.
CAS PubMed Web of Science® Google Scholar
41Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007; 146: 657-665.
10.7326/0003-4819-146-9-200705010-00009
PubMed Web of Science® Google Scholar
42St Claire K, Kaul S, Caldito EG, Kramer ON, Griffin T, Albrecht J. Dapsone-induced agranulocytosis: symptoms may alert more reliably than the current blood monitoring protocol. Br J Dermatol. 2021; 184: 962-963.
10.1111/bjd.19708
CAS PubMed Web of Science® Google Scholar
43Billat P-A, Woillard JB, Essig M, et al. Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity? J Antimicrob Chemother. 2016; 71: 484-489.
10.1093/jac/dkv342
CAS PubMed Web of Science® Google Scholar
44Billat P-A, Ossman T, Saint-Marcoux F, et al. Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients. Pharmacol Res. 2016; 111: 501-508.
10.1016/j.phrs.2016.07.012
CAS PubMed Web of Science® Google Scholar
45Otokubo M, Wada K, Ikura M, et al. Risk assessment of neutropenia during low-dose valganciclovir prophylaxis for heart transplant recipients. Biol Pharm Bull. 2022; 45: 452-459.
10.1248/bpb.b21-00860
CAS PubMed Web of Science® Google Scholar
46Molina Perez E, Fernández Castroagudín J, Seijo Ríos S, et al. Valganciclovir-induced leukopenia in liver transplant recipients: influence of concomitant use of mycophenolate mofetil. Transplant Proc. 2009; 41: 1047-1049.
10.1016/j.transproceed.2009.02.033
CAS PubMed Web of Science® Google Scholar
47Padullés A, Colom H, Bestard O, et al. Contribution of population pharmacokinetics to dose optimization of ganciclovir-valganciclovir in solid-organ transplant patients. Antimicrob Agents Chemother. 2016; 60: 1992-2002.
10.1128/AAC.02130-15
CAS PubMed Web of Science® Google Scholar
48Brum S, Nolasco F, Sousa J, et al. Leukopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil. Transplant Proc. 2008; 40: 752-754.
10.1016/j.transproceed.2008.02.048
CAS PubMed Web of Science® Google Scholar
49 Valganciclovir: Drug information–UpToDate. https://www.uptodate.com/contents/valganciclovir-drug-information?search=valganciclovir&source=panel_search_result&selectedTitle=1~55&usage_type=panel&kp_tab=drug_general&display_rank=1
Google Scholar
50Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients—Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl. 2019; 33:e13512.
10.1111/ctr.13512
PubMed Web of Science® Google Scholar
51Segel GB, Halterman JS. Neutropenia in pediatric practice. Pediatr Rev. 2008; 29: 12-24.
10.1542/pir.29-1-12
PubMed Web of Science® Google Scholar
52Allen UD, Preiksaitis JK. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl. 2019; 33:e13652.
10.1111/ctr.13652
PubMed Web of Science® Google Scholar
53Hammond WP, Harlan JM, Steinberg SE. Severe Neutropenia in Infectious Mononucleosis. West J Med. 1979; 131(2): 92-97.
CAS PubMed Google Scholar
54Hyun H, Park E, Cho M, et al. Post-transplant lymphoproliferative diseases in pediatric kidney allograft recipients with epstein-barr virus viremia. J Korean Med Sci. 2019; 34:e203.
10.3346/jkms.2019.34.e203
CAS PubMed Web of Science® Google Scholar
55Hadou T, André JL, Bourquard R, Krier-Coudert MJ, Venard V, le Faou A. Long-term follow-up of Epstein-Barr virus viremia in pediatric recipients of renal transplants. Pediatr Nephrol. 2005; 20: 76-80.
10.1007/s00467-004-1701-z
PubMed Web of Science® Google Scholar
56Jarasvaraparn C et al. Characteristics, risk factors, and outcomes of neutropenia after liver or kidney transplantation in children. Pediatr Transplant. 2022; 26:e14131.
10.1111/petr.14131
CAS PubMed Web of Science® Google Scholar
57Chow JKL et al. Factors associated with neutropenia post heart transplantation. Transpl Infect Dis. 2021; 23:e13634.
10.1111/tid.13634
PubMed Web of Science® Google Scholar
58Mavrakanas TA, Fournier MA, Clairoux S, et al. Neutropenia in kidney and liver transplant recipients: risk factors and outcomes. Clin Transpl. 2017; 31. Online ahead of print.
10.1111/ctr.13058
Web of Science® Google Scholar
59Schoettler M, Elisofon SA, Kim HB, et al. Treatment and outcomes of immune cytopenias following solid organ transplant in children. Pediatr Blood Cancer. 2015; 62: 214-218.
10.1002/pbc.25215
PubMed Web of Science® Google Scholar
60Rose-Felker K, Mukhtar A, Kelleman MS, Deshpande SR, Mahle WT. Neutropenia in pediatric heart transplant recipients. Pediatr Transplant. 2018; 22:e13130.
10.1111/petr.13130
PubMed Web of Science® Google Scholar
61Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood. 1998; 91: 181-186.
10.1182/blood.V91.1.181
CAS PubMed Web of Science® Google Scholar
62Ozdemir ZC, Kar YD, Kasaci B, Bor O. Etiological causes and prognosis in children with neutropenia. North Clin Istanbul. 2021; 8: 236.
PubMed Web of Science® Google Scholar
63Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood. 2014; 124: 1251-1258.
10.1182/blood-2014-02-482612
CAS PubMed Web of Science® Google Scholar
64Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007; 146: 486-492.
10.7326/0003-4819-146-7-200704030-00004
PubMed Web of Science® Google Scholar
65Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol. 1988; 41: 273-277.
10.1111/j.1600-0609.1988.tb01192.x
CAS PubMed Web of Science® Google Scholar
66Mason BA, Lessin L, Schechter GP. Marrow granulocyte reserves in black Americans. hydrocortisone-induced granulocytosis in the ‘benign’ neutropenia of the black. Am J Med. 1979; 67: 201-205.
10.1016/0002-9343(79)90391-7
CAS PubMed Web of Science® Google Scholar
67Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J. The outcome of bacterial infection in subjects with benign familial leukopenia (BFL). Biomed Pharmacother. 1985; 39: 23-26.
CAS PubMed Web of Science® Google Scholar
68Nalls MA, Wilson JG, Patterson NJ, et al. Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. Am J Hum Genet. 2008; 82: 81-87.
10.1016/j.ajhg.2007.09.003
CAS PubMed Web of Science® Google Scholar
69Rappoport N, Simon AJ, Amariglio N, Rechavi G. The Duffy antigen receptor for chemokines, ACKR1,- ‘Jeanne DARC’ of benign neutropenia. Br J Haematol. 2019; 184: 497-507.
10.1111/bjh.15730
CAS PubMed Web of Science® Google Scholar
70Grann VR, Ziv E, Joseph CK, et al. Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean. Br J Haematol. 2008; 143: 288-293.
10.1111/j.1365-2141.2008.07335.x
CAS PubMed Web of Science® Google Scholar
71Tigue CC et al. Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the research on adverse drug events and reports project. Bone Marrow Transplant. 2007; 403(40): 185-192.
10.1038/sj.bmt.1705722
Web of Science® Google Scholar
72Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007; 49: 609-614.
10.1002/pbc.21282
PubMed Web of Science® Google Scholar
73Tague LK, Scozzi D, Wallendorf M, et al. Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony-stimulating factor treatment. Am J Transplant. 2020; 20: 250-261.
10.1111/ajt.15581
CAS PubMed Web of Science® Google Scholar
74Dube GK, Morris HK, Crew RJ, et al. Febrile neutropenia after kidney transplantation. Am J Transplant. 2021; 21: 3436-3443.
10.1111/ajt.16714
CAS PubMed Web of Science® Google Scholar
75Becker-Cohen R, Ben-Shalom E, Rinat C, Feinstein S, Geylis M, Frishberg Y. Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor. Pediatr Nephrol. 2015; 30: 2029-2036.
10.1007/s00467-015-3113-7
PubMed Web of Science® Google Scholar
76Fioredda F, Calvillo M, Bonanomi S, et al. Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Am J Hematol. 2012; 87: 238-243.
10.1002/ajh.22242
PubMed Web of Science® Google Scholar
77Nguyen AB, Lourenço L, Chung BB, et al. Increase in short-term risk of rejection in heart transplant patients receiving granulocyte colony-stimulating factor. J Heart Lung Transplant. 2018; 37: 1322-1328.
10.1016/j.healun.2018.06.009
PubMed Web of Science® Google Scholar
78Robinson PD, Lehrnbecher T, Phillips R, Lee Dupuis L, Sung L. Strategies for empiric management of pediatric fever and neutropenia in patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic review of randomized trials. J Clin Oncol. 2016; 34: 2054-2060.
10.1200/JCO.2015.65.8591
CAS PubMed Web of Science® Google Scholar
79Turgeon N, Hovingh GK, Fishman JA, et al. Safety and efficacy of granulocyte colony-stimulating factor in kidney and liver transplant recipients. Transpl Infect Dis. 2000; 2: 15-21.
10.1034/j.1399-3062.2000.020104.x
CAS PubMed Google Scholar
80Peddi VR, Hariharan S, Schroeder TJ, First MR. Role of granulocyte colony stimulating factor (G-CSF) in reversing neutropenia in renal allograft recipients. Clin Transpl. 1996; 10: 20-23.
CAS PubMed Web of Science® Google Scholar
81Hamel S et al. Single-center, real-world experience with granulocyte colony-stimulating factor for management of leukopenia following kidney transplantation. Clin Transpl. 2019; 33:e13541.
10.1111/ctr.13541
PubMed Web of Science® Google Scholar
82Schneider J, Henningsen M, Pisarski P, Walz G, Jänigen B. Impact of G-CSF Therapy on Leukopenia and Acute Rejection Following Kidney Transplantation. Int J Organ Transplant Med. 2021; 12: 1-8.
CAS PubMed Google Scholar
83Winston DJ, Foster PF, Somberg KA, et al. Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients. Transplantation. 1999; 68: 1298-1304.
10.1097/00007890-199911150-00014
CAS PubMed Web of Science® Google Scholar
84Engen RM et al. Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: a pediatric nephrology research consortium study. Pediatr Transplant. 2022; 26:e14202.
10.1111/petr.14202
CAS PubMed Web of Science® Google Scholar
85Ho S, Ly P, Riesgo-Gil F, et al. Incidence and risk factors for neutropenia in adult heart transplant recipients: single centre experience. J Heart Lung Transplant. 2020; 39:S503.
10.1016/j.healun.2020.01.104
Google Scholar
86Smith A, Couvillion R, Zhang R, et al. Incidence and management of leukopenia/neutropenia in 233 kidney transplant patients following single dose alemtuzumab induction. Transplant Proc. 2014; 46: 3400-3404.
10.1016/j.transproceed.2014.07.070
CAS PubMed Web of Science® Google Scholar
87Ingold L et al. Short- and long-term impact of neutropenia within the first year after kidney transplantation. Transpl Int. 2021; 34: 1875-1885.
10.1111/tri.13976
CAS PubMed Web of Science® Google Scholar

Volume26, Issue8

Special Issue:CLINICAL APPROACH TO PRACTICE VARIATION IN PEDIATRIC HEART TRANSPLANTATION

December 2022

e14378

Neutropenia in pediatric solid organ transplant