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Cryptococcal fungemia and Mycobacterium haemophilum cellulitis in a patient receiving ruxolitinib: a case report and literature review



Ruxolitinib is a novel oral Janus kinase inhibitor that is used for treatment of myeloproliferative diseases. It exhibits potent anti-inflammatory and immunosuppressive effects, and may increase the risk of opportunistic infections. Here, we report a rare case of Cryptococcus neoformans and Mycobacterium haemophilum coinfection in a myelofibrosis patient who was receiving ruxolitinib.

Case presentation

A 70-year-old Thai man who was diagnosed with JAK2V617F-mutation-positive primary myelofibrosis had been treated with ruxolitinib for 4 years. He presented with cellulitis at his left leg for 1 week. Physical examination revealed fever, dyspnea, desaturation, and sign of inflammation on the left leg and ulcers on the right foot. Blood cultures showed positive for C. neoformans. He was prescribed intravenous amphotericin B deoxycholate with a subsequent switch to liposomal amphotericin B due to the development of acute kidney injury. He developed new onset of fever after 1 month of antifungal treatment, and the lesion on his left leg had worsened. Biopsy of that skin lesion was sent for mycobacterial culture, and the result showed M. haemophilum. He was treated with levofloxacin, ethambutol, and rifampicin; however, the patient eventually developed septic shock and expired.


This is the first case of C. neoformans and M. haemophilum coinfection in a patient receiving ruxolitinib treatment. Although uncommon, clinicians should be aware of the potential for multiple opportunistic infections that may be caused by atypical pathogens in patients receiving ruxolitinib.

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Ruxolitinib is a novel biologic agent used for the treatment of myeloproliferative diseases, that inhibits Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). Although it is effective and had a survival benefit in such patients, this immunosuppressive agent may increase the risk of opportunistic infections. However, reports related to its infectious complications is limited. Previous studies reported bacteria, Mycobacterium tuberculosis, Cryptococcus neoformans, Pneumocystis jirovecii, herpes simplex, and varicella zoster virus to be etiologic agents that were isolated from patients receiving ruxolitinib [1]. Furthermore, no previous case has been reported of Mycobacterium haemophilum infection or concurrent infection by two pathogens in a patient receiving ruxolitinib treatment. Here, we report a ruxolitinib-treated patient with rare infectious complication of C. neoformans fungemia who was co-infected with M. haemophilum cellulitis at his left leg.

Case presentation

A 70-year-old Thai man with a 5-year history of primary myelofibrosis, hypertension, pulmonary hypertension due to left-sided heart disease, asthma, and osteoporosis presented with an erythematous swollen left leg for 7 days (Fig. 1). He also complained of fever, dyspnea on exertion, and orthopnea for 6 days. He had multiple ulcers on his right foot for 10 days, and was treated with ceftriaxone for 3 days prior to hospitalization. He received ruxolitinib for treatment of primary myelofibrosis for 4 years. His other medications included warfarin, omeprazole, furosemide, diltiazem, spironolactone, bisoprolol, and seretide evohaler for his pulmonary and heart diseases.

Fig. 1
figure 1

Patient’s left leg showed erythematous lesion with swelling and tenderness

Ruxolitinib was initiated in November 2015 after the patient developed pancytopenia following hydroxyurea and allopurinol treatment. Total duration of ruxolitinib therapy was 48 months, and the most recent dose was 20 mg/day. He denied smoking and alcohol drinking. He reported no exposure to herbal drug use or animals, and he had no known tuberculosis contact.

Physical examination revealed a low-grade fever [temperature (T) 38.3 °C], blood pressure (BP) 117/64 mmHg, pulse 72/min, respiratory rate 24/min, oxygen saturation 85% at room air, and 98% with oxygen cannula 3 l per minute (LPM). He was alert, had mild pallor, and was tachypneic. Cardiovascular examination showed jugular vein distension with apical and parasternal heaving, loud P2, and irregular pulse. Fine crepitations were detected at both lower lung fields. Abdominal examination revealed mild splenomegaly. Ill-defined erythematous swelling of the left leg with mild tenderness, and multiple ulcers at his right foot with minimal pus discharge were noted. Neurological examination and other systems were unremarkable.

Complete blood count (CBC) revealed a white blood cell count (WBC) of 21,130 cells/μL (81% neutrophil, 9% band form, 5% metamyelocyte, and 2% promyelocyte), hemoglobin (Hb) level of 7.2 g/dL, platelet (PLT) count of 536,000 cells/μL, blood urea nitrogen (BUN) of 23.9 mg/dL, and serum creatinine (SCr) of 1.21 mg/dL. Liver function tests showed direct bilirubin (DBIL) of 0.66 mg/dL, total bilirubin (TBIL) of 0.45 mg/ dL, aspartate transaminase (AST) of 16 U/L, alanine transaminase (ALT) of 10 U/L, alkaline phosphatase (ALP) of 84 U/L, albumin (ALB) of 2.8 g/dL, and total protein of 5.4 g/dL. The urinalysis was unremarkable. Chest radiograph (CXR) showed bilateral interstitial infiltration with blunt costophrenic angles and increased cardiothoracic ratio. One of his 2 blood cultures grew round budding yeasts on the fourth day after blood collection, which were identified as C. neoformans (Fig. 2). Serum cryptococcal antigen was positive at a titer of 1:2. Lumbar puncture was attempted; however, no cerebrospinal fluid was collected.

Fig. 2
figure 2

Gram stain from blood culture showed encapsulated budding yeasts

On the admission date, the patient was empirically treated with intravenous ceftazidime and azithromycin. Following the blood culture result, intravenous amphotericin B deoxycholate 50 mg/day (0.87 mg/kg/day) and oral fluconazole 800 mg/day were added. The patient was improved. Subsequently, the patient developed acute kidney injury (AKI) and the antifungal agent was changed to liposomal amphotericin B 180 mg (3 mg/kg/day). The patient received induction therapy with 28 days of intravenous amphotericin B plus fluconazole 800 mg/day, followed by oral fluconazole at the dose of 400 mg/day thereafter. However, ruxolitinib was still continued.

After 1 month of hospitalization and antifungal treatment, the patient developed new onset of fever and worsening of the lesion on his left leg. Intravenous vancomycin was initiated for empirical treatment of suspected nosocomial skin and soft tissue infection. Skin biopsy at the left leg lesion was performed. The tissue pathology showed suppurative granuloma involving dermis and subcutis that suggested mycobacterial skin and soft tissue infection, and Ziehl-Neelsen staining demonstrated numerous acid-fast bacilli (Fig. 3). Tissue mycobacterial culture revealed positive organisms from acid-fast stain, and isolate identification by INNO-LiPA assay technique from liquid medium was compatible with M. haemophilum. The mycobacterium colony grew on chocolate plate agar after 42 days of incubation, but failed to grow on solid (Lowenstein-Jensen) medium.

Fig. 3
figure 3

Histopathological findings of skin biopsy from the patient’s left leg revealed suppurative granuloma involving dermis and subcutis (a) with numerous acid-fast bacilli visualized by Ziehl-Neelsen staining method (b)

The patient was treated with levofloxacin 750 mg/day, rifampicin 300 mg/day, and ethambutol 800 mg/day; however, the patient was not improved after 7 days of antimicrobial treatment. He then developed septic shock and expired on the 48th day of hospitalization.

Discussion and conclusions

Abnormal regulation of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) signaling pathway is the major pathophysiology of myelofibrosis. In addition to chemotherapy and hematopoietic stem cell transplantation, many immunomodulatory agents have recently been approved for treatment of this condition [1]. On the other hand, ruxolitinib adversely affects host immune response [2]. The involved immune response components include both innate and adaptive immunity, such as natural killer cells, dendritic cells, T helper cells, regulatory T cells and several cytokines. Therefore, either intracellular or extracellular pathogens can proliferate in the absence of an effective immune response [3].

We searched the term “ruxolitinib AND infection” and “ruxolitinib AND infectious” in the PUBMED database, and there were 59 results of clinical trials, case reports, and literature reviews. From those results, the most common opportunistic pathogens that benefit from these immune defects include bacteria, mycobacteria, viruses, and fungi, similar to those seen in human immunodeficiency virus (HIV)-related infections. The causative pathogens in previously reported cases of ruxolitinib-associated infections are summarized in Table 1 [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. Consistent with the foregoing, it appears that Cryptococcus and nontuberculous mycobacteria were able to simultaneously infect our patient due to the downregulation of multiple cytokines.

Table 1 Types of organisms and infections in previously reported cases of ruxolitinib-associated infection [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]

From previous case reports of cryptococcal infection, which are summarized in Table 2 [4,5,6, 9,10,11], 6 patients with a history of ruxolitinib treatment developed cryptococcal infection. Wysham NG, et al. [4] and Hirano A, et al. [5] reported 2 cases of pulmonary cryptococcosis, but the other four cases presented as fungemia, pericardial involvement, and meningitis or meningoencephalitis. The duration of ruxolitinib treatment was 5–46 months. One patient had a concurrent infection with Histoplasma capsulatum [6]. Three of six patients received intravenous amphotericin B deoxycholate for induction therapy, and the other antifungal drugs that were used were fluconazole, voriconazole, flucytosine, and isavuconazole. The outcome was favorable in 5 of 6 patients, and one patient deteriorated during treatment and expired. These observations suggest a benefit of discontinuing ruxolitinib to achieve a good outcome in management of ruxolitinib-associated cryptococcal diseases.

Table 2 Literature review for reported cases of cryptococcal infection in patients receiving ruxolitinib

Ruxolitinib treatment is also associated with mycobacterial reactivation [1, 2, 7]. Case reports of ruxolitinib-associated mycobacterial infections during 2011–2018 are shown in Table 3 [1, 8, 18, 19]. Anand K, et al. reported 91 cases of M. tuberculosis, and 23 cases of atypical mycobacterial infections [8]. In previous reports, the site of M. tuberculosis infection was identified in 17 cases, with the most common form being disseminated disease, followed by lymphadenitis, pulmonary diseases, and peritonitis [1, 18, 19]. For infections caused by nontuberculous mycobacteria, there were 11 (47.8%) cases of Mycobacterium avium complex, 9 (39.1%) unspecified atypical mycobacterium infections, 2 (8.7%) Mycobacterium kansasii, and 1 (4.3%) Mycobacterium abscessus [8]. Salvator H, et al. reported 1 case of M. abscessus lung infection in a 66-year-old female diagnosed with a myelodysplastic syndrome with blastic transformation who underwent allogeneic hematopoietic stem cell transplantation. The patient received ruxolitinib treatment for severe chronic cutaneous graft-versus-host disease, and she developed dyspnea 8 months later. Mycobacterium abscessus was identified from lung biopsies. She was treated with imipenem, amikacin, and azithromycin, and ruxolitinib was discontinued. Her symptoms were rapidly improved [20]. To our knowledge, there is no previous case report of M. haemophilum infection in a patient treated with ruxolitinib. Here, we report a rare case of primary myelofibrosis treated with ruxolitinib for 4 years who had bloodstream infection with C. neoformans, and concurrent cellulitis at his left leg due to M. haemophilum.

Table 3 Causative organism in reported cases of mycobacterial infection in patients receiving ruxolitinib [1, 8, 18, 19]

M. haemophilum causes skin infections as well as disseminated infection in immunocompromised individuals. It is classified as a nonchromogen by Runyon group classification. Routine microbiological laboratory may report “no growth”, despite the presence of acid fast bacilli in the stain. This is because the bacterium requires heme or iron supplementation in culture media. There is no standard guideline for management of M. haemophilum infection, but treatment with a combination of macrolides, fluoroquinolones, and rifampicin has been suggested, with the details of treatment determined on a case-by-case basis [21, 22].

In conclusion, this is the first case of dual infection with C. neoformans and M. haemophilum in a patient diagnosed with primary myelofibrosis that was being treated with ruxolitinib. This case highlights the possibility of infection caused by multiple atypical pathogens in immunosuppressed patients, especially those receiving ruxolitinib.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.



Alanine transaminase


Alkaline phosphatase


Aspartate transaminase


Blood pressure


Food and Drug Administration


Human immunodeficiency virus




Liters per minute


Primary myelofibrosis


Signal transducer and activator of transcription


Transforming growth factor


Tumor necrosis factor


United States


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The authors gratefully acknowledge the family of the patient profiled in this report for granting us permission to describe his case. We would like to thank Ms. Amiroh Waesamaae for her assistance with manuscript formatting and preparation.


There was no funding source for this article. Dr. Methee Chayakulkeeree and Dr. Piriyaporn Chongtrakool were both supported by a Chalermphrakiat Grant from the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

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NS wrote the draft, and critically revised the manuscript; MC critically revised the manuscript and served as the guarantor; and, PC provided laboratory data and approved the manuscript. All authors read and approved the final manuscript.

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Correspondence to Methee Chayakulkeeree.

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Sayabovorn, N., Chongtrakool, P. & Chayakulkeeree, M. Cryptococcal fungemia and Mycobacterium haemophilum cellulitis in a patient receiving ruxolitinib: a case report and literature review. BMC Infect Dis 21, 27 (2021).

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  • Ruxolitinib
  • Myelofibrosis
  • Cryptococcosis
  • Cryptococcus
  • Mycobacterium haemophilum