Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient

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While it’s commonly associated with rheumatic diseases, infections can also trigger MAS, with tuberculosis being a rare but significant cause. This case report discusses a rare occurrence of Macrophage Activation Syndrome (MAS) caused by multifocal tuberculosis in an immunocompromised patient with Crohn’s disease receiving immunosuppressive treatment. The patient is a 26-year-old woman with Crohn’s disease who is being treated with azathioprine. She arrived at the hospital battling persistent abdominal pain, overwhelming fatigue, and fever. Upon examination, splenomegaly and ascites were noted. A chest X-ray revealed bilateral pleural effusion consistent with tuberculosis. A CT scan confirmed the presence of pleural, pericardial, and intraperitoneal fluid. Blood tests indicated pancytopenia, hyperferritinemia, and hypofibrinogenemia. The analysis of ascitic fluid suggested an exudate. The PCR test of the bone marrow aspirate was positive for tuberculosis without rifampicin resistance, and the smear showed hemophagocytosis images. The patient was diagnosed with Macrophage Activation Syndrome secondary to multifocal tuberculosis. This report delves into the complex relationship between MAS and tuberculosis, emphasizing the challenges in diagnosing MAS in such cases and the potential link to tuberculosis. The complex diagnostic landscape of multifocal tuberculosis, which can often mimic malignancies, underscores the importance of promptly detecting and starting anti-tuberculosis interventions for improved clinical outcomes and the prevention of associated complications." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-1439/v2", "name": "Case Report: Macrophage activation syndrome due to multifocal tuberculosis..." } } ] } Home Browse Case Report: Macrophage activation syndrome due to multifocal tuberculosis... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Riahi S, Ammar S, Hassen H et al. Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.12688/f1000research.158982.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Case Report Revised Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] Salma Riahi https://orcid.org/0009-0006-6398-1610 1,2 , Sana Ammar 2,3 , Houssem Hassen 4,5 , [...] Emna Souilem 1,5 , Donia Mbarki 2,3 , Yosra Dhaha 1,2 , Mehdi Ksiaa 1,5 , Amina Bouatay 2,3 Salma Riahi https://orcid.org/0009-0006-6398-1610 1,2 , Sana Ammar 2,3 , [...] Houssem Hassen 4,5 , Emna Souilem 1,5 , Donia Mbarki 2,3 , Yosra Dhaha 1,2 , Mehdi Ksiaa 1,5 , Amina Bouatay 2,3 PUBLISHED 17 Apr 2025 Author details Author details 1 University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia 2 Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia 3 University of Monastir Faculty of Pharmacy of Monastir, Monastir, Monastir, Tunisia 4 University of Monastir Faculty of Medicine of Monastir, Monastir, Monastir, Tunisia 5 Department of Gastroenterology, Sahloul Hospital, Sousse, Sousse, Tunisia Salma Riahi Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Sana Ammar Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Houssem Hassen Roles: Data Curation, Formal Analysis, Investigation, Project Administration Emna Souilem Roles: Data Curation, Formal Analysis, Investigation, Project Administration Donia Mbarki Roles: Investigation, Methodology, Resources, Supervision Yosra Dhaha Roles: Investigation, Methodology, Resources, Supervision Mehdi Ksiaa Roles: Supervision, Validation, Visualization Amina Bouatay Roles: Project Administration, Supervision, Validation, Visualization OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Macrophage Activation Syndrome (MAS) is a serious and life-threatening complication defined by excessive immune activation. While it’s commonly associated with rheumatic diseases, infections can also trigger MAS, with tuberculosis being a rare but significant cause. This case report discusses a rare occurrence of Macrophage Activation Syndrome (MAS) caused by multifocal tuberculosis in an immunocompromised patient with Crohn’s disease receiving immunosuppressive treatment. The patient is a 26-year-old woman with Crohn’s disease who is being treated with azathioprine. She arrived at the hospital battling persistent abdominal pain, overwhelming fatigue, and fever. Upon examination, splenomegaly and ascites were noted. A chest X-ray revealed bilateral pleural effusion consistent with tuberculosis. A CT scan confirmed the presence of pleural, pericardial, and intraperitoneal fluid. Blood tests indicated pancytopenia, hyperferritinemia, and hypofibrinogenemia. The analysis of ascitic fluid suggested an exudate. The PCR test of the bone marrow aspirate was positive for tuberculosis without rifampicin resistance, and the smear showed hemophagocytosis images. The patient was diagnosed with Macrophage Activation Syndrome secondary to multifocal tuberculosis. This report delves into the complex relationship between MAS and tuberculosis, emphasizing the challenges in diagnosing MAS in such cases and the potential link to tuberculosis. The complex diagnostic landscape of multifocal tuberculosis, which can often mimic malignancies, underscores the importance of promptly detecting and starting anti-tuberculosis interventions for improved clinical outcomes and the prevention of associated complications. READ ALL READ LESS Keywords Macrophage activation syndrome, Multifocal tuberculosis, Immunosuppressive treatement. Corresponding Author(s) Salma Riahi ( [email protected] ) Close Corresponding author: Salma Riahi Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Riahi S et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Riahi S, Ammar S, Hassen H et al. Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.12688/f1000research.158982.2 ) First published: 27 Nov 2024, 13 :1439 ( https://doi.org/10.12688/f1000research.158982.1 ) Latest published: 17 Apr 2025, 13 :1439 ( https://doi.org/10.12688/f1000research.158982.2 ) Revised Amendments from Version 1 We thank the reviewers for their insightful feedback. Below, we provide a point-by-point response highlighting the changes made following their recommendations. 1. Specification of Crohn’s Disease Diagnosis Age Modification: We have updated the text to explicitly state that the patient was diagnosed with Crohn’s disease at 21. 2. Clarification of the Case’s Novelty and Teaching Points The reviewer noted that our case lacked unique features or instructive points. Modification: We have strengthened the discussion to emphasize the importance of rapid diagnosis in resource-limited settings where certain laboratory tests are unavailable. 3. Inclusion of Clinical Course and Treatment Outcome The reviewer requested additional details on the patient’s outcome and evolution under anti-tuberculosis therapy. Modification: We have added specific details on the resolution of fever, thrombocytopenia, and coagulopathy after starting treatment and included a follow-up assessment. 4. Immunological Workup for Underlying Autoimmune or Immunodeficiency Conditions The reviewer suggested providing details on immune testing performed to rule out other conditions. Modification: We specified that an immunoglobulin test was normal, ANA testing was negative, and there were no clinical signs of congenital immunodeficiency. 5. Justification for the Lack of PCR and Cultures on Pleural and Ascitic Fluids The reviewer inquired about microbiological investigations of pleural and ascitic fluids. Modification: We clarified that PCR and cultures were not performed on these fluids due to resource constraints. 6. Differentiation Between Immune and Non-Immune Thrombocytopenia The reviewer asked for details about the additional Immunomodulatory Treatment. Modification: We noted that the patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment and we revised our discussion to state that our patient's thrombocytopenia was likely non-immune, as it resolved with anti-tuberculosis therapy alone. We contrasted this with immune-mediated cases. We believe these modifications have strengthened our manuscript and addressed the reviewers’ concerns comprehensively. We thank the reviewers for their insightful feedback. Below, we provide a point-by-point response highlighting the changes made following their recommendations. 1. Specification of Crohn’s Disease Diagnosis Age Modification: We have updated the text to explicitly state that the patient was diagnosed with Crohn’s disease at 21. 2. Clarification of the Case’s Novelty and Teaching Points The reviewer noted that our case lacked unique features or instructive points. Modification: We have strengthened the discussion to emphasize the importance of rapid diagnosis in resource-limited settings where certain laboratory tests are unavailable. 3. Inclusion of Clinical Course and Treatment Outcome The reviewer requested additional details on the patient’s outcome and evolution under anti-tuberculosis therapy. Modification: We have added specific details on the resolution of fever, thrombocytopenia, and coagulopathy after starting treatment and included a follow-up assessment. 4. Immunological Workup for Underlying Autoimmune or Immunodeficiency Conditions The reviewer suggested providing details on immune testing performed to rule out other conditions. Modification: We specified that an immunoglobulin test was normal, ANA testing was negative, and there were no clinical signs of congenital immunodeficiency. 5. Justification for the Lack of PCR and Cultures on Pleural and Ascitic Fluids The reviewer inquired about microbiological investigations of pleural and ascitic fluids. Modification: We clarified that PCR and cultures were not performed on these fluids due to resource constraints. 6. Differentiation Between Immune and Non-Immune Thrombocytopenia The reviewer asked for details about the additional Immunomodulatory Treatment. Modification: We noted that the patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment and we revised our discussion to state that our patient's thrombocytopenia was likely non-immune, as it resolved with anti-tuberculosis therapy alone. We contrasted this with immune-mediated cases. We believe these modifications have strengthened our manuscript and addressed the reviewers’ concerns comprehensively. See the authors' detailed response to the review by Luisa Berenise Gámez-González See the authors' detailed response to the review by W Winn Chatham READ REVIEWER RESPONSES Introduction Macrophage Activation Syndrome (MAS) is a rare but life-threatening disease characterized by excessive activation and proliferation of macrophages and T lymphocytes, leading to a cytokine storm and multi-organ dysfunction. 1 While MAS is most commonly associated with rheumatic diseases, mainly systemic juvenile idiopathic arthritis and adult-onset Still’s disease, it can also be triggered by infections, malignancies, and certain medications. 2 However, it is rarely reported as a complication of tuberculosis, especially in immunocompromised patients. The clinical presentation of MAS is generally brutal, associating persistent fever with bi or pancytopenia. The diagnosis of MAS can be challenging, as its clinical and laboratory features may overlap with those of the underlying disease or infection. 3 We present a case of a 26-year-old woman treated with azathioprine for her Crohn’s disease complicated with multifocal tuberculosis and MAS. Case presentation A 26-year-old- woman was referred to our hospital with abdominal pain for five days, fatigue, and fever (39°C). Her medical history included Crohn’s disease diagnosed at the age of 21 with inflammation located in the terminal ileum, initially treated with corticosteroids followed by azathioprine as maintenance therapy. The patient declared no exposure history to active tuberculosis in the past. Her heart rate was 121 beats per minute, blood pressure 110/77 mmHg, respiratory rate 25 breaths per minute, and temperature 39°C. The patient had splenomegaly without hepatomegaly or adenopathy. Shifting dullness and a positive fluid wave test were found. No other signs were reported on physical examination. A chest X-ray was performed, showing bilateral pleural effusion compatible with tuberculosis. An abdominal CT scan was conducted, revealing the presence of both pleural effusion and a significant volume of ascites. High axial sections through the thoracic base showed bilateral pleural and pericardial effusion ( Figure 1 ). Figure 1. Axial contrast-enhanced CT scan of the chest shows bilateral low abundance pleural effusion (green arrows) and low abundance pericardial effusion (red arrows). Axial sections taken at portal time after injection of contrast agent showed abundant intra-peritoneal effusion ( Figure 2 ). Figure 2. Axial contrast-enhanced abdominal CT scan after contrast injection showing abundant peritoneal effusion (green arrows). A complete blood count showed normochromic normocytic anaemia, neutropenia, lymphopenia, and thrombocytopenia ( Table 1 ). Table 1. The Hemogram results. Hematology parameters Patient values on admission Patient values on Day 1 Patient values on Day 7 Patient values after treatment completion Reference ranges Hemoglobin (g/dL) 7.6 6.9 8.7 13.9 Male: 13–18 Female: 12.0–16.0 WBC (cell/mm 3 ) 1400 1300 2900 6200 4500–11,000 Neutrophils (cell/mm 3 ) 1200 1100 2400 4000 1500–8000 Lymphocytes (cell/mm 3 ) 100 100 300 1400 1000–4000 Platelets (cell/mm 3 ) 109,000 98,000 198,000 216,000 150,000–400,000 The patient had elevated lactate dehydrogenase (LDH: 670 UI/L), D-dimer (7.017 μg/ml), prolonged prothrombin time (PT: 61%), and activated partial thromboplastin time (aPTT: 37.7 sec, ratio M/T = 1.3). Additionally, there was hyperferritinemia (1050 ng/mL), and low Fibrinogen level (1.5 g/L). Mild liver cholestasis was noticed (gamma-glutamyl transpeptidase (GGT) at 52 UI/L; alkaline phosphatase (ALP) at 184 UI/L). The triglyceride level was normal (0.8 mmol/L) and the electrolyte test showed hyponatremia (125 mmol/L). The low serum Ascites Albumin Gradient (SAAG) (<1.1g/dL) suggested that the ascitic fluid is an exudate. Fluid’s direct microscopic examination revealed no tuberculosis bacilli and the acid-fast stain was negative. Unfortunately, cultures and PCR studies were not performed on pleural and ascitic fluids due to resource limitations, as PCR testing is not always available in our facility. No renal function abnormality was found. Viral serology HIV, HSV, HBV, HCV, EBV, and CMV were negative. Azathioprine toxicity was not ruled out, as testing was not available in our facility. An immune workup was performed, including antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin assay, which was normal. There were no clinical signs suggestive of congenital immunodeficiency, but no further immunological tests were carried out due to resource limitations. The febrile cytopenia associated with the splenomegaly led to a bone marrow aspirate; an Xpert MTB/RIF PCR was performed and turned out positive. Rifampicin resistance was not detected. The bone marrow aspirate smear showed a reactional plasmocytosis and multiple hemophagocytosis images ( Figure 3 ). Figure 3. Bone marrow aspirate smear colored with MGG staining displays features of haemophagocytosis with erythroids engulfed by macrophages (Black arrows). Bone Marrow Biopsy was not performed. The diagnosis of macrophage activation syndrome (MAS) was established based on clinical and laboratory criteria. Given the clinical presentation and laboratory findings, multifocal tuberculosis complicated by MAS was diagnosed in an immunocompromised patient. The patient was started on a standard daily oral anti-tuberculosis regimen, including isoniazid, rifampicin, pyrazinamide, and ethambutol hydrochloride. The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. Apyrexia was achieved within 72 hours of treatment initiation, and there was a progressive improvement in platelet count after one week (Table 1). The fibrinogen level increased to 2.02 g/L by day 7, while LDH decreased to 352 UI/L, PT improved to 70%, and aPTT to 35.4 sec (ratio M/T = 1.22). No adverse effects of anti-tuberculosis treatment were observed. The patient was discharged to continue treatment at home. At follow-up, there was radiological resolution of pleural and ascitic effusions at the end of therapy, and a normal blood count was observed ( Table 1 ). Discussion Tuberculosis (TB) remains a significant cause of death globally. According to WHO, there were approximately 10.6 million new TB cases in 2021. 4 TB is endemic in Tunisia, with an estimated incidence of 22.46/100,000 inhabitants in 2021. 5 It is widely recognized that immunosuppressive therapy elevates the risk of tuberculosis, particularly in endemic regions like Tunisia. 6 A study by Fortes et al. assessed 301 patients with inflammatory bowel disease (IBD) and found that azathioprine treatment increased the risk of developing active tuberculosis by 6.87 times compared to patients who were not receiving this medication. 7 In our case, the patient had Crohn's disease diagnosed at the age of 21, initially treated with corticosteroids, followed by azathioprine as maintenance therapy. MAS is a serious medical condition that can be triggered by infectious agents, particularly certain viruses and mycobacteria . The majority of cases involving tuberculosis complicated by MAS occur in individuals who are immunocompromised such as transplant recipients, cancer patients, or those receiving immunosuppressive therapy. 8 The disease presents significant challenges and is often associated with a poor prognosis. However, it is essential to approach this matter with a focus on early diagnosis and targeted treatment options, which can lead to improved outcomes and better management of the condition. In our case, MAS was due to multifocal tuberculosis, which involves multiple systems with associated symptoms, making the diagnosis challenging. Multifocal tuberculosis is characterised by large multifocal tuberculosis areas in the same or different adjacent or distant organs; in our case, the organs concerned were the lungs, the digestive system, and the hematopoietic organs. 9 Regarding microbiological investigations, cultures and PCR studies were not performed on pleural and ascitic fluids due to resource constraints. However, a bone marrow aspirate was analyzed, and PCR for Mycobacterium tuberculosis (Xpert MTB/RIF) was positive, confirming the diagnosis. This highlights the challenges faced in settings with limited access to advanced diagnostic tools, where a rapid clinical assessment remains crucial for timely diagnosis and management. Especially when the prognosis is severe, with a mortality rate of 16 to 25%, depending on the author. 10 , 11 Sporadic cases of multifocal tuberculosis have been reported; most of them presented with anaemia, leucopenia, and/or thrombocytopenia. In our case, the patient had pancytopenia, which could have been multifactorial. While azathioprine toxicity was considered, we were unable to definitively rule it out due to the unavailability of specific diagnostic tests in our facility. MAS is an acute, sometimes fatal complication of multifocal tuberculosis. The clinical presentation is usually non-specific and can be misleading. MAS is a condition associated with hemophagocytic lymphohistiocytosis (HLH), which is categorized into primary and secondary HLH. Primary HLH is a genetic disorder, while secondary HLH arises from other conditions, such as cancers, autoimmune disorders, and infections like tuberculosis, as seen in this instance. EBV is the most prevalent infectious cause, but MAS can also be related to various infections, including viral (HIV, CMV), bacterial (Salmonella typhi), and parasitic (Leishmania sp., Toxoplasma gondii) origins. 12 There is a set of clinical and biological criteria to define a MAS, but according to the literature, some remain more important than others. The most used criteria were Hepatosplenomegaly, fever, cytopenia, hypofibrinogenemia, hyperferritinemia, hypertriglyceridemia, hemophagocytosis, and hepatopathy. Six out of all the criteria cited below ( Table 2 ) were found in our patient. 13 Table 2. Diagnostic criteria of hemophagocytic lymphohistiocytosis: HLH-2004. 14 Diagnosis will be established if one of either (1) or (2) is fulfilled (1) Molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria shown below) - Fever ≥38.5°C for ≥7 days - Splenomegaly ≥3 finger breadth below the left subcostal margin - Cytopenias affecting ≥2 of 3 lineages in peripheral blood • Hemoglobin <9 g/L • Platelets <100×109/L • Absolute neutrophil count <1.0×109/L - Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides ≥265 mg/dL, Fibrinogen ≤1.5 g/L - Hemophagocytosis in the bone marrow or spleen or lymph node - Low or absent NK cell activity (according to the local laboratory reference) - Ferritin ≥500 μg/L - Soluble CD25 (sIL-2 receptor) ≥2,400 U/mL A study examined 37 documented instances of tuberculosis linked to MAS, revealing that half of the patients were immunocompromised (due to renal transplants, cancer, or HIV). The clinical symptoms remained consistent (such as fever and hepatosplenomegaly). In 80% of the cases, it was a disseminated tuberculosis. 15 In most bone marrow aspirations, cellularity appears quite normal, and hemophagocytic histiocytes typically account for 2 to 75% of total nucleated cells. The mortality rate associated with MAS and tuberculosis reaches 50%, rising to 100% for those who do not receive any antituberculous treatment. 16 The observed therapeutic response in our patient was characterized by the resolution of fever within 72 hours and improvement in platelet count after one week of initiating anti-tuberculosis therapy without additional immunomodulatory treatment suggesting a direct impact of Mycobacterium tuberculosis on bone marrow suppression rather than an autoimmune process. Kalra et al. reported a case of immune thrombocytopenia associated with disseminated tuberculosis, in which the patient required both anti-tuberculosis therapy and corticosteroids to achieve platelet normalization. 17 This suggests a distinction from immune-mediated thrombocytopenia, where corticosteroids are often required for platelet recovery. Conclusion In conclusion, we would like to present a rare case of MAS triggered by multifocal tuberculosis in a Crohn’s disease patient receiving immunosuppressive therapy. MAS is a severe complication that necessitates prompt diagnosis and management. Our case underscores the significance of considering atypical infectious symptoms in immunocompromised patients and promptly suspecting tuberculosis, particularly in patients exhibiting signs of MAS. Timely diagnosis and initiating antitubercular therapy are imperative for enhancing outcomes and averting complications. Ethical consideration Ethical approval was not required. Consent statement to Publish Written informed consent was obtained from the patient upon admission, permitting the use of their de-identified data for research and publication purposes. All identifying information has been removed to ensure the patient’s confidentiality following ethical guidelines. Data availability statement No data associated with this article. References 1. Ravelli A, et al. : Macrophage Activation Syndrome. Hematol. Oncol. Clin. North Am. 2015; 29 (5): 927–941. Publisher Full Text 2. Carter SJ, et al. : Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford). 2019; 58 (1): 5–17. PubMed Abstract | Publisher Full Text 3. Minoia F, et al. : Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J. Rheumatol. 2015; 42 (6): 994–1001. PubMed Abstract | Publisher Full Text 4. WHO: TB incidence, Global Tuberculosis Report 2022. Reference Source 5. Mansouri A, Bouguerra H, Belkahla M, et al. : Epidemiological Profile of Tuberculosis in Tunisia. Eur. J. Pub. Health. 1 oct 2023; 33 (Supplement_2): ckad160.636. Publisher Full Text 6. Kedia S, Mouli VP, Kamat N, et al. : Risk of Tuberculosis in Patients With Inflammatory Bowel Disease on Infliximab or Adalimumab Is Dependent on the Local Disease Burden of Tuberculosis: A Systematic Review and Meta-Analysis. Am. J. Gastroenterol. March 2020; 115 (3): 340–349. Publisher Full Text 7. Fortes FML, Rocha R, Santana GO: Thiopurines are an independent risk factor for active tuberculosis in inflammatory bowel disease patients. World J. Gastroenterol. 7 March 2023; 29 (9): 1536–1538. PubMed Abstract | Publisher Full Text | Free Full Text 8. Gartini S, Bougrini Y, Rhazari M, et al. : Macrophagic activation syndrome revealing disseminated multifocal tuberculosis: A case report of a rare clinical situation. Ann. Med. Surg. 1 April 2022; 76 : 103487. 9. Wang C, Luan Y, Liu S, et al. : Multifocal tuberculosis simulating a cancer-a case report. BMC Infect. Dis. 10 July 2020; 20 (1): 495. PubMed Abstract | Publisher Full Text | Free Full Text 10. Denis-Delpierre N, Merrien D, Billaud E, et al. : Multifocal tuberculosis. Apropos of 49 cases in the midwest region. GERICCO (Group for Epidemiology and Research in Clinical Infections of the Central West of France), 1991-1993. Pathol. Biol (Paris). June 1998; 46 (6): 375–379. PubMed Abstract 11. Rezgui A, Fredj FB, Mzabi A, et al. : Tuberculose multifocale chez les immunocompétents. Pan Afr. Med. J. 4 May 2016; 24 : 13. 12. Le Hô H, Barbarot N, Desrues B: Pancytopenia in disseminated tuberculosis: Think of macrophage activation syndrome. Rev. Mal. Respir. March 2010; 27 (3): 257–260. PubMed Abstract | Publisher Full Text 13. Bojan A, Parvu A, Zsoldos IA, et al. : Macrophage activation syndrome: A diagnostic challenge (Review). Exp. Ther. Med. August 2021; 22 (2): 904. PubMed Abstract | Publisher Full Text | Free Full Text 14. Kim YR, Kim DY: Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res. 2021 Apr 30; 56 (Suppl 1): S17–S25. Publisher Full Text 15. Brastianos PK, Swanson JW, Torbenson M, et al. : Tuberculosis-associated haemophagocytic syndrome. Lancet Infect. Dis. July 2006; 6 (7): 447–454. Publisher Full Text 16. Azzeddine R, Elyassir F, Bourkadi JE: Multifocal tuberculosis complicated by a macrophage activation syndrome: about two cases. Pan Afr. Med. J. 2019; 32 : 41. 17. Kalra A, Kalra A, Palaniswamy C, et al. : Immune Thrombocytopenia in a Challenging Case of Disseminated Tuberculosis: A Case Report and Review of the Literature. Case Rep. Med. 2010; 2010 : 946278. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 27 Nov 2024 ADD YOUR COMMENT Comment Author details Author details 1 University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia 2 Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia 3 University of Monastir Faculty of Pharmacy of Monastir, Monastir, Monastir, Tunisia 4 University of Monastir Faculty of Medicine of Monastir, Monastir, Monastir, Tunisia 5 Department of Gastroenterology, Sahloul Hospital, Sousse, Sousse, Tunisia Salma Riahi Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Sana Ammar Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation Houssem Hassen Roles: Data Curation, Formal Analysis, Investigation, Project Administration Emna Souilem Roles: Data Curation, Formal Analysis, Investigation, Project Administration Donia Mbarki Roles: Investigation, Methodology, Resources, Supervision Yosra Dhaha Roles: Investigation, Methodology, Resources, Supervision Mehdi Ksiaa Roles: Supervision, Validation, Visualization Amina Bouatay Roles: Project Administration, Supervision, Validation, Visualization Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 17 Apr 2025, 13:1439 https://doi.org/10.12688/f1000research.158982.2 version 1 Published: 27 Nov 2024, 13:1439 https://doi.org/10.12688/f1000research.158982.1 Copyright © 2025 Riahi S et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Riahi S, Ammar S, Hassen H et al. Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.12688/f1000research.158982.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 17 Apr 2025 Revised Views 0 Cite How to cite this report: Gámez-González LB. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378709 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378709 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 21 Apr 2025 Luisa Berenise Gámez-González , Autonomous University of Chihuahua, Chihuahua, Mexico Approved VIEWS 0 https://doi.org/10.5256/f1000research.180247.r378709 The manuscript has been adequately improved, and all of my suggestions ... Continue reading READ ALL The manuscript has been adequately improved, and all of my suggestions and concerns have been addressed. I have no further modifications to suggest. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Immunology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Gámez-González LB. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378709 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378709 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Chatham WW. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378710 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378710 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Apr 2025 W Winn Chatham , University of Nevada Las Vegas, Las Vegas, Nevada, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.180247.r378710 This is now fine to publish as is ... Continue reading READ ALL This is now fine to publish as is - authors have sufficiently addressed the initial criticisms. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Systemic Lupus, Macrophage activation syndromes, Immunodeficiency associated autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chatham WW. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378710 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378710 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 27 Nov 2024 Views 0 Cite How to cite this report: Gámez-González LB. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r357485 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-357485 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 03 Feb 2025 Luisa Berenise Gámez-González , Autonomous University of Chihuahua, Chihuahua, Mexico Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.174644.r357485 It would be relevant to mention whether an immune workup was performed to rule out an underlying autoimmune or primary immunodeficiency condition, given the patient’s immunosuppressed state and the development of MAS. It would be valuable to ... Continue reading READ ALL It would be relevant to mention whether an immune workup was performed to rule out an underlying autoimmune or primary immunodeficiency condition, given the patient’s immunosuppressed state and the development of MAS. It would be valuable to specify whether the patient required additional immuno-modulatory treatment (e.g., corticosteroids, ) beyond anti-tuberculosis therapy. Additionally, a more detailed description of the clinical course, including the time to improvement and resolution of MAS-related complications, would strengthen the discussion I suggest specifying the age at which Crohn’s disease was diagnosed instead of the year, as this provides clearer clinical context. Is the background of the case’s history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical Immunology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Gámez-González LB. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r357485 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-357485 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Apr 2025 Salma Riahi , Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia 17 Apr 2025 Author Response We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency ... Continue reading We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency Conditions We acknowledge the importance of assessing underlying immune disorders in the context of MAS. In this case, the immune workup was limited to antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin test, which was normal. Due to resource limitations, further immunological investigations were not performed. However, there were no clinical or biological signs strongly suggestive of a primary immunodeficiency or additional autoimmune condition beyond Crohn’s disease and its treatment-related immunosuppression. We will clarify this point in the revised manuscript. Additional Immunomodulatory Treatment The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. The clinical decision was based on the patient’s overall condition and response to tuberculosis therapy. We will specify this in the revised discussion. Clinical Course and Time to Improvement A more detailed description of the patient’s evolution will enhance the discussion. In the revised manuscript, we will provide a clearer timeline of the resolution of MAS-related complications and the patient’s response to treatment. Age at Crohn’s Disease Diagnosis We appreciate this suggestion and will specify the patient’s age at diagnosis instead of the year to provide a clearer clinical context. Thank you again for your valuable feedback. We believe these revisions will strengthen our manuscript. We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency Conditions We acknowledge the importance of assessing underlying immune disorders in the context of MAS. In this case, the immune workup was limited to antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin test, which was normal. Due to resource limitations, further immunological investigations were not performed. However, there were no clinical or biological signs strongly suggestive of a primary immunodeficiency or additional autoimmune condition beyond Crohn’s disease and its treatment-related immunosuppression. We will clarify this point in the revised manuscript. Additional Immunomodulatory Treatment The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. The clinical decision was based on the patient’s overall condition and response to tuberculosis therapy. We will specify this in the revised discussion. Clinical Course and Time to Improvement A more detailed description of the patient’s evolution will enhance the discussion. In the revised manuscript, we will provide a clearer timeline of the resolution of MAS-related complications and the patient’s response to treatment. Age at Crohn’s Disease Diagnosis We appreciate this suggestion and will specify the patient’s age at diagnosis instead of the year to provide a clearer clinical context. Thank you again for your valuable feedback. We believe these revisions will strengthen our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Apr 2025 Salma Riahi , Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia 17 Apr 2025 Author Response We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency ... Continue reading We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency Conditions We acknowledge the importance of assessing underlying immune disorders in the context of MAS. In this case, the immune workup was limited to antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin test, which was normal. Due to resource limitations, further immunological investigations were not performed. However, there were no clinical or biological signs strongly suggestive of a primary immunodeficiency or additional autoimmune condition beyond Crohn’s disease and its treatment-related immunosuppression. We will clarify this point in the revised manuscript. Additional Immunomodulatory Treatment The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. The clinical decision was based on the patient’s overall condition and response to tuberculosis therapy. We will specify this in the revised discussion. Clinical Course and Time to Improvement A more detailed description of the patient’s evolution will enhance the discussion. In the revised manuscript, we will provide a clearer timeline of the resolution of MAS-related complications and the patient’s response to treatment. Age at Crohn’s Disease Diagnosis We appreciate this suggestion and will specify the patient’s age at diagnosis instead of the year to provide a clearer clinical context. Thank you again for your valuable feedback. We believe these revisions will strengthen our manuscript. We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency Conditions We acknowledge the importance of assessing underlying immune disorders in the context of MAS. In this case, the immune workup was limited to antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin test, which was normal. Due to resource limitations, further immunological investigations were not performed. However, there were no clinical or biological signs strongly suggestive of a primary immunodeficiency or additional autoimmune condition beyond Crohn’s disease and its treatment-related immunosuppression. We will clarify this point in the revised manuscript. Additional Immunomodulatory Treatment The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. The clinical decision was based on the patient’s overall condition and response to tuberculosis therapy. We will specify this in the revised discussion. Clinical Course and Time to Improvement A more detailed description of the patient’s evolution will enhance the discussion. In the revised manuscript, we will provide a clearer timeline of the resolution of MAS-related complications and the patient’s response to treatment. Age at Crohn’s Disease Diagnosis We appreciate this suggestion and will specify the patient’s age at diagnosis instead of the year to provide a clearer clinical context. Thank you again for your valuable feedback. We believe these revisions will strengthen our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Chatham WW. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r347815 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-347815 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 30 Dec 2024 W Winn Chatham , University of Nevada Las Vegas, Las Vegas, Nevada, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.174644.r347815 This is a brief case report describing a patient diagnosed with disseminated tuberculosis who had features of associated macrophage activation syndrome, a previously recognized association. Comments: As written, this report adds little if anything to existing ... Continue reading READ ALL This is a brief case report describing a patient diagnosed with disseminated tuberculosis who had features of associated macrophage activation syndrome, a previously recognized association. Comments: As written, this report adds little if anything to existing knowledge. There are no apparent unique features of the case or relevant emphasized instructive teaching points. Perhaps discussions of the outcome of this case (no information was provided) would provide some instructive insights. What exactly is meant by "MAS was retained"? Did the MAS features abate with anti-tuberculous therapy and if so, what was the time frame? Missing relevant data: Were cultures or PCR studies performed and positive on the pleural and ascites fluids? As the fibrinogen was only borderline abnormal, were there other features of coagulopathy (elevated serum LDH, d-dimer, elevated PT/INR)? Was azathioprine toxicity considered or ruled out as a cause of the pancytopenia? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No Is the case presented with sufficient detail to be useful for other practitioners? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Systemic Lupus, Macrophage activation syndromes, Immunodeficiency associated autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chatham WW. Reviewer Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r347815 ) The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-347815 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Apr 2025 Salma Riahi , Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia 17 Apr 2025 Author Response We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance ... Continue reading We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance of our case report. Outcome and Evolution Under Anti-Tuberculosis Therapy We acknowledge the importance of providing details on the patient’s clinical course. Our revised manuscript will include a detailed discussion on the evolution of the patient’s condition, highlighting how the MAS features evolved under anti-tuberculosis treatment and the time frame of clinical and biological improvements. Clarification of "MAS was retained" We recognize that this phrasing may be unclear. In the revised version, we will clarify that the diagnosis of MAS was established based on clinical and laboratory criteria and elaborate on how the condition evolved after initiating anti-tuberculosis treatment. Additional Diagnostic Data Cultures and PCR Studies: Unfortunately, due to resource limitations, cultures and PCR studies were not performed on pleural and ascitic fluids. PCR testing is not always available in our facility. We will clarify this limitation in the revised manuscript. Coagulopathy Markers: While fibrinogen was only borderline abnormal, we will include additional coagulation markers (serum LDH, D-dimer, PT/INR) if available in our records to further assess coagulopathy. Azathioprine Toxicity: We acknowledge that azathioprine toxicity is a differential diagnosis for pancytopenia. However, due to limited laboratory resources in our facility, we were unable to promptly confirm or rule out this possibility. We will explicitly mention this limitation in the revised discussion. Significance of the Case Report We appreciate the concern regarding the novelty of our case. This report's main contribution is to emphasize the importance of early recognition and diagnosis of MAS in disseminated tuberculosis, particularly in resource-limited settings where certain diagnostic tests may not be readily available. We will strengthen this point in our discussion to highlight the clinical relevance of our case. Thank you again for your constructive feedback. We believe these revisions will enhance the clarity and impact of our manuscript. We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance of our case report. Outcome and Evolution Under Anti-Tuberculosis Therapy We acknowledge the importance of providing details on the patient’s clinical course. Our revised manuscript will include a detailed discussion on the evolution of the patient’s condition, highlighting how the MAS features evolved under anti-tuberculosis treatment and the time frame of clinical and biological improvements. Clarification of "MAS was retained" We recognize that this phrasing may be unclear. In the revised version, we will clarify that the diagnosis of MAS was established based on clinical and laboratory criteria and elaborate on how the condition evolved after initiating anti-tuberculosis treatment. Additional Diagnostic Data Cultures and PCR Studies: Unfortunately, due to resource limitations, cultures and PCR studies were not performed on pleural and ascitic fluids. PCR testing is not always available in our facility. We will clarify this limitation in the revised manuscript. Coagulopathy Markers: While fibrinogen was only borderline abnormal, we will include additional coagulation markers (serum LDH, D-dimer, PT/INR) if available in our records to further assess coagulopathy. Azathioprine Toxicity: We acknowledge that azathioprine toxicity is a differential diagnosis for pancytopenia. However, due to limited laboratory resources in our facility, we were unable to promptly confirm or rule out this possibility. We will explicitly mention this limitation in the revised discussion. Significance of the Case Report We appreciate the concern regarding the novelty of our case. This report's main contribution is to emphasize the importance of early recognition and diagnosis of MAS in disseminated tuberculosis, particularly in resource-limited settings where certain diagnostic tests may not be readily available. We will strengthen this point in our discussion to highlight the clinical relevance of our case. Thank you again for your constructive feedback. We believe these revisions will enhance the clarity and impact of our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Apr 2025 Salma Riahi , Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia 17 Apr 2025 Author Response We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance ... Continue reading We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance of our case report. Outcome and Evolution Under Anti-Tuberculosis Therapy We acknowledge the importance of providing details on the patient’s clinical course. Our revised manuscript will include a detailed discussion on the evolution of the patient’s condition, highlighting how the MAS features evolved under anti-tuberculosis treatment and the time frame of clinical and biological improvements. Clarification of "MAS was retained" We recognize that this phrasing may be unclear. In the revised version, we will clarify that the diagnosis of MAS was established based on clinical and laboratory criteria and elaborate on how the condition evolved after initiating anti-tuberculosis treatment. Additional Diagnostic Data Cultures and PCR Studies: Unfortunately, due to resource limitations, cultures and PCR studies were not performed on pleural and ascitic fluids. PCR testing is not always available in our facility. We will clarify this limitation in the revised manuscript. Coagulopathy Markers: While fibrinogen was only borderline abnormal, we will include additional coagulation markers (serum LDH, D-dimer, PT/INR) if available in our records to further assess coagulopathy. Azathioprine Toxicity: We acknowledge that azathioprine toxicity is a differential diagnosis for pancytopenia. However, due to limited laboratory resources in our facility, we were unable to promptly confirm or rule out this possibility. We will explicitly mention this limitation in the revised discussion. Significance of the Case Report We appreciate the concern regarding the novelty of our case. This report's main contribution is to emphasize the importance of early recognition and diagnosis of MAS in disseminated tuberculosis, particularly in resource-limited settings where certain diagnostic tests may not be readily available. We will strengthen this point in our discussion to highlight the clinical relevance of our case. Thank you again for your constructive feedback. We believe these revisions will enhance the clarity and impact of our manuscript. We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance of our case report. Outcome and Evolution Under Anti-Tuberculosis Therapy We acknowledge the importance of providing details on the patient’s clinical course. Our revised manuscript will include a detailed discussion on the evolution of the patient’s condition, highlighting how the MAS features evolved under anti-tuberculosis treatment and the time frame of clinical and biological improvements. Clarification of "MAS was retained" We recognize that this phrasing may be unclear. In the revised version, we will clarify that the diagnosis of MAS was established based on clinical and laboratory criteria and elaborate on how the condition evolved after initiating anti-tuberculosis treatment. Additional Diagnostic Data Cultures and PCR Studies: Unfortunately, due to resource limitations, cultures and PCR studies were not performed on pleural and ascitic fluids. PCR testing is not always available in our facility. We will clarify this limitation in the revised manuscript. Coagulopathy Markers: While fibrinogen was only borderline abnormal, we will include additional coagulation markers (serum LDH, D-dimer, PT/INR) if available in our records to further assess coagulopathy. Azathioprine Toxicity: We acknowledge that azathioprine toxicity is a differential diagnosis for pancytopenia. However, due to limited laboratory resources in our facility, we were unable to promptly confirm or rule out this possibility. We will explicitly mention this limitation in the revised discussion. Significance of the Case Report We appreciate the concern regarding the novelty of our case. This report's main contribution is to emphasize the importance of early recognition and diagnosis of MAS in disseminated tuberculosis, particularly in resource-limited settings where certain diagnostic tests may not be readily available. We will strengthen this point in our discussion to highlight the clinical relevance of our case. Thank you again for your constructive feedback. We believe these revisions will enhance the clarity and impact of our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 27 Nov 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 17 Apr 25 read read Version 1 27 Nov 24 read read W Winn Chatham , University of Nevada Las Vegas, Las Vegas, USA Luisa Berenise Gámez-González , Autonomous University of Chihuahua, Chihuahua, Mexico Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Gámez-González L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 21 Apr 2025 | for Version 2 Luisa Berenise Gámez-González , Autonomous University of Chihuahua, Chihuahua, Mexico 0 Views copyright © 2025 Gámez-González L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript has been adequately improved, and all of my suggestions and concerns have been addressed. I have no further modifications to suggest. Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical Immunology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Gámez-González LB. Peer Review Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378709) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378709 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Chatham W. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Apr 2025 | for Version 2 W Winn Chatham , University of Nevada Las Vegas, Las Vegas, Nevada, USA 0 Views copyright © 2025 Chatham W. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is now fine to publish as is - authors have sufficiently addressed the initial criticisms. Competing Interests No competing interests were disclosed. Reviewer Expertise Systemic Lupus, Macrophage activation syndromes, Immunodeficiency associated autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Chatham WW. Peer Review Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.180247.r378710) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1439/v2#referee-response-378710 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Gámez-González L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 03 Feb 2025 | for Version 1 Luisa Berenise Gámez-González , Autonomous University of Chihuahua, Chihuahua, Mexico 0 Views copyright © 2025 Gámez-González L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions It would be relevant to mention whether an immune workup was performed to rule out an underlying autoimmune or primary immunodeficiency condition, given the patient’s immunosuppressed state and the development of MAS. It would be valuable to specify whether the patient required additional immuno-modulatory treatment (e.g., corticosteroids, ) beyond anti-tuberculosis therapy. Additionally, a more detailed description of the clinical course, including the time to improvement and resolution of MAS-related complications, would strengthen the discussion I suggest specifying the age at which Crohn’s disease was diagnosed instead of the year, as this provides clearer clinical context. Is the background of the case’s history and progression described in sufficient detail? Partly Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical Immunology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 17 Apr 2025 Salma Riahi, Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia We sincerely appreciate your insightful comments and suggestions, which have helped us refine our manuscript. Below, we address each point raised: Immune Workup for Autoimmune or Primary Immunodeficiency Conditions We acknowledge the importance of assessing underlying immune disorders in the context of MAS. In this case, the immune workup was limited to antinuclear antibody (ANA) testing, which was negative, and an immunoglobulin test, which was normal. Due to resource limitations, further immunological investigations were not performed. However, there were no clinical or biological signs strongly suggestive of a primary immunodeficiency or additional autoimmune condition beyond Crohn’s disease and its treatment-related immunosuppression. We will clarify this point in the revised manuscript. Additional Immunomodulatory Treatment The patient did not receive corticosteroids or other immunomodulatory therapy beyond anti-tuberculosis treatment. The clinical decision was based on the patient’s overall condition and response to tuberculosis therapy. We will specify this in the revised discussion. Clinical Course and Time to Improvement A more detailed description of the patient’s evolution will enhance the discussion. In the revised manuscript, we will provide a clearer timeline of the resolution of MAS-related complications and the patient’s response to treatment. Age at Crohn’s Disease Diagnosis We appreciate this suggestion and will specify the patient’s age at diagnosis instead of the year to provide a clearer clinical context. Thank you again for your valuable feedback. We believe these revisions will strengthen our manuscript. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Gámez-González LB. Peer Review Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r357485) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-357485 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Chatham W. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 30 Dec 2024 | for Version 1 W Winn Chatham , University of Nevada Las Vegas, Las Vegas, Nevada, USA 0 Views copyright © 2025 Chatham W. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is a brief case report describing a patient diagnosed with disseminated tuberculosis who had features of associated macrophage activation syndrome, a previously recognized association. Comments: As written, this report adds little if anything to existing knowledge. There are no apparent unique features of the case or relevant emphasized instructive teaching points. Perhaps discussions of the outcome of this case (no information was provided) would provide some instructive insights. What exactly is meant by "MAS was retained"? Did the MAS features abate with anti-tuberculous therapy and if so, what was the time frame? Missing relevant data: Were cultures or PCR studies performed and positive on the pleural and ascites fluids? As the fibrinogen was only borderline abnormal, were there other features of coagulopathy (elevated serum LDH, d-dimer, elevated PT/INR)? Was azathioprine toxicity considered or ruled out as a cause of the pancytopenia? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No Is the case presented with sufficient detail to be useful for other practitioners? No Competing Interests No competing interests were disclosed. Reviewer Expertise Systemic Lupus, Macrophage activation syndromes, Immunodeficiency associated autoimmunity I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 17 Apr 2025 Salma Riahi, Laboratory of Hematology, Sahloul Hospital, Sousse, Tunisia We sincerely appreciate your thoughtful review of our manuscript and your valuable suggestions. Below, we address the points raised and outline the revisions made to improve the clarity and relevance of our case report. Outcome and Evolution Under Anti-Tuberculosis Therapy We acknowledge the importance of providing details on the patient’s clinical course. Our revised manuscript will include a detailed discussion on the evolution of the patient’s condition, highlighting how the MAS features evolved under anti-tuberculosis treatment and the time frame of clinical and biological improvements. Clarification of "MAS was retained" We recognize that this phrasing may be unclear. In the revised version, we will clarify that the diagnosis of MAS was established based on clinical and laboratory criteria and elaborate on how the condition evolved after initiating anti-tuberculosis treatment. Additional Diagnostic Data Cultures and PCR Studies: Unfortunately, due to resource limitations, cultures and PCR studies were not performed on pleural and ascitic fluids. PCR testing is not always available in our facility. We will clarify this limitation in the revised manuscript. Coagulopathy Markers: While fibrinogen was only borderline abnormal, we will include additional coagulation markers (serum LDH, D-dimer, PT/INR) if available in our records to further assess coagulopathy. Azathioprine Toxicity: We acknowledge that azathioprine toxicity is a differential diagnosis for pancytopenia. However, due to limited laboratory resources in our facility, we were unable to promptly confirm or rule out this possibility. We will explicitly mention this limitation in the revised discussion. Significance of the Case Report We appreciate the concern regarding the novelty of our case. This report's main contribution is to emphasize the importance of early recognition and diagnosis of MAS in disseminated tuberculosis, particularly in resource-limited settings where certain diagnostic tests may not be readily available. We will strengthen this point in our discussion to highlight the clinical relevance of our case. Thank you again for your constructive feedback. We believe these revisions will enhance the clarity and impact of our manuscript. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Chatham WW. Peer Review Report For: Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1439 ( https://doi.org/10.5256/f1000research.174644.r347815) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1439/v1#referee-response-347815 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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