Laura Dotta1, Lucia Dora Notarangelo2, Daniele Moratto3, Rajesh Kumar3, Fulvio Porta2, Annarosa Soresina4, Vassilios Lougaris5, Alessandro Plebani5, C I Edvard Smith6, Anna-Carin Norlin7, Andrea Cecilia Gòmez Raccio8, Eva Bubanska9, Patrizia Bertolini10, Giovanni Amendola11, Marcella Visentini12, Massimo Fiorilli12, Aldo Venuti13, Raffaele Badolato5. 1. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli," Asst Spedali Civili of Brescia, Brescia, Italy. Electronic address: lauradotta@icloud.com. 2. Pediatric Hematology Oncology Unit, Asst Spedali Civili of Brescia, Brescia, Italy. 3. Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Asst Spedali Civili of Brescia, Brescia, Italy. 4. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli," Asst Spedali Civili of Brescia, Brescia, Italy. 5. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Asst Spedali Civili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Asst Spedali Civili of Brescia, Brescia, Italy. 6. Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden. 7. Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden. 8. Immunology Unit, Children's Hospital Ricardo Gutierrez, Buenos Aires, Argentina. 9. Department of Pediatric Oncology and Hematology, University Children's Hospital, Banska Bystrica, Slovakia. 10. Pediatric Hematology Oncology Unit, Azienda Ospedaliero Universitaria of Parma, Parma, Italy. 11. Department of Pediatrics, Nocera Inferiore Hospital, Salerno, Italy. 12. Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy. 13. HPV-Unit, UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Abstract
BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.
BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.
Authors: Lauren E Heusinkveld; Shamik Majumdar; Ji-Liang Gao; David H McDermott; Philip M Murphy Journal: J Clin Immunol Date: 2019-07-16 Impact factor: 8.317
Authors: Assiya El Kettani; Fatima Ailal; Jalila El Bakkouri; Khalid Zerouali; Vivien Béziat; Emmanuelle Jouanguy; Jean-Laurent Casanova; Ahmed Aziz Bousfiha Journal: Pathogens Date: 2022-07-29
Authors: Alexandra Laberko; Ekaterina Deordieva; Gergely Krivan; Vera Goda; Saleh Bhar; Yuta Kawahara; Kanchan Rao; Austen Worth; David H McDermott; Dmitry Balashov; Alexey Maschan; Anna Shcherbina Journal: J Clin Immunol Date: 2021-10-26 Impact factor: 8.317