Abstract
Objective
Glycogen storage disease type Ib (GSD-Ib) is a very rare disease complicated by neutropenia with consequent recurrent bacterial infections. Treatment with Filgrastim is not always effective.
The low CD4 count observed in our patient is likely the underlying cause of this treatment failure. This low value was previously examined in a small-scale study. Therefore, adding sulfamethoxazole-trimethoprim (SMX-TMP) might be a good strategy.
Methods
We present the case of a male patient with GSD-Ib. He has severe neutropenia (380/mm3) with recurrent infections. Despite neutrophil improvement with Filgrastim, he developed three severe infections requiring hospitalization. Lymphocyte phenotyping showed a deficit in T CD4 + cells (280/mm3) which led us to HIV testing returning negative. Based on this finding we initiated prophylaxis with SMX-TMP.
Results
Since the start of SMX-TMP along with Filgrastim, the patient was not admitted to the hospital for any bacterial infection.
Conclusion
To date, no study has examined the significance of incorporating antibiotic prophylaxis for neutropenic patients with GSD-Ib based on CD4 count, akin to the approach of adding SMX-TMP to antiretroviral therapy for HIV patients. Cotrimoxazole is empirically prescribed without assessing the CD4 count or conducting a comparative analysis of the advantages of its addition to Filgrastim. Such practices could potentially exert a significant influence on the disease’s presentation and severity.
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Introduction
Glycogen storage diseases (GSDs) are a group of inherited genetics resulting from defects in the process of glycogen synthesis or breakdown within mainly the muscles and the liver. There are at least 13 types of GSD. Glycogen storage disease type I (GSD I) encompasses two different types. Glycogen storage disease type Ia (GSD-Ia), also known as von Gierke disease, is an autosomal recessive disorder caused by mutations in the G6PC gene which encodes glucose-6-phosphatase (G6Pase), affecting glucose metabolism and preventing glucose release outside the cells, which leads to hypoglycemia and excessive glycogen accumulation [1, 2]. GSD type Ib (GSD-Ib) is secondary to a mutation in G6PT gene (SLC37A4), which encodes for the glucose-6-phosphate transporter [3]. In the latter form, there is neutropenia with impairment of neutrophil function, leading to immune deficiency and recurrent bacterial infections [4]. In a European study performed among 57 patients with GSD-Ib, 95% of the patients had neutropenia, which appeared during the first year of life in 64% of these patients, and between ages 6 to 9 years in 18% of the cases [5]. Granulocyte-colony stimulating factor (G-CSF) therapy is one of the main treatments of GSD-Ib, as it contributes to neutrophil function improvement and reduction of infection frequency and severity [6]. G-CSF treatment is limited by splenomegaly and resulting abdominal pain, long-term risk of acute myelogenous leukemia, and infection recurrence in GSD-Ib despite optimal treatment [7].
Here, we present the case of an adult male affected by GSD-Ib disease who presented with recurrent infections despite optimal treatment with G-CSF. Follow-up, laboratory exams, and antibiotic prophylaxis protocol are discussed.
Case presentation
A young male patient, diagnosed with GSD-Ib during childhood presented to our clinic for recurrent infections. He is the 3rd child of healthy not related Lebanese parents. Shortly after birth, he presented recurrent seizures precipitated by hypoglycemia. Hypotonia, protuberant abdomen, irritability, failure to thrive, and neutropenia were complicating his early childhood. Given the hypoglycemia, the lactic acidosis and the clinical/paraclinical spectrum, the diagnosis of GSD was evoked at the age of around 2 years but the diagnosis of GSD-Ib was confirmed at the age of 18 by the presence of two pathogenic variants in the SCL37A4 gene (NM_001164277.1) identified by direct fluorescent sequencing: p.W393* (c.1179G > A) and p.V236del (c.706_708delGTG). Numerous systemic problems related to his chronic condition, including hypothyroidism, hypertriglyceridemia, hyperuricemia, hypertension, and hepatomegaly complicated his medical treatment during his teenage years. Moreover, throughout his life, he had been admitted to the hospital multiple times because of pneumonia and recurrent cutaneous and digestive bacterial infections and was also being treated for bipolar disorder.
When first seen by us, he was 22 years old. He had severe neutropenia with an absolute neutrophil count of 380/mm3 and recurrent pyogenic skin infections including a wound complicated with left knee cellulitis. In order to treat these recurrent infections, he was started on G-CSF. The dose of Filgrastim used for this 90 kg patient was 600 µg 3 times weekly. Nevertheless, he kept developing recurrent mild ENT and skin infections. One year later, he was hospitalized for erysipelas and severe furunculosis manifesting on the upper and lower left extremities. Cultures revealed methicillin-resistant Staphylococcus aureus and he was treated with Ceftaroline. During this hospitalization, an abdominal CT-scan revealed an enlarged 19 cm spleen confirming splenomegaly without other abnormal findings. As a result, we opted against increasing the G-CSF dose to prevent further worsening of the splenomegaly. Neutropenia remained stable until 2019 when he was admitted for infectious colitis. During this hospitalization, he had a high total protein of 92.6 g/L, which could have been a sign of chronic inflammation or an early sign of bone marrow disorder. We conducted additional workup, including immunofixation of serum proteins, which showed elevated levels of IgM (3.79 g/L), IgG1 (22.52 g/L), and IgG2 (8.22 g/L), and light chain quantification showed elevated levels of Lambda chains (3.26 g/L) and Kappa chains (5.68 g/L). A bone marrow aspirate revealed lymphopenia, a blast count within normal limits, with no metastatic infiltration. On immunophenotyping, the predominant expression of myeloid markers was noted. Neutrophils showed increased expression of CD14 and CD64 with slightly decreased myeloperoxidase (MPO) expression. Immaturity markers such as CD34 and CD117 were not overexpressed. Lymphocyte phenotyping showed a deficit in T CD4 + cells (280/mm3) which led us to test for HIV, returning a negative result. Based on this finding, we initiated treatment with sulfamethoxazole-trimethoprim (SMX-TMP) 800/160 mg three times per week along with G-CSF.
The digestive symptoms decreased after the use of Filgrastim and nearly disappeared when we introduced cotrimoxazole. Consequently, there were no further hospitalizations due to digestive complications, and episodes of abdominal pain and diarrhea became sporadic.
Since that time, the patient has not been admitted to the hospital for any bacterial infection. He also developed mild COVID-19 illness and recovered without hospitalization or any complications in January 2021 and January 2022.
Discussion
The patient presented herein, has a GSD-Ib confirmed molecularly. GSD-Ib represents 20% of all GSD-I cases and the incidence of this disease is 1/100,000 in the overall population [8]. It is secondary to a mutation in the SLC37A4 gene, which encodes for the glucose-6-phosphate transporter [3]. The enzyme glucose-6-phosphate translocase plays an important role in neutrophil homeostasis via endogenous glucose production, and a mutation in GSD-Ib induces a reduction and impairment in neutrophil count and function respectively [9]. Therefore, recurrent bacterial infections occur among these patients and mainly involve the skin, respiratory, and digestive systems [10]. This was the case with our patient who developed recurrent skin, ENT, and digestive infections. These patients are usually treated with (G-CSF) in order to stimulate the proliferation and differentiation of neutrophils, boost their function, and enhance their oxidative burst [6, 9]. When our patient received Filgrastim (recombinant G-CSF with the same biological activity as endogenous G-CSF [6], his absolute neutrophil count increased, in the space of 2 years, from 378/mm3 to 2550/mm3. Despite the increasing number of neutrophils, he developed three severe infections requiring hospitalization. Treatment with G-CSF can reduce the severity of infections, but recurrent infections remain present among many patients despite the increase in absolute neutrophil count [10]. Increasing the dose of G-CSF is limited by both splenomegaly and the long-term risk of acute myelogenous leukemia [7]. According to a meta-analysis of 19 articles involving 35,328 patients performed by Suthar et al., SMX-TMP plays an important role in mortality reduction among HIV patients with a CD4 count inferior to 350/mm3, when added to antiretroviral therapy, and hence should be given as a prophylactic therapy among these patients [11]. Due to the low CD4 count (280/mm3) in our patient, we initiated prophylactic antibiotic therapy with SMX-TMP in addition to G-CSF. The only study that reported a low CD4 count is the one published by Melis and collaborators, which includes 8 GSD1b patients [12].
In our case, the regimen proved to be effective and safe because the patient did not develop any severe infection requiring hospitalization when he was put on prophylactic SMX-TMP. While the efficiency of antibiotic prophylaxis has already been established among patients with neutropenia due to hematologic malignancies and solid tumors [11], no study has addressed the importance of adding antibiotic prophylaxis to neutropenic patients with GSD Ib, similarly to the addition of SMX-TMP to antiretroviral therapy among HIV patients. It is noteworthy that Cotrimoxazole is prescribed empirically, often without a comprehensive assessment of the patient’s CD4 count or a meticulous evaluation of the potential benefits when used in conjunction with Filgrastim [6, 13].
In the 2002 European Study on GSD1, Visser et al. recommended prophylactic use of cotrimoxazole in symptomatic patients or those with a neutrophil count of less than 500 × 10/l. However, it is important to note that cotrimoxazole demonstrates its benefits primarily in patients with lymphopenia rather than neutropenia.
This might have an important impact on the presentation and severity of the disease.
The high levels of IgM, IgG, and protein could be attributed to chronic lymphopenia, which may lead to the proliferation of immune populations that respond to self-antigens, thereby promoting autoimmunity. Additionally, these levels could also be explained by the chronic use of filgrastim causing an increased hematopoietic activity of the bone marrow and an extramedullary hematopoiesis [12, 14]. For Melis and collaborators, patients showed a high frequency of autoimmunity (five out of eight were affected): autoimmune thyroiditis, myasthenia gravis, inflammatory bowel disease, and rheumatoid arthritis [12].
The new oral antidiabetic drug Empagliflozin, an SGLT2 inhibitor or Gliflozins, shows great promise in improving outcomes for patients with GSD1b but is still considered experimental. Investigating inhibitors of 1,5-anhydroglucitol(1,5-AG) reuptake, reducing dietary 1,5-AG content, or exploring its intestinal production represent potential avenues for further research [15].
According to the Catalogue for Transmission Genetics in Arabs (CTGA) database (https://cags.org.ae/en), no other Lebanese patients with glycogen storage disease type Ib were reported [16]. With an estimated incidence of 1 in 100,000 live births, we can consider that this disease is either underreported in the Lebanese population or not well-diagnosed. Thus, there is at least an urgent need for a better newborn screening in order not to delay getting a correct diagnosis that might not only help the individual who is diagnosed but also their relatives.
Conclusion
Our case is an example of the effective use of SMX-TMP prophylactic antibiotic therapy in GSD-Ib patients with recurrent infections requiring hospitalization. Trials need to be done to evaluate the efficiency of the addition of SMX-TMP in the reduction of severe infections among these patients so that it can be added to management guidelines if the results prove favorable. Moreover, our patient is the first reported case of GSD-Ib in Lebanon.
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MAK, AW, ER, ED, AF, and AM have made a substantial contribution to the concept of the case report and the interpretation of data for the article. MAK and AM drafted the article content. MAK, AW, ER, ED, AF, and AM approved the version to be published. MAK, AW, ER, ED, AF, and AM agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.
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The Institutional Review Board (IRB) of the Lebanese American University has determined that this case report involving one patient is exempt from IRB review, and informed written consent was taken from the patient.
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Professor Andre Megarbane is a co-author of this study and an Editorial Board member of the journal. He was not involved in handling this manuscript during the review process. The rest of the authors have no conflict of interest to declare.
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Khalil, MA., Fata, A., Diab, E. et al. Positive impact of sulfamethoxazole-trimethoprim prophylaxis on prevention of severe infections in a patient with glycogen storage disease type Ib. J Rare Dis 2, 19 (2023). https://doi.org/10.1007/s44162-023-00023-w
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DOI: https://doi.org/10.1007/s44162-023-00023-w