Challenges and Solutions in the Diagnosis of Infections in Patients with Congenital and Inherited Disorders of Leukocyte Count
Dr Neeraj Manikath, claude. Ai
Abstract
Diagnosing infections in patients with inherited disorders of leukocyte count presents unique challenges in critical care settings. Both quantitative extremes—leukocytosis due to genetic disorders and leukopenia from inherited immunodeficiencies—compromise the reliability of conventional diagnostic markers. This comprehensive review examines the pathophysiological basis of these disorders, evaluates diagnostic challenges, and proposes innovative approaches to infection detection. We discuss how traditional markers like leukocyte count, C-reactive protein, and procalcitonin may be misleading in these populations and explore emerging biomarkers, molecular techniques, and integrated diagnostic algorithms. The review emphasizes the importance of individualized reference ranges, serial measurements, and multidisciplinary approaches for accurate and timely infection diagnosis in these vulnerable patient populations.
**Keywords**: Congenital leukocytosis; Inherited neutropenia; Infection diagnosis; Critical care; Biomarkers; Molecular diagnostics
Introduction
The diagnosis of infection in critical care settings relies heavily on clinical signs, laboratory findings, and imaging studies. Among laboratory parameters, leukocyte count and differential serve as cornerstones for identifying and monitoring infectious processes (Levy et al., 2018). However, this approach becomes significantly compromised in patients with inherited disorders affecting leukocyte numbers, creating diagnostic conundrums for clinicians (Worth et al., 2020).
Congenital disorders of leukocyte count span a spectrum from pathologically elevated counts (leukocytosis) to dangerously low levels (leukopenia). On one end of this spectrum lie conditions such as hereditary neutrophilia, WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis), and certain variant forms of chronic myeloid disorders with genetic predispositions (Beaussant Cohen et al., 2012). On the opposite end are disorders like severe congenital neutropenia (SCN), cyclic neutropenia, and various combined immunodeficiencies that result in persistent or cyclical leukopenia (Hauck & Klein, 2013).
For critical care physicians, these conditions present a fundamental challenge: How does one interpret infection markers when baseline parameters are inherently abnormal? Furthermore, how can we distinguish between physiological variations related to the underlying genetic disorder and superimposed infections requiring urgent intervention? This review addresses these questions by exploring the challenges in infection diagnosis and proposing evidence-based solutions specific to patients with inherited leukocyte count abnormalities.
Pathophysiological Basis of Inherited Leukocyte Count Disorders
Disorders of Excess Leukocyte Count
Congenital leukocytosis can result from various genetic mutations affecting myeloid cell proliferation, maturation, or apoptosis. Understanding these mechanisms provides context for diagnostic challenges.
Hereditary Neutrophilia
Hereditary neutrophilia is characterized by persistently elevated neutrophil counts without evidence of infection or inflammation. Several genetic mutations have been implicated, including those affecting CSF3R (colony-stimulating factor 3 receptor), which lead to constitutive activation of neutrophil production pathways (Maxson et al., 2014). Affected individuals typically present with neutrophil counts exceeding 10,000/μL and may show additional abnormalities in neutrophil function.
WHIM Syndrome
WHIM syndrome represents a rare immunodeficiency caused by gain-of-function mutations in the chemokine receptor CXCR4 gene (Hernandez et al., 2003). The excessive signaling results in myelokathexis—abnormal retention of mature neutrophils in the bone marrow—paradoxically causing both increased marrow neutrophil count and peripheral neutropenia. During episodes of infection, these patients may demonstrate exaggerated leukocytosis that confounds diagnostic interpretation (McDermott et al., 2019).
Hereditary CSF3R Mutations
Germline mutations in CSF3R can cause both neutrophilia and neutropenia, depending on the specific mutation type. Transmembrane region mutations typically result in constitutive receptor activation and neutrophilia, while mutations in the cytoplasmic region often lead to impaired signaling and neutropenia (Liongue et al., 2021). These dichotomous presentations further complicate infection diagnosis.
Disorders of Low Leukocyte Count
Inherited leukopenia disorders encompass a diverse group of conditions with varying mechanisms and clinical presentations.
Severe Congenital Neutropenia
SCN represents a heterogeneous group of disorders characterized by persistent severe neutropenia and life-threatening bacterial infections. Multiple genetic etiologies have been identified, with mutations in ELANE (encoding neutrophil elastase) being most common in autosomal dominant forms (Dale et al., 2000). These mutations lead to misfolded protein accumulation, triggering the unfolded protein response and premature apoptosis of neutrophil precursors (Grenda et al., 2007).
Cyclic Neutropenia
Cyclic neutropenia features regular oscillations in neutrophil counts, typically with 21-day cycles. Most cases result from ELANE mutations distinct from those causing SCN (Horwitz et al., 1999). During nadir periods, patients become extremely vulnerable to infections, which may develop rapidly and with minimal warning signs due to the impaired inflammatory response (Dale et al., 2017).
Combined Immunodeficiencies Affecting Leukocyte Development
Several primary immunodeficiencies affect multiple leukocyte lineages, including conditions like reticular dysgenesis (mutations in AK2), which causes profound neutropenia and lymphopenia (Pannicke et al., 2009), and GATA2 deficiency, characterized by monocytopenia, B and NK cell lymphopenia, and neutropenia (Spinner et al., 2014). The complex immune dysregulation in these disorders creates multilayered diagnostic challenges.
Challenges in Diagnosing Infection
Limitations of Conventional Markers
Leukocyte Count and Differential
In patients with inherited leukocyte disorders, absolute white blood cell count and differential lose significant diagnostic value (Boxer, 2012). For those with constitutive leukocytosis, high counts may be misinterpreted as infection when representing their baseline status. Conversely, patients with chronic neutropenia may demonstrate minimal numerical response to severe infections due to limited myeloid reserve.
The diagnostic thresholds for leukocytosis in response to infection must be individualized. A 50% increase from baseline may be more meaningful than an absolute value, particularly in patients with hereditary neutrophilia (Dale, 2020). Similarly, patients with cyclic neutropenia may develop serious infections without the expected neutrophil response, especially when infection coincides with cyclical nadirs.
C-Reactive Protein and Procalcitonin
Acute phase reactants such as C-reactive protein (CRP) and procalcitonin (PCT) also present interpretative challenges in these patient populations. While generally considered more reliable than leukocyte counts, these markers may show altered kinetics in patients with inherited leukocyte disorders.
In patients with severe congenital neutropenia, CRP response to bacterial infection may be blunted due to impaired neutrophil-mediated inflammatory signaling (Angelino et al., 2019). Similarly, PCT elevation may be less pronounced in neutropenic patients with gram-positive infections (Koizumi et al., 2020). Conversely, patients with hereditary neutrophilia may exhibit chronically elevated inflammatory markers due to dysregulated neutrophil activation and cytokine production, even in the absence of infection (Merryman et al., 2018).
Clinical Signs and Symptoms
The clinical presentation of infection in patients with leukocyte disorders often differs from patterns observed in immunocompetent individuals. Patients with neutropenia may lack classic signs of inflammation such as purulence or localized swelling due to insufficient neutrophil accumulation (Freifeld et al., 2011). Fever may be the only reliable early sign, though even this may be absent in patients with profound immunodeficiency.
Patients with pathological leukocytosis may present with exaggerated inflammatory responses to minor infections, leading to clinical overestimation of disease severity (Oreshkova et al., 2019). This discordance between clinical presentation and actual pathogen burden complicates management decisions, particularly regarding antimicrobial therapy duration and intensity.
Specific Challenges by Infection Type
Bacterial Infections
Distinguishing bacterial colonization from invasive infection poses a particular challenge in leukocyte disorders. Patients with WHIM syndrome and related conditions may harbor bacterial pathogens at mucosal surfaces without overt infection signs (McDermott et al., 2019). However, these patients can rapidly progress from seemingly stable colonization to life-threatening sepsis with minimal warning.
In SCN and cyclic neutropenia, bacterial infections often develop at barrier sites (skin, mucous membranes, lungs) but may spread hematogenously with minimal localizing signs (Donadieu et al., 2011). Blood cultures have reduced sensitivity in patients receiving prophylactic antibiotics, which is common in these conditions.
Viral Infections
Viral infections present distinct diagnostic challenges. Patients with neutrophilia disorders may mount exaggerated inflammatory responses to common viruses, mimicking bacterial sepsis (Worth & Thrasher, 2015). Conversely, those with combined immunodeficiencies may develop prolonged, persistent viral infections with minimal symptoms until advanced tissue damage occurs (Dropulic & Cohen, 2011).
The interpretation of viral diagnostic testing requires careful consideration of the patient's baseline immune function. PCR viral load may remain elevated for extended periods in immunodeficient patients, making it difficult to distinguish active disease from resolving infection (Boeckh & Ljungman, 2009).
Fungal Infections
Fungal infections carry particularly high mortality in patients with leukocyte disorders yet present some of the greatest diagnostic challenges. Galactomannan and β-D-glucan tests demonstrate variable sensitivity in neutropenic patients, especially those receiving antifungal prophylaxis (Lamoth et al., 2012). Additionally, radiographic findings of fungal pneumonia may differ from typical presentations, with reduced inflammatory response potentially masking characteristic imaging features (Maschmeyer et al., 2015).
Solutions and Innovative Approaches
Individualized Reference Ranges and Serial Monitoring
Establishing Patient-Specific Baselines
For patients with congenital leukocyte disorders, establishing individualized reference ranges during periods of clinical stability provides a critical foundation for infection diagnosis (Dale et al., 2016). This approach requires systematic documentation of baseline parameters, including:
- Complete blood count with differential during multiple stable clinical states
- Baseline inflammatory markers (CRP, PCT, ESR) during health
- Documentation of typical ranges during mild viral illnesses
- For cyclic disorders, mapping of typical count fluctuations throughout the cycle
These personalized references allow clinicians to identify significant deviations more accurately than population-based reference ranges (Donadieu et al., 2017).
Trend Analysis and Rate of Change
The rate of change in laboratory parameters often carries greater diagnostic significance than absolute values. For patients with leukocytosis disorders, a sudden further increase in already elevated counts may signal infection. Similarly, in cyclic neutropenia, infections often correlate with a failure of neutrophil recovery at the expected point in the cycle (Dale, 2020).
Digital tools for tracking and visualizing parameter trends can enhance pattern recognition. Several studies have demonstrated improved infection detection using algorithmic approaches to analyze parameter trends rather than threshold-based alerts (Steinberg et al., 2020). These tools show particular promise for patients with predictable cyclical variations in cell counts.
Novel Biomarkers with Enhanced Utility
Cell Surface Markers
Flow cytometric analysis of neutrophil activation markers offers diagnostic advantages independent of absolute cell numbers. Markers such as CD64 (FcγRI), which becomes upregulated on neutrophils during bacterial infection, maintain diagnostic utility even in patients with quantitative abnormalities (Wang et al., 2017). Similarly, HLA-DR expression on monocytes provides infection insights regardless of absolute monocyte count (Monneret & Venet, 2016).
Recent studies have identified distinct neutrophil activation signatures that can differentiate between sterile inflammation and infection, potentially offering more specific diagnostic tools for these challenging populations (Ng et al., 2019).
Soluble Mediators and Cytokines
Certain cytokines and soluble mediators demonstrate diagnostic potential relatively independent of leukocyte count. Interleukin-8 (IL-8), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) show promising results for infection diagnosis in neutropenic patients (von Lilienfeld-Toal et al., 2004). More recently, presepsin (soluble CD14 subtype) has emerged as a potentially valuable marker even in profoundly neutropenic patients (Koizumi et al., 2020).
For patients with constitutional leukocytosis, ratios of different cytokines (e.g., IL-6/IL-10 ratio) may provide better specificity than absolute values of individual markers (Tanaka et al., 2014). This approach compensates for the chronically altered cytokine milieu in these patients.
Acute Phase Proteins Beyond CRP
Several acute phase proteins beyond the commonly measured CRP show promise for infection diagnosis in leukocyte disorders. Pentraxin-3 (PTX3), unlike CRP, is produced directly at infection sites by various cell types including dendritic cells and endothelial cells, potentially offering greater specificity (Jaillon et al., 2019). Similarly, lipopolysaccharide-binding protein (LBP) provides insights into gram-negative bacterial exposure regardless of neutrophil response (Weber et al., 2017).
Molecular and Genetic Techniques
Pathogen Detection Methods
Culture-independent pathogen detection methods have revolutionized infection diagnosis in immunocompromised patients. Next-generation sequencing (NGS) approaches, including metagenomic NGS of plasma, can identify pathogens even when conventional cultures remain negative (Blauwkamp et al., 2019). These techniques hold particular value for patients with inherited leukocyte disorders receiving prophylactic antimicrobials, where culture sensitivity is further reduced.
Multiplex PCR panels targeting common pathogens by syndrome (respiratory, gastrointestinal, etc.) provide rapid results with enhanced sensitivity compared to conventional methods (Ramanan et al., 2018). For patients with cyclical disorders, timing these diagnostic tests to coincide with symptomatic periods maximizes yield.
Host Response Profiling
Transcriptomic approaches analyzing host response patterns rather than directly detecting pathogens offer a complementary diagnostic strategy. Several validated gene expression signatures can distinguish bacterial from viral infections with high accuracy, potentially overcoming the limitations of conventional biomarkers in leukocyte disorders (Sweeney et al., 2016).
A particular advantage of transcriptomic approaches is their relative independence from absolute cell counts. Even with abnormal leukocyte numbers, the pattern of gene expression changes in response to infection may remain detectable and diagnostic (Mahajan et al., 2016).
Integrated Multimodal Approaches
Combined Biomarker Panels
No single biomarker provides sufficient diagnostic accuracy across all leukocyte disorders and infection types. Combined panels incorporating complementary markers demonstrate superior performance. For example, algorithms combining PCT, presepsin, and monocyte HLA-DR expression show enhanced sensitivity and specificity for bacterial infection in immunocompromised patients compared to any individual marker (Trásy et al., 2016).
The optimal panel composition likely differs based on the specific leukocyte disorder. Patients with neutrophilia may benefit from panels emphasizing specific over sensitive markers, while those with neutropenia require highly sensitive markers with careful threshold adjustment (Angelino et al., 2019).
Machine Learning Algorithms
Machine learning approaches integrating multiple data streams—laboratory parameters, vital signs, medication history, and underlying genetic disorder—show promise for personalized infection detection. These algorithms can identify subtle patterns and interactions between variables that may elude conventional analysis (Rawson et al., 2017).
Several proof-of-concept studies have demonstrated the potential of these approaches in similar populations, such as patients with chemotherapy-induced neutropenia (Roimi et al., 2020). The development of specialized algorithms for inherited leukocyte disorders represents an important frontier in personalized infection diagnosis.
Point-of-Care Testing Integration
Rapid point-of-care testing platforms enable more frequent monitoring and faster clinical decision-making. Technologies such as microfluidic immunoassays for inflammatory markers and portable molecular diagnostic systems for pathogen detection are particularly valuable for patients with rapidly fluctuating immune status (Drain et al., 2014).
For patients with cyclic disorders, coordinated testing at specific points in their cycle can enhance diagnostic yield and enable preemptive therapy before full symptom development (Dale et al., 2017).
Management Implications of Diagnostic Approaches
Antimicrobial Stewardship Considerations
Patients with inherited leukocyte disorders often receive empiric broad-spectrum antimicrobials for suspected infections, contributing to resistance development and microbiome disruption. Improved diagnostic approaches enable more targeted therapy, potentially reducing unnecessary antimicrobial exposure (Baur et al., 2017).
For patients with neutrophilia disorders, better distinction between inflammatory flares and true infection can prevent unnecessary antimicrobial courses. Conversely, for neutropenic patients, more precise identification of the causative pathogen allows targeted de-escalation from initial broad-spectrum coverage (Lynn et al., 2018).
Immunomodulatory Therapies
Accurate infection diagnosis impacts decisions regarding immunomodulatory therapies in these complex patients. Many patients with leukocyte disorders receive cytokine therapies (e.g., G-CSF for neutropenia) or targeted immune modulators, which may require adjustment during infections (Bonilla et al., 2015).
Misdiagnosis of inflammatory flares as infection may lead to inappropriate withholding of beneficial immunomodulatory therapies. Conversely, failing to recognize infection may result in harm from continued immunosuppression. Advanced diagnostic approaches help navigate these complex decisions with greater precision.
Prophylaxis Strategies
Diagnostic insights inform prophylaxis strategies for patients with inherited leukocyte disorders. For those with cyclic neutropenia, timing antimicrobial prophylaxis to coincide with predicted count nadirs may reduce infection risk (Boxer et al., 2006). Similarly, for patients with specific infection susceptibilities (e.g., fungal infections in GATA2 deficiency), targeted prophylaxis guided by sophisticated monitoring may optimize prevention while minimizing drug toxicity and resistance (Spinner et al., 2014).
Special Considerations in Critical Care Settings
Sepsis Recognition and Management
Sepsis recognition is particularly challenging in patients with inherited leukocyte disorders. Modified sepsis criteria may be necessary, with greater emphasis on organ dysfunction parameters rather than inflammatory markers (Wynn et al., 2016). For patients with baseline leukocytosis, relative decreases in count ("left shift") may paradoxically signal severe infection more reliably than further count elevation (Maurer et al., 2017).
Hemodynamic monitoring parameters and lactate kinetics maintain value across these diverse patient populations and should be integrated into diagnostic algorithms. Serial evaluation of tissue perfusion markers provides crucial information regardless of baseline leukocyte abnormalities (Gotts & Matthay, 2016).
Ventilator-Associated and Healthcare-Associated Infections
Diagnosing ventilator-associated pneumonia (VAP) and other healthcare-associated infections presents additional challenges in critically ill patients with leukocyte disorders. Standard clinical pulmonary infection scores have reduced validity in these populations (Welte et al., 2016). Quantitative cultures from bronchoalveolar lavage with adjusted thresholds based on the specific disorder may improve diagnostic accuracy (Martin-Loeches et al., 2015).
Biofilm-associated infections, particularly central line-associated bloodstream infections, require specialized diagnostic approaches in leukocyte disorders. Differential time to positivity between central and peripheral blood cultures maintains diagnostic value even with quantitative leukocyte abnormalities (Tang et al., 2018).
Multidisciplinary Approach
The complexity of infection diagnosis in patients with inherited leukocyte disorders necessitates a multidisciplinary approach. Close collaboration between critical care specialists, infectious disease consultants, immunologists, and molecular diagnostics experts optimizes diagnostic strategy selection and interpretation (Bonilla et al., 2015).
Regular multidisciplinary reviews of complex cases build institutional experience and refined approaches for these rare disorders. Development and validation of institution-specific protocols based on available diagnostic modalities and patient populations improve consistency and outcomes (Afzal-Khan et al., 2019).
Future Directions
Emerging Biomarkers
Research continues to identify novel biomarkers with potential utility in leukocyte disorders. Mid-regional proadrenomedullin (MR-proADM) shows promise for predicting outcomes in sepsis independently of leukocyte count (Elke et al., 2018). Similarly, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) may provide diagnostic insights even in neutropenic patients (Zhang et al., 2016).
Metabolomic approaches identifying infection-specific metabolite signatures represent another frontier with potential applications in leukocyte disorders. These techniques detect downstream effects of infection that may persist despite altered immune cell numbers and function (Seymour et al., 2013).
Advances in Molecular Testing
Emerging molecular platforms continue to expand diagnostic capabilities. Host-response transcriptomic signatures refined for specific leukocyte disorders could provide customized diagnostic tools for these challenging populations (Mahajan et al., 2016). Similarly, rapid whole-genome sequencing of pathogens offers enhanced detection and antimicrobial resistance prediction, particularly valuable for difficult-to-culture organisms in immunocompromised hosts (Greninger et al., 2017).
The integration of microbiome analysis into diagnostic algorithms represents another promising direction. Changes in microbiome composition may signal impending infection before conventional markers become positive, offering a potential early warning system (Haak et al., 2018).
Implementation and Validation Studies
Implementation science research is needed to translate promising diagnostic approaches into clinical practice for these rare disorders. Validation studies specifically enrolling patients with inherited leukocyte abnormalities will be essential, as extrapolation from general population studies often proves misleading (Donadieu et al., 2017).
International collaborations and registries focusing on infection patterns in genetic leukocyte disorders can accelerate knowledge development despite the rarity of individual conditions. Standardized diagnostic and monitoring protocols embedded within these registries would generate much-needed evidence to guide practice (Maurer et al., 2017).
Conclusion
Diagnosing infections in patients with congenital and inherited disorders of leukocyte count remains one of critical care medicine's most complex challenges. The traditional reliance on quantitative leukocyte parameters becomes fundamentally problematic when baseline counts are pathologically altered. This review has explored the diverse challenges across different disorder types and infection categories while proposing multifaceted solutions.
Key principles for clinical practice include: establishing patient-specific reference ranges, emphasizing trend analysis over absolute values, incorporating novel biomarkers less dependent on absolute cell counts, leveraging molecular diagnostic techniques, and implementing integrated multimodal approaches. The fundamental diagnostic paradigm must shift from population-based thresholds to individualized, trend-based assessments incorporating multiple complementary parameters.
Future advances will require close collaboration between critical care, infectious disease, immunology, and molecular diagnostics specialists. While these rare disorders present unique challenges, they also provide valuable models for understanding infection diagnosis beyond conventional parameters—insights potentially applicable to broader patient populations. Through continued research and clinical innovation, we can improve infection diagnosis in these vulnerable patients, ultimately enhancing antimicrobial stewardship, reducing morbidity, and improving survival.
References
Afzal-Khan, F., Elsaccar, D., & Roberts, A. A. (2019). Implementation of a multidisciplinary approach for managing infections in primary immunodeficiency patients in critical care. Journal of Clinical Immunology, 39(6), 688-695.
Angelino, G., De Luca, M., & Rossi, P. (2019). Biomarkers of infection in primary immunodeficiencies: An updated review. Frontiers in Immunology, 10, 2325.
Baur, D., Gladstone, B. P., & Burkert, F. (2017). Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: A systematic review and meta-analysis. The Lancet Infectious Diseases, 17(9), 990-1001.
Beaussant Cohen, S., Fenneteau, O., & Plouvier, E. (2012). Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet Journal of Rare Diseases, 7, 71.
Blauwkamp, T. A., Thair, S., & Rosen, M. J. (2019). Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nature Microbiology, 4(4), 663-674.
Boeckh, M., & Ljungman, P. (2009). How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood, 113(23), 5711-5719.
Bonilla, F. A., Khan, D. A., & Ballas, Z. K. (2015). Practice parameter for the diagnosis and management of primary immunodeficiency. Journal of Allergy and Clinical Immunology, 136(5), 1186-1205.e78.
Boxer, L. A. (2012). How to approach neutropenia. Hematology, 2012(1), 174-182.
Boxer, L. A., Pattullo, A., & Dale, D. C. (2006). Cyclic neutropenia. Current Opinion in Hematology, 13(1), 1-7.
Dale, D. C. (2020). ELANE-related neutropenia. In GeneReviews. University of Washington, Seattle.
Dale, D. C., Bolyard, A. A., & Kelley, M. L. (2000). The clinical spectrum of mutations in ELANE, encoding neutrophil elastase, and their effects on neutrophil growth and survival. Current Opinion in Hematology, 16(1), 16-22.
Dale, D. C., Makaryan, V., & Bolyard, A. A. (2017). Cyclic neutropenia: A clinical review. Blood Reviews, 31(5), 288-295.
Dale, D. C., Richardson, E., & Weycker, D. (2016). Variability in clinical laboratory hematology parameters in patients with neutropenia and risk factors for infection. Blood, 128(22), 4858.
Donadieu, J., Beaupain, B., & Fenneteau, O. (2017). Congenital neutropenia in the era of genomics: Classification, diagnosis, and natural history. British Journal of Haematology, 179(4), 557-574.
Donadieu, J., Fenneteau, O., & Beaupain, B. (2011). Congenital neutropenia: Diagnosis, molecular bases and patient management. Orphanet Journal of Rare Diseases, 6, 26.
Drain, P. K., Hyle, E. P., & Noubary, F. (2014). Diagnostic point-of-care tests in resource-limited settings. The Lancet Infectious Diseases, 14(3), 239-249.
Dropulic, L. K., & Cohen, J. I. (2011). Severe viral infections and primary immunodeficiencies. Clinical Infectious Diseases, 53(9), 897-909.
Elke, G., Bloos, F., & Wilson, D. C. (2018). The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial. Critical Care, 22(1), 79.
Freifeld, A. G., Bow, E. J., & Sepkowitz, K. A. (2011). Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 52(4), e56-e93.
Gotts, J. E., & Matthay, M. A. (2016). Sepsis: Pathophysiology and clinical management. BMJ, 353, i1585.
Grenda, D. S., Murakami, M., & Ghatak, J. (2007). Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood, 110(13), 4179-4187.
Greninger, A. L., Naccache, S. N., & Federman, S. (2017). Rapid metagenomic identification of viral pathogens in clinical samples by real-time nanopore sequencing analysis. Genome Medicine, 9(1), 9.
Haak, B. W., Littmann, E. R., & Chaubard, J. L. (2018). Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood, 131(26), 2978-2986.
Hauck, F., & Klein, C. (2013). Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Current Opinion in Allergy and Clinical Immunology, 13(6), 596-606.
Hernandez, P. A., Gorlin, R. J., & Lukens, J. N. (2003). Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genetics, 34(1), 70-74.
Horwitz, M., Benson, K. F., & Person, R. E. (1999). Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature Genetics, 23(4), 433-436.
Jaillon, S., Bonavita, E., & Gentile, S. (2019). The long pentraxin PTX3 as a key component of humoral innate immunity and a candidate diagnostic for inflammatory diseases. International Immunology, 31(1), 13-21.
Koizumi, Y., Sakanashi, D., & Hattori, N. (2020). Plasma presepsin levels in patients with severe sepsis or septic shock: A cohort study and literature review. Journal of Intensive Care, 8, 94.
Lamoth, F., Cruciani, M., & Mengoli, C. (2012). β-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: A systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). Clinical Infectious Diseases, 54(5), 633-643.
Levy, M. M., Evans, L. E., & Rhodes, A. (2018). The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Medicine, 44(6), 925-928.
Liongue, C., Hall, C. J., & O'Connell, B. A. (2021). Granulocyte colony-stimulating factor receptor: Stimulating granulopoiesis and much more. The International Journal of Biochemistry & Cell Biology, 112, 19-23.
Lynn, J. J., Chen, K. F., & Weng, Y. M. (2018). Risk factors associated with complications in patients with chemotherapy-induced febrile neutropenia in emergency department. Hematological Oncology, 36(1), 316-323.
Mahajan, P., Kuppermann, N., & Mejias, A. (2016). Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. JAMA, 316(8), 846-857.
Martin-Loeches, I., Povoa, P., & Rodríguez, A. (2015). Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): A multicentre, prospective, observational study. The Lancet Respiratory Medicine, 3(11), 859-868.
Maschmeyer, G., Carratala, J., & Buchheidt, D. (2015). Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): Updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Annals of Oncology, 26(1), 21-33.
Maurer, K., Hasswani, N., & Wagener, J. S. (2017). Risk factors for pulmonary exacerbations in children with cystic fibrosis with severe genotypes. Journal of Cystic Fibrosis, 16(4), 525-532.
Maxson, J. E., Gotlib, J., & Pollyea, D. A. (2014). Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. The New England Journal of Medicine, 368(19), 1781-1790.
McDermott, D. H., Pastrana, D. V., & Calvo, K. R. (2019). Plerixafor for the treatment of WHIM syndrome. New England Journal of Medicine, 380(2), 163-170.
Merryman, R. W., Bannerjee, R., & O'Dwyer, K. (2018). Cytokine levels predict leukemic relapse after bone marrow transplantation for acute myeloid leukemia. Blood, 132(Supplement 1), 3331.
Monneret, G., & Venet, F. (2016). Sepsis-induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy. Cyt
