Disseminated Mycobacterium haemophilum infection in an immunocompromised host: A complex case with immune reconstitution inflammatory syndrome (IRIS) manifestation

Disseminated Mycobacterium haemophilum infection in an immunocompromised host: A complex case with immune reconstitution inflammatory syndrome (IRIS) manifestation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Disseminated Mycobacterium haemophilum infection in an immunocompromised host: A complex case with immune reconstitution inflammatory syndrome (IRIS) manifestation Ming Hong Choi, Hao Wu, Kwok Yung Yuen, Ivan Fan Ngai Hung This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3963700/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background Mycobacterium haemophilum is a rare but significant opportunistic pathogen known to cause infections in immunocompromised individuals. Despite its low prevalence, disseminated infections with this organism can present diagnostic and therapeutic challenges, particularly in hosts with compromised immune systems. The phenomenon of Immune Reconstitution Inflammatory Syndrome (IRIS) further complicates the clinical course and management of such cases. Case Presentation : A 39-year-old male patient with a medical history of T-cell acute lymphoblastic leukaemia (T-ALL) who underwent a matched unrelated donor haematopoietic stem cell transplantation four years prior presented with fever and rash affecting all four limbs and the back. Subsequent evaluation confirmed a diagnosis of cutaneous Mycobacterium haemophilum infection, which was found to have disseminated to multiple organ systems including the lungs, gastrointestinal tract, and nasal turbinate. Treatment initiation resulted in immune reconstitution inflammatory syndrome (IRIS), posing challenges in managing the infection in the context of heightened immune response post-reconstitution. This case highlights the complexities involved in managing disseminated mycobacterial infections with IRIS following immune reconstitution. Conclusion This case highlights the diagnostic dilemmas and therapeutic considerations in managing disseminated Mycobacterium Haemophilum infection in immunocompromised hosts. The manifestation of IRIS further complicates the clinical course, necessitating a multidisciplinary approach to optimize patient outcomes. Our experience underscores the importance of early recognition, tailored antimicrobial therapy, and meticulous monitoring in managing such cases, with implications for clinicians caring for immunocompromised patients. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Nontuberculous mycobacteria (NTM) are acid-fast bacilli distinct from Mycobacterium tuberculosis and Mycobacterium leprae and can be further classified as rapidly growing or slowly growing based on their growth rate. NTM is widely distributed in environmental sources, such as soil, water, dust, food items, and moist hospital areas. Cutaneous NTM infections exhibit diverse clinical manifestations, including cellulitis, non-healing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, and verrucous lesions 1 . The prevalence of cutaneous NTM infections in Hong Kong is currently unknown, but there has been a significant increase in recent years. Several factors contribute to this rise, including the use of immunosuppressive therapies and an increase in surgical and cosmetic procedures. Advances in diagnostic techniques, such as cultures and polymerase chain reaction (PCR) methods, have improved the identification of NTM infections, facilitating more accurate diagnosis 2 . Immunocompromised individuals, particularly recipients of stem cell or organ transplants, are at a higher risk of NTM infection. Case Presentation In July 2023, a 39-year-old Chinese engineer, presented with a month-long history of fever and a non-tender, non-pruritic rash affecting all four limbs and his back. Upon admission to the haematology unit of Queen Mary Hospital, he denied any recent trauma or symptoms related to the respiratory, neurological, or urinary systems. Moreover, the patient indicated no recent travel, hiking, freshwater exposure, or insect bites. The patient has a medical history of hypertension and T-cell acute lymphoblastic leukaemia (T-ALL), which was diagnosed in November 2018. He underwent a matched unrelated donor haematopoietic stem cell transplantation on 29th June 2019 and is currently in complete remission. He developed gut and liver graft-versus-host disease (GVHD), for which he requires ongoing immunosuppressive therapy. A recent bone marrow examination on 19th June 2020, showed regenerating marrow with no signs of recurrence. The patient's current medication regimen includes Acyclovir, Amlodipine, Betaloc, Pepcidine, Trimethoprim-sulfamethoxazole (TMP-SMX), Ursodeoxycholic acid, Mycophenolate mofetil, Prednisolone, Ruxolitinib phosphate, and Sirolimus. The dosage of these medications has remained unchanged for the past 6 months. Regarding his social background, the patient never smokes and denied any regular alcohol or drug use. He also denied taking any over-the-counter medication or traditional Chinese medication. Physical examination revealed multiple erythematous non-tender non-pruritic nodules over four limbs and painful swelling over the right second to fourth metatarsal pharyngeal joints (Fig. 1 – 3 ). There were no palpable cervical, axillary, or inguinal lymph nodes. The oral mucosal surface and conjunctiva were not involved. There were no obvious nail changes. Initial investigations include: Clinical photographs Blood tests: Complete blood count, liver and renal function test, lactate dehydrogenase (LDH), C-reactive protein (CPR), Erythrocytes sedimentation rate (ESR), creatine kinase (CK), Sirolimus level, autoimmune markers (Table 1 ) Microbiological workup including bacterial and fungal culture (Table 2 ) Skin biopsy Table 1 Investigations Result (reference range) Haemoglobin 10.1 g/dL (13.3–17.1) WBC 6.38 x 10 9 /L (3.89–9.93) Platelet 216 x 10 9 /L (167–396) Sodium 137 mmol/L (135–145) Potassium 4.1 mmol/L (3.5–5.5) Creatinine 142 µmol/L (67–109) eGFR (CKD-EPI) 53 (> 90) Total bilirubin 7 umol/L (4–23) Alkaline Phosphatase 92 U/L (42–110) Alanine Aminotransferase 45 U/L (8–58) Aspartate Aminotransferase 33 U/L (15–38) Albumin adjusted calcium 2.21 mmol/L (2.11–2.55) CRP 3.02 mg/dL ( 140 mm/h (< 7) Creatine kinase 166 U/L (65–355) Sirolimus level 10 (Therapeutic 5–15 ug/L) LDH 360 U/L (118–221) Hepatitis B screen (HBsAg and Anti-HBc) Non-reactive Autoimmune markers including ANA, Anti-dsDNA, ANCA and Anti-ENA Negative Table 2 Cytomegalovirus Antigen pp65 Not detected Cryptococcal antigen Negative Aspergillus antigen Negative Epstein Barr Virus DNA PCR: < 100 IU/mL Blood culture No growth Urine culture No growth HIV antigen and Anti-HIV 1/2 Negative Following a skin biopsy on the patient's right forearm, acid-fast bacilli were identified in the deep dermis and subcutis, suggestive of mycobacterial infection (Fig. 4 ). Absence of granulomas, leukemic infiltrate, or graft-versus-host disease was noted. Subsequent molecular testing utilizing 16S rRNA and hsp65 sequencing definitively identified the presence of Mycobacterium haemophilum . Concurrently, Mycobacterium haemophilum was isolated from the patient's sputum and stool samples, corroborating the systemic dissemination of the infection. A positron emission tomography-computed tomography (PET-CT) scan revealed new hypermetabolic lesions in various locations, including the left inferior turbinate, lymph nodes (left cervical level IIA, left level IB, right level VA, left supraclavicular fossa), and subcutaneous areas (left leg, right thigh, left arm, dorsum of right hand, right ear). Additionally, generalized increased uptake in the spleen was observed. Based on these findings, the patient was diagnosed with disseminated Mycobacterium haemophilium infection. The patient received comprehensive care from a multidisciplinary team comprising infectious disease physicians, dermatologists, and haematologists in our hospital. The infectious disease physician prescribed Rifabutin 300mg PO daily, Levofloxacin 500 mg PO daily, and Clarithromycin 500mg PO BD as treatment. The haematologist promptly reduced the Prednisolone dosage and tapered off the Mycophenolate mofetil and sirolimus medications the patient had been taking. Following two weeks of treatment, the patient experienced recurring fever, particularly at night, along with the emergence of new erythematous nodules on his face and upper back (Fig. 5 ). To further investigate, a repeated skin biopsy was conducted on his upper back, revealing granulomatous inflammation (Fig. 6 ). However, multiple Ziehl-Neelsen stain assessments did not indicate the presence of acid-fast bacilli (Fig. 7 ). Additionally, a thorough septic workup, inclusive of blood, sputum, urine, and stool cultures, yielded negative results. The decline in AFB load in sputum and reappearance of granulomatous inflammation indicated a recovery of immune function, suggesting a diagnosis of Immune Reconstitution Inflammatory Syndrome (IRIS) instead of a drug-resistant mycobacterial infection. The patient's treatment regimen was changed to include Prednisolone 35mg daily in addition to continued levofloxacin, rifabutin, and clarithromycin. After one week, the patient's fever subsided and the erythematous rash on their trunk, face, and scalp significantly improved. Inflammatory markers showed a downward trend. The Prednisolone dosage was gradually reduced to 5mg daily. Discussion Mycobacterium haemophilum is a prevalent, slow-growing non-tuberculous mycobacterium (NTM) that thrives at temperatures between 28 to 32°C. It possesses unique growth requirements and cannot be cultured on standard mycobacterial media like Lowenstein-Jensen or Middlebrook 7H11 unless supplemented with hemin or ferric iron-containing compounds 3 – 5 . M. haemophilum is associated with various subcutaneous infections, lymphadenitis, septic arthritis, osteomyelitis, pneumonitis, and disseminated disease 1 . Cutaneous Mycobacterium haemophilum infection commonly manifests as nodules in immunosuppressed individuals, particularly in areas of lower temperature, such as the extremities 4 . It can also present as ulcers, abscesses, pustules, or localized swelling. Diagnosis is challenging due to the time-consuming nature of mycobacterial cultures, which may require up to six weeks for growth 5 . However, 16S rRNA sequencing and hsp65 sequencing can provide valuable diagnostic assistance 6 . In patients with clinical signs suggestive of nontuberculous mycobacteriosis and negative routine mycobacterial cultures, it is important to consider M. haemophilum infection as a possible underlying cause. A standardized guideline for managing cutaneous Mycobacterium haemophilum infection is currently lacking. Existing literature suggests a regimen of triple-drug therapy, consisting of clarithromycin, ciprofloxacin, and rifamycin, for at least twelve to twenty-four months. The course of antibiotics should be individualized, considering the extent of disease dissemination and the level of immune suppression 7 . Prolonged treatment with single-agent therapy is not recommended for atypical mycobacterial infections due to the heightened risk of antibiotic resistance 8 . Immune Reconstitution Inflammatory Syndrome (IRIS) was initially observed in individuals infected with Human Immunodeficiency Virus (HIV) infection undergoing anti-retroviral therapy (ART) 8 . However, it has also been reported in non-HIV patients, including solid organ and stem cell transplant recipients, as well as individuals who have ceased tumour necrosis factor (TNF)-α antagonists or steroids 8 – 9 . In the context of HIV-negative patients, non-HIV IRIS is broadly defined as an inflammatory response against antigens or pathogenic microorganisms that were likely present before the restoration of immune function. This immune response can manifest as an unmasking of new inflammatory events or exacerbation of preexisting or previously treated inflammatory events shortly after immune reconstitution 8 – 10 . The mechanism underlying IRIS is thought to involve a delicate balance between proinflammatory responses, primarily regulated by macrophages and natural killer cells, and anti-inflammatory responses, regulated by T helper 2 (Th2) cells and regulatory T cells 8 . However, certain conditions or medications, such as immunosuppressants, can disrupt this balance, leading to heightened proinflammatory responses upon recovery from immunosuppression 8 . Currently, there is no specific diagnostic test for IRIS, and its clinical presentation can vary depending on which organ was affected by the pathogen before immune recovery. Distinguishing IRIS from disease relapse or exacerbation after antimicrobial treatment, as well as from inflammation caused by a new pathogenic microorganism, represents a significant challenge. In this case, we believe the rapid tapering of immunosuppression contributes to the development of IRIS. In the treatment of IRIS associated with mycobacterial infection, corticosteroids are commonly utilized as the initial therapy. In cases of resistance or inadequate response to corticosteroids, TNF-α antagonists can serve as alternate therapeutic agents, as IRIS encompasses an overabundance of pro-inflammatory cytokines including TNF-α, interleukin-1, and interleukin-6 9–10 . Conclusion In conclusion, this case report illustrates the occurrence of disseminated Mycobacterium haemophilum infection in a post-stem cell transplant recipient, complicated by IRIS and successfully treated with steroids. Despite challenges in identifying the pathogen through routine septic workup, molecular diagnostics, including PCR and sequencing, facilitated accurate diagnosis. The management approach involved implementing timely interventions, comprehensive evaluation, and vigilant surveillance, underscoring the significance of a multidimensional approach to effectively manage intricate infections in immunocompromised hosts. Declarations Written informed consent was obtained from the patient for the publication of this case report. Ethics approval and consent to participate Ethics approval is not required as there was no experimental protocol Consent for publication Written informed consent from the patient was obtained for the publication of identifying information/images in an online open-access publication (when applicable) Availability of data and materials Not applicable Competing interests None Funding No Acknowledgements The authors are grateful to Dr. Wai Ching Wong for looking after the patient Authors' contributions MHC wrote the main manuscript text and HW prepared Figures 4,6, and 7. KYY and IFNH reviewed the final version of the manuscript. All authors revised and approved the final draft of the manuscript critically for important intellectual content. References Franco-Paredes C, Marcos LA, Henao-Martínez AF, Rodríguez-Morales AJ, Villamil-Gómez WE, Gotuzzo E, Bonifaz A. Cutaneous Mycobacterial Infections. Clin Microbiol Rev. 2018;32(1):e00069–18. Lindeboom JA. et.al. Clinical manifestations, diagnosis, and treatment of Mycobacterium haemophilum infections. Clin Microbiol Rev. 2011 Oct. Khan FA. et.al. Nontuberculous mycobacterial cutaneous infections: an updated review. Cutis. 2011 Oct. Lamb RC, editor. et.al. Cutaneous non-tuberculous mycobacterial infections. Int J Dermatol. 2014 Oct. Kaul S, Kaur I. et.al. Cutaneous tuberculosis. Part I: Pathogenesis, classification, and clinical features. J Am Acad Dermatol. 2023 Dec. Lau SK. et.al. First report of disseminated Mycobacterium skin infections in two liver transplant recipients and rapid diagnosis by hsp65 gene sequencing. J Clin Microbiol. 2011 Nov. Yasen D. et.al. Mycobacterium haemophilum infection with cutaneous involvement: two case reports and an updated literature review: Mycobacterium haemophilum skin infection. J Dtsch Dermatol Ges. 2023 Nov. Kobayashi M. et.al. Nontuberculous Mycobacterium-associated immune reconstitution inflammatory syndrome in a non-HIV immunosuppressed patient. Respirol Case Rep. 2022 Feb. Armange L. et.al. The use of TNF-α antagonists in tuberculosis to control severe paradoxical reaction or immune reconstitution inflammatory syndrome: a case series and literature review. Eur J Clin Microbiol Infect Dis. 2023 Apr. Sueki H. et.al. Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol. 2018 Jan. Additional Declarations No competing interests reported. Supplementary Files Histologyslides.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 14 Mar, 2024 Submission checks completed at journal 14 Mar, 2024 First submitted to journal 17 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3963700","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":279709452,"identity":"3604a8b4-dba0-42fd-b6cf-fe035eb693bf","order_by":0,"name":"Ming Hong Choi","email":"","orcid":"","institution":"Queen Mary Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"Hong","lastName":"Choi","suffix":""},{"id":279709453,"identity":"d2a5e0fb-059e-4bb8-9766-31f6d6ce5bdb","order_by":1,"name":"Hao Wu","email":"","orcid":"","institution":"Queen Mary Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Wu","suffix":""},{"id":279709454,"identity":"c6be041a-629b-496f-ac53-492b27d3cf94","order_by":2,"name":"Kwok Yung Yuen","email":"","orcid":"","institution":"State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection","correspondingAuthor":false,"prefix":"","firstName":"Kwok","middleName":"Yung","lastName":"Yuen","suffix":""},{"id":279709455,"identity":"be473995-2f88-48a9-83cc-a61aeb64b31c","order_by":3,"name":"Ivan Fan Ngai Hung","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACNiBmBjH4JYBMxoYEErRIziBWCwNMi8ENYrXwSSQ/e1zYdsdu8+22NAnGHWlEOEwizdx4Ztuz5G13jh2TYDyTQ4QWngNm0rxth5PNbqS3STC2VRCj5fg3sBbjGURrYe8B22JnIJEGdFgbMQ5j7ymT5jl3OEHiRlqyRWIbEd6Xb2bfJs1Tdtief0aa4Y2PbcmEtcBAYgOITCBeAwODPSmKR8EoGAWjYIQBAPAeNLSV/EUFAAAAAElFTkSuQmCC","orcid":"","institution":"Queen Mary Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ivan","middleName":"Fan Ngai","lastName":"Hung","suffix":""}],"badges":[],"createdAt":"2024-02-17 10:00:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3963700/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3963700/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52902702,"identity":"61fadec4-5bd3-4cdb-9780-c13884d87dba","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":9047,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photos of the patient’s right upper limb showing scattered erythematous nodules\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/a3705b37f063db02dc6076a4.jpg"},{"id":52902703,"identity":"ebbd04fb-489d-48a2-b189-b708a12d962b","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":25806,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photos of the patient’s left leg\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/645fc38d8e75ccf95ca7ab61.jpg"},{"id":52902704,"identity":"453af851-c465-44cd-b247-0d1cc1311f1d","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30586,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photos of the patient’s hands\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/b9b3c85742623df18880a2fd.jpg"},{"id":52902708,"identity":"c7348a87-5567-47a4-aaec-dc0492f9c833","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":155579,"visible":true,"origin":"","legend":"\u003cp\u003eHistology of the skin biopsy at the right forearm showed many acid-fast bacilli in the deep dermis and subcutis. (Ziehl-Neelsen stain 10 x 40)\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/51064e76d0220260166015ff.jpg"},{"id":52902710,"identity":"3f13be0b-e303-4b72-b0e0-77cd84a47a76","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":8795,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photos of the patient’s back showing multiple erythematous nodules\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/404da6fc78c225a1f5b4b54a.jpg"},{"id":52902709,"identity":"4052f6b9-1416-4c88-805e-71225dbbff31","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":108907,"visible":true,"origin":"","legend":"\u003cp\u003eHistology of the skin biopsy at the back showed granulomas composed of epithelioid histiocytes, mixed acute and chronic inflammatory cells and Langhans giant cells are seen. (Hematoxylin and eosin stain: 10×20)\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/9c7e561a89179d7320b613b0.jpg"},{"id":52902706,"identity":"4db8932f-e012-468a-840b-016164f44107","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":104457,"visible":true,"origin":"","legend":"\u003cp\u003eZiehl-Neelsen staining on multiple levels do not show definite acid-fast bacilli. (Ziehl-Neelsen stain 10 x 40)\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/aa9b5e2df325688a8983761b.jpg"},{"id":52903526,"identity":"86327a84-8309-42e1-9923-44b1596230e4","added_by":"auto","created_at":"2024-03-18 14:25:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":542932,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/3dd7be36-758c-41ac-bfac-bf0362986402.pdf"},{"id":52902705,"identity":"cd20eefc-7aee-4109-a7ae-96b752f950b3","added_by":"auto","created_at":"2024-03-18 14:17:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1278650,"visible":true,"origin":"","legend":"","description":"","filename":"Histologyslides.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3963700/v1/b29e714584b0f109f2a23e09.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disseminated Mycobacterium haemophilum infection in an immunocompromised host: A complex case with immune reconstitution inflammatory syndrome (IRIS) manifestation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNontuberculous mycobacteria (NTM) are acid-fast bacilli distinct from \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e and \u003cem\u003eMycobacterium leprae\u003c/em\u003e and can be further classified as rapidly growing or slowly growing based on their growth rate. NTM is widely distributed in environmental sources, such as soil, water, dust, food items, and moist hospital areas. Cutaneous NTM infections exhibit diverse clinical manifestations, including cellulitis, non-healing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, and verrucous lesions\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe prevalence of cutaneous NTM infections in Hong Kong is currently unknown, but there has been a significant increase in recent years. Several factors contribute to this rise, including the use of immunosuppressive therapies and an increase in surgical and cosmetic procedures. Advances in diagnostic techniques, such as cultures and polymerase chain reaction (PCR) methods, have improved the identification of NTM infections, facilitating more accurate diagnosis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Immunocompromised individuals, particularly recipients of stem cell or organ transplants, are at a higher risk of NTM infection.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eIn July 2023, a 39-year-old Chinese engineer, presented with a month-long history of fever and a non-tender, non-pruritic rash affecting all four limbs and his back. Upon admission to the haematology unit of Queen Mary Hospital, he denied any recent trauma or symptoms related to the respiratory, neurological, or urinary systems. Moreover, the patient indicated no recent travel, hiking, freshwater exposure, or insect bites.\u003c/p\u003e \u003cp\u003eThe patient has a medical history of hypertension and T-cell acute lymphoblastic leukaemia (T-ALL), which was diagnosed in November 2018. He underwent a matched unrelated donor haematopoietic stem cell transplantation on 29th June 2019 and is currently in complete remission. He developed gut and liver graft-versus-host disease (GVHD), for which he requires ongoing immunosuppressive therapy. A recent bone marrow examination on 19th June 2020, showed regenerating marrow with no signs of recurrence. The patient's current medication regimen includes Acyclovir, Amlodipine, Betaloc, Pepcidine, Trimethoprim-sulfamethoxazole (TMP-SMX), Ursodeoxycholic acid, Mycophenolate mofetil, Prednisolone, Ruxolitinib phosphate, and Sirolimus. The dosage of these medications has remained unchanged for the past 6 months. Regarding his social background, the patient never smokes and denied any regular alcohol or drug use. He also denied taking any over-the-counter medication or traditional Chinese medication.\u003c/p\u003e \u003cp\u003ePhysical examination revealed multiple erythematous non-tender non-pruritic nodules over four limbs and painful swelling over the right second to fourth metatarsal pharyngeal joints (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There were no palpable cervical, axillary, or inguinal lymph nodes. The oral mucosal surface and conjunctiva were not involved. There were no obvious nail changes.\u003c/p\u003e \u003cp\u003eInitial investigations include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eClinical photographs\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBlood tests: Complete blood count, liver and renal function test, lactate dehydrogenase (LDH), C-reactive protein (CPR), Erythrocytes sedimentation rate (ESR), creatine kinase (CK), Sirolimus level, autoimmune markers (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMicrobiological workup including bacterial and fungal culture (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSkin biopsy\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResult (reference range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.1 g/dL (13.3\u0026ndash;17.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.38 x 10\u003csup\u003e9\u003c/sup\u003e/L (3.89\u0026ndash;9.93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e216 x 10\u003csup\u003e9\u003c/sup\u003e/L (167\u0026ndash;396)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137 mmol/L (135\u0026ndash;145)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.1 mmol/L (3.5\u0026ndash;5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142 \u0026micro;mol/L (67\u0026ndash;109)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (CKD-EPI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (\u0026gt;\u0026thinsp;90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 umol/L (4\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline Phosphatase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 U/L (42\u0026ndash;110)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine Aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 U/L (8\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate Aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 U/L (15\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin adjusted calcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.21 mmol/L (2.11\u0026ndash;2.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.02 mg/dL (\u0026lt;\u0026thinsp;0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;140 mm/h (\u0026lt;\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatine\u0026nbsp;kinase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e166 U/L (65\u0026ndash;355)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSirolimus level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (Therapeutic 5\u0026ndash;15 ug/L)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360 U/L (118\u0026ndash;221)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis B screen (HBsAg and Anti-HBc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-reactive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAutoimmune markers including ANA, Anti-dsDNA, ANCA and Anti-ENA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus Antigen pp65\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot detected\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCryptococcal antigen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspergillus antigen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpstein Barr Virus DNA PCR:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;100 IU/mL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood culture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo growth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine culture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo growth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV antigen and Anti-HIV 1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFollowing a skin biopsy on the patient's right forearm, acid-fast bacilli were identified in the deep dermis and subcutis, suggestive of mycobacterial infection (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Absence of granulomas, leukemic infiltrate, or graft-versus-host disease was noted. Subsequent molecular testing utilizing 16S rRNA and hsp65 sequencing definitively identified the presence of \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e. Concurrently, \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e was isolated from the patient's sputum and stool samples, corroborating the systemic dissemination of the infection.\u003c/p\u003e \u003cp\u003eA positron emission tomography-computed tomography (PET-CT) scan revealed new hypermetabolic lesions in various locations, including the left inferior turbinate, lymph nodes (left cervical level IIA, left level IB, right level VA, left supraclavicular fossa), and subcutaneous areas (left leg, right thigh, left arm, dorsum of right hand, right ear). Additionally, generalized increased uptake in the spleen was observed. Based on these findings, the patient was diagnosed with disseminated \u003cem\u003eMycobacterium haemophilium\u003c/em\u003e infection.\u003c/p\u003e \u003cp\u003eThe patient received comprehensive care from a multidisciplinary team comprising infectious disease physicians, dermatologists, and haematologists in our hospital. The infectious disease physician prescribed Rifabutin 300mg PO daily, Levofloxacin 500 mg PO daily, and Clarithromycin 500mg PO BD as treatment. The haematologist promptly reduced the Prednisolone dosage and tapered off the Mycophenolate mofetil and sirolimus medications the patient had been taking.\u003c/p\u003e \u003cp\u003eFollowing two weeks of treatment, the patient experienced recurring fever, particularly at night, along with the emergence of new erythematous nodules on his face and upper back (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). To further investigate, a repeated skin biopsy was conducted on his upper back, revealing granulomatous inflammation (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). However, multiple Ziehl-Neelsen stain assessments did not indicate the presence of acid-fast bacilli (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Additionally, a thorough septic workup, inclusive of blood, sputum, urine, and stool cultures, yielded negative results.\u003c/p\u003e \u003cp\u003eThe decline in AFB load in sputum and reappearance of granulomatous inflammation indicated a recovery of immune function, suggesting a diagnosis of Immune Reconstitution Inflammatory Syndrome (IRIS) instead of a drug-resistant mycobacterial infection. The patient's treatment regimen was changed to include Prednisolone 35mg daily in addition to continued levofloxacin, rifabutin, and clarithromycin. After one week, the patient's fever subsided and the erythematous rash on their trunk, face, and scalp significantly improved. Inflammatory markers showed a downward trend. The Prednisolone dosage was gradually reduced to 5mg daily.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e is a prevalent, slow-growing non-tuberculous mycobacterium (NTM) that thrives at temperatures between 28 to 32\u0026deg;C. It possesses unique growth requirements and cannot be cultured on standard mycobacterial media like Lowenstein-Jensen or Middlebrook 7H11 unless supplemented with hemin or ferric iron-containing compounds\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eM. haemophilum\u003c/em\u003e is associated with various subcutaneous infections, lymphadenitis, septic arthritis, osteomyelitis, pneumonitis, and disseminated disease\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCutaneous \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infection commonly manifests as nodules in immunosuppressed individuals, particularly in areas of lower temperature, such as the extremities\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. It can also present as ulcers, abscesses, pustules, or localized swelling. Diagnosis is challenging due to the time-consuming nature of mycobacterial cultures, which may require up to six weeks for growth\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, 16S rRNA sequencing and hsp65 sequencing can provide valuable diagnostic assistance\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In patients with clinical signs suggestive of nontuberculous mycobacteriosis and negative routine mycobacterial cultures, it is important to consider \u003cem\u003eM. haemophilum\u003c/em\u003e infection as a possible underlying cause.\u003c/p\u003e \u003cp\u003eA standardized guideline for managing cutaneous \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infection is currently lacking. Existing literature suggests a regimen of triple-drug therapy, consisting of clarithromycin, ciprofloxacin, and rifamycin, for at least twelve to twenty-four months. The course of antibiotics should be individualized, considering the extent of disease dissemination and the level of immune suppression\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Prolonged treatment with single-agent therapy is not recommended for atypical mycobacterial infections due to the heightened risk of antibiotic resistance\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImmune Reconstitution Inflammatory Syndrome (IRIS) was initially observed in individuals infected with Human Immunodeficiency Virus (HIV) infection undergoing anti-retroviral therapy (ART)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, it has also been reported in non-HIV patients, including solid organ and stem cell transplant recipients, as well as individuals who have ceased tumour necrosis factor (TNF)-α antagonists or steroids\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In the context of HIV-negative patients, non-HIV IRIS is broadly defined as an inflammatory response against antigens or pathogenic microorganisms that were likely present before the restoration of immune function. This immune response can manifest as an unmasking of new inflammatory events or exacerbation of preexisting or previously treated inflammatory events shortly after immune reconstitution\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mechanism underlying IRIS is thought to involve a delicate balance between proinflammatory responses, primarily regulated by macrophages and natural killer cells, and anti-inflammatory responses, regulated by T helper 2 (Th2) cells and regulatory T cells\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, certain conditions or medications, such as immunosuppressants, can disrupt this balance, leading to heightened proinflammatory responses upon recovery from immunosuppression\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Currently, there is no specific diagnostic test for IRIS, and its clinical presentation can vary depending on which organ was affected by the pathogen before immune recovery. Distinguishing IRIS from disease relapse or exacerbation after antimicrobial treatment, as well as from inflammation caused by a new pathogenic microorganism, represents a significant challenge. In this case, we believe the rapid tapering of immunosuppression contributes to the development of IRIS.\u003c/p\u003e \u003cp\u003eIn the treatment of IRIS associated with mycobacterial infection, corticosteroids are commonly utilized as the initial therapy. In cases of resistance or inadequate response to corticosteroids, TNF-α antagonists can serve as alternate therapeutic agents, as IRIS encompasses an overabundance of pro-inflammatory cytokines including TNF-α, interleukin-1, and interleukin-6\u003csup\u003e9\u0026ndash;10\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this case report illustrates the occurrence of disseminated \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infection in a post-stem cell transplant recipient, complicated by IRIS and successfully treated with steroids. Despite challenges in identifying the pathogen through routine septic workup, molecular diagnostics, including PCR and sequencing, facilitated accurate diagnosis. The management approach involved implementing timely interventions, comprehensive evaluation, and vigilant surveillance, underscoring the significance of a multidimensional approach to effectively manage intricate infections in immunocompromised hosts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eEthics approval and consent to participate\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval is not required as there was no experimental protocol\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent from the patient was obtained for the publication of identifying information/images in an online open-access publication (when applicable)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAvailability of data and materials\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Dr. Wai Ching Wong for looking after the patient\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAuthors\u0026apos; contributions\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMHC wrote the main manuscript text and HW prepared Figures 4,6, and 7. KYY and IFNH reviewed the final version of the manuscript. All authors revised and approved the final draft of the manuscript critically for important intellectual content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFranco-Paredes C, Marcos LA, Henao-Mart\u0026iacute;nez AF, Rodr\u0026iacute;guez-Morales AJ, Villamil-G\u0026oacute;mez WE, Gotuzzo E, Bonifaz A. Cutaneous Mycobacterial Infections. Clin Microbiol Rev. 2018;32(1):e00069\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLindeboom JA. et.al. Clinical manifestations, diagnosis, and treatment of \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infections. Clin Microbiol Rev. 2011 Oct.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan FA. et.al. Nontuberculous mycobacterial cutaneous infections: an updated review. Cutis. 2011 Oct.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLamb RC, editor. et.al. Cutaneous non-tuberculous mycobacterial infections. Int J Dermatol. 2014 Oct.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaul S, Kaur I. et.al. Cutaneous tuberculosis. Part I: Pathogenesis, classification, and clinical features. J Am Acad Dermatol. 2023 Dec.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLau SK. et.al. First report of disseminated Mycobacterium skin infections in two liver transplant recipients and rapid diagnosis by hsp65 gene sequencing. J Clin Microbiol. 2011 Nov.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYasen D. et.al. \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infection with cutaneous involvement: two case reports and an updated literature review: \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e skin infection. J Dtsch Dermatol Ges. 2023 Nov.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobayashi M. et.al. Nontuberculous Mycobacterium-associated immune reconstitution inflammatory syndrome in a non-HIV immunosuppressed patient. Respirol Case Rep. 2022 Feb.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmange L. et.al. The use of TNF-α antagonists in tuberculosis to control severe paradoxical reaction or immune reconstitution inflammatory syndrome: a case series and literature review. Eur J Clin Microbiol Infect Dis. 2023 Apr.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSueki H. et.al. Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol. 2018 Jan.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3963700/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3963700/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e is a rare but significant opportunistic pathogen known to cause infections in immunocompromised individuals. Despite its low prevalence, disseminated infections with this organism can present diagnostic and therapeutic challenges, particularly in hosts with compromised immune systems. The phenomenon of Immune Reconstitution Inflammatory Syndrome (IRIS) further complicates the clinical course and management of such cases.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e \u003cp\u003e: A 39-year-old male patient with a medical history of T-cell acute lymphoblastic leukaemia (T-ALL) who underwent a matched unrelated donor haematopoietic stem cell transplantation four years prior presented with fever and rash affecting all four limbs and the back. Subsequent evaluation confirmed a diagnosis of cutaneous \u003cem\u003eMycobacterium haemophilum\u003c/em\u003e infection, which was found to have disseminated to multiple organ systems including the lungs, gastrointestinal tract, and nasal turbinate. Treatment initiation resulted in immune reconstitution inflammatory syndrome (IRIS), posing challenges in managing the infection in the context of heightened immune response post-reconstitution. This case highlights the complexities involved in managing disseminated mycobacterial infections with IRIS following immune reconstitution.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case highlights the diagnostic dilemmas and therapeutic considerations in managing disseminated Mycobacterium Haemophilum infection in immunocompromised hosts. The manifestation of IRIS further complicates the clinical course, necessitating a multidisciplinary approach to optimize patient outcomes. Our experience underscores the importance of early recognition, tailored antimicrobial therapy, and meticulous monitoring in managing such cases, with implications for clinicians caring for immunocompromised patients.\u003c/p\u003e","manuscriptTitle":"Disseminated Mycobacterium haemophilum infection in an immunocompromised host: A complex case with immune reconstitution inflammatory syndrome (IRIS) manifestation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-18 14:17:46","doi":"10.21203/rs.3.rs-3963700/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-03-14T17:12:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-14T16:03:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-02-17T09:59:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b5f26de7-3fff-409a-a7f6-0895ef70fb78","owner":[],"postedDate":"March 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-03-18T14:17:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-18 14:17:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3963700","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3963700","identity":"rs-3963700","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}