Background
Infection is among the main causes of morbidity and mortality in patients diagnosed with multiple myeloma. Ten to twenty-two percent of deaths are attributed to infections [ 7 , 11 , 16 ].
The disease itself and its associated innate immunodeficiency, but also comorbidities and organ-dysfunction related to multiple myeloma contribute to this increased infection risk. Additionally, age (and geriatric and frailty-associated conditions) and multiple myeloma therapies further increase this risk.
Therapies for multiple myeloma include (combinations of) proteasome inhibitors such as bortezomib and carfilzomib, immunomodulators such as lenalidomide, conventional chemotherapy such as cyclophosphamide and corticosteroids such as dexamethasone.
In one study of a Swedish population, patients with myeloma had a sevenfold increased risk of bacterial infections and a tenfold increased risk of viral infections compared to matched controls [ 4 ].
Opportunistic infections can also occur in this patient group. Candida spp ., [ 14 ] Aspergillus spp. [ 2 ] and Nocardia spp . [ 21 ] have been described as causing infections in patients diagnosed with multiple myeloma.
This case report describes an infection with N. farcinica causing brain abscesses , C. dubliniensis septicaemia and probable invasive aspergillosis in a patient diagnosed with multiple myeloma, who had completed previous treatment but subsequently had recurring disease, requiring third-line therapy.
Case Presentation
We describe a case of a 72-year-old male multiple myeloma patient who presented with persistent dyspnea and episodes of transient loss of consciousness.
He has a medical history of multiple myeloma immunoglobulin A (IgA) lambda since 2017. He was initially treated with bortezomib, cyclophosphamide and dexamethasone (12/2017), following consolidation therapy with high dose melphalan and autologous stem cell transplantation (6/2018). He reached complete remission in 8/2018. After this treatment, he had a first full-blown relapse of multiple myeloma in 4/2020, diagnosed after a progressive cytopenia and increasing levels of paraprotein. Second-line treatment with daratumumab-lenalidomide-dexamethasone was initiated. In 5/2021 he reached complete remission for the second time. However, due to increasing levels of paraprotein in September 2022, we switched to carfilzomib-dexamethasone as a third-line treatment. Secondary to the treatment for multiple myeloma, he developed hypogammaglobulinemia for which he received intravenous immunoglobulins every 4 weeks. (See Fig. 1 for summary of treatment history).
On the 21st of September 2022, the patient presented at our day oncology clinic with complaints of persistent dyspnea. Computed Tomography (CT) scan of the thorax showed two cavitated consolidations with irregular borders in the left lung upper lobe, as well as a consolidation with halo sign in the right lung lower lobe (Fig. 2 ). A bronchoscopy was performed on the 3rd of October 2022 and showed a galactomannan index of 8.7, thus confirming the diagnosis of probable invasive lung aspergillosis based on EORTC criteria [ 5 ]. Absolute neutrophil count (ANC) was 1.02 × 10 9 /L. Mycelium staining on the lung biopsy was positive, however anatomic pathology was rather suggestive for yeast than for Aspergillus . Cultures remained negative (for Aspergillus as well as for N. farcinica ). Voriconazole was started on the 11th of October 2022 in outpatient setting, at a dose of 2 × 200 mg/d after a loading dose of 2 × 300 mg/d on the first day. Dose adjustments were needed based on therapeutic drug monitoring.
On the 16th of October 2022, the patient presented at the emergency department and was subsequently hospitalized at the haematology ward, following two episodes of transient loss of consciousness and apathy. His oxygen saturation was 85% at presentation. At admission, C-reactive protein level was elevated to 91 mg/L, there was a mild thrombopenia (29 * 10 9 /L) but there was no neutropenia. Covid-19 PCR tested positive at admission with a Ct-value of 24, suggesting an active infection. Treatment with nirmatrelvir/ritonavir was not started due to the presence of respiratory symptoms for more than 14 days, and the interaction of ritonavir with voriconazole. CT scan and eventually MRI scan (Magnetic Resonance Imaging) of the brain showed two cystic lesions, one in the right frontal lobe and one in the right cerebellum, with a thickened, contrast-capturing wall and surrounding oedema (Fig. 3 ). The initial differential diagnoses were intracranial abscesses, metastases of myeloma (plasmacytomas) or Aspergillus brain abscesses.
Empirically, we started meropenem 3 × 2g/d intravenously (IV) and administered voriconazole 2 × 200 mg/d IV, the latter to properly treat a possible Aspergillus brain abscess. Because of the brain oedema, we started high dose methylprednisolone 3 × 40 mg/d IV. Blood cultures of the 18th of October became positive for C. dubliniensis (in vitro susceptible to voriconazole), therefore anidulafungin 100 mg/d was added from the 21st of October (after a loading dose of 200 mg). There were no signs of endocarditis on transesophageal echocardiography. A fundoscopy was performed and ruled out Candida endophthalmitis. The patient had a port device, which was removed shortly after the laboratory results were completed, as blood cultures remained positive. A deep venous catheter was placed simultaneously to continue intravenous antibiotic therapy.
On the 27th of October, a stereotactic biopsy of the lesion in the right frontal lobe was performed to differentiate between a bacterial or fungal brain abscess, an Aspergillus brain abscess or an intracranial plasmacytoma. The culture of this biopsy was positive for N. farcinica , for which on the 30th of October high dose co-trimoxazole IV (5 × 240 mg/ 1200 mg) was associated empirically.
Culture as well as pathology of the brain biopsy could rule out involvement of Aspergillus fumigatus or C. dubliniensis, which was first suspected following the persistently positive blood cultures. On the 16th of November, the Nocardia strain appeared to be resistant against meropenem and thus meropenem was subsequently switched to moxifloxacin 1 × 400 mg IV, in combination with co-trimoxazole IV. Intravenous treatment with moxifloxacin and co-trimoxazole was continued during 6 weeks because of persistent confusion. Anidulafungin was discontinued on the 15th of November, 14 days after the last positive blood culture. On the 3rd of January 2023, intravenous treatment with moxifloxacin and co-trimoxazole was switched to oral administration, after a CT scan of the brain showed a decrease of the lesions and neurological symptoms were resolved (Fig. 4 ).
During hospitalization (16th of October 2022 until the 4th of January 2023), the ongoing treatment with carfilzomib- dexamethasone was discontinued because of the multiple infectious complications. However, the patient’s IgA protein levels were increasing again, and CT scan showed progressive skeletal lesions. At discharge, fourth line treatment with pomalidomide was initiated.
While the infectious diseases from this admission were controlled, the patient was re-admitted to in-patient care on the 15th of March 2023 with an influenza A infection. CT scan of the brain on the 16th of March showed a clear decrease of both lesions as well as the surrounding oedema and there were no residual neurological symptoms. This admission was complicated with a urinary tract infection (treated with temocillin IV 6g divided in 3 doses) and suspected pulmonary bacterial superinfection (treated with amoxicillin/clavulanic acid IV 6g, divided in 3 doses). Ultimately, on the patient’s request, treatment for myeloma (pomalidomide) as well as the antimicrobial therapy were halted and he went into hospice care, where he passed away.
Discussion
Nocardia is a species of gram-positive bacilli, and is found environmentally in soil, water, and air. It rarely causes infection but can disseminate after an initial local infection through the respiratory tract, skin, or soft tissues. N. farcinica is specifically associated with infections in the central nervous system [ 21 ].
C. dubliniensis was first described in 1995 in HIV (human immunodeficiency virus) patients with oral candidiasis [ 18 ], and has been associated with invasive infections [ 17 ].
Aspergillus spp. are filamentous fungi and can also cause invasive infections. In a recent study by Fuchs et al., this is especially present in multiple myeloma patients who received three or more lines of anti-myeloma treatment, as is the case in the patient described in this report [ 8 ].
COVID-19 is associated with high morbidity and mortality in patients with haematological malignancies, and COVID-related mortality numbers seem to be among the highest in myeloma patients [ 15 ]. We did not treat our patient with nirmatrelvir/ritonavir because symptoms of dyspnea had been present for more than 2 weeks, and because of its interaction with voriconazole, which was considered more clinically relevant in this case [ 6 ].
The patient presented with 2 bouts of loss of consciousness, and central nervous system involvement was quickly investigated and confirmed with radiography. N. farcinica is especially associated with central nervous system disease and has been described in three other cases of multiple myeloma [ 21 ].
Strikingly, the three aforementioned infections occurred simultaneously in the patient. Due to shared foci (brain abscesses/septicaemia/pulmonary tissue) the diagnosis of nocardiosis was delayed, as the brain abscesses were deemed to be caused by a probable invasive aspergillosis or cerebral disseminated candidiasis. Stereotactic biopsy then subsequently was able to discover N. farcinica . The admission was further complicated with a bloodstream C. dubliniensis infection. The source was likely either from the brain abscesses, or was catheter related. However, the organism was not cultured from the abscess biopsy (27th of October 2022) or either the port-a-cath (removed and cultured on the 27th of October 2022).
While N. farcinica and C. dubliniensis have been reliably diagnosed using MALDI-TOF [ 19 , 22 ], Aspergillus spp. was not cultured from any sampling, as specified above. The diagnosis is based on the IMMY Sona Aspergillus test, a novel lateral flow rapid test, and the EORTC criteria for invasive aspergillosis. Since the test detects galactomannan, other molds apart from Aspergillus spp. could be detected, as well as contaminants from the upper respiratory airway [ 1 ]. Technical reasons such as delayed reading of the lateral flow test can also contribute to decreased specificity, i.e., the test could be false positive, including due to nocardiosis [ 9 , 13 ]. In our case, the galactomannan index was strongly positive (8.7), whereas it was only slightly positive in the in vitro isolates analyzed by Haran et al . , supporting the diagnosis of Aspergillus infection in our patient. The question remains whether there was a pulmonary nocardiosis causing the Nocardia brain abscess, however cultures of bronchoalveolar lavage fluid remained negative for both Nocardia and Aspergillus . In our case, we decided to treat a probable invasive aspergillosis because of the high risk in this immunocompromised patient, combined with compatible findings on CT and a very high galactomannan index.
The patient received three lines of multiple myeloma therapy, and even a fourth compound (pomalidomide) after the infectious complications were controlled. As previously mentioned, this is found to increase the risk for infectious complications [ 8 ]. Bortezomib and carfilzomib are reversible and irreversible inhibitors of the 20S proteasome. This leads to cellular apoptosis and tumour regression, but also decreased activity of T cells, B cells, NK cells of the cellular immune system [ 12 ]. Despite the better safety profile of carfilzomib, a recent systematic review and meta-analysis reports carfilzomib-based regimens are associated with a higher risk of severe infections, particularly respiratory infections [ 20 ]. All previously reported cases of N. farcinica with central nervous system infections, describe treatment regimens that feature proteasome inhibitors, but also glucocorticoids, lenalidomide and cyclophosphamide. [ 21 ]. Finally, the immune modulators lenalidomide and pomalidomide can lead to neutropenia, thus increasing infection risk. [ 3 ].
The staggered occurrence and diagnosis of etiologic pathogens and the presentation of the patient presented challenges in the therapeutic management of the patient. While the treatment of C. dubliniensis was halted after 4 weeks (2 weeks initially + at least 2 weeks after negative blood cultures), initial antibiotic therapy was broad-spectrum meropenem empirically, and then focused on the treatment of Aspergillus spp. , using voriconazole. Upon diagnosis of N. farcinica , co-trimoxazole was started, and meropenem was continued. Lebeaux et al. investigated the antimicrobial susceptibility of Nocardia spp. A large percentage of N. farcinica isolates tested displayed resistance against amoxicillin (91.9%), piperacillin-tazobactam (97.0%) and cephalosporins (69.6–91.2%). Against meropenem, 73% of isolates were found to be resistant, while against co-trimoxazole (4%) and moxifloxacin (9.5%) a lower proportion of resistance was found. [ 10 ] Unfortunately, in this case, resistance against meropenem was found, and subsequently this antibiotic was replaced with moxifloxacin. Both the timing of the stereotactic biopsy and the antibiotic susceptibility test contributed to a delay of appropriate antibiotic therapy against N. farcinica . However, after starting the adequate treatment, the patient recovered both clinically and radiographically.
Conclusion
This case report describes concurrent infection with three pathogens: N. farcinica causing brain abscesses, C. dubliniensis septicaemia and a probable pulmonary aspergilloma . The patient was diagnosed with multiple myeloma and received multiple treatment regimens. With this report, we advocate the importance of expedited and thorough diagnostics (radiology, clinical laboratory, pathology) to rule out (co-)infections and to optimize appropriate antibiotic and antifungal therapy in these patients, who are particularly vulnerable to infectious complications.
Supplementary Information
Supplementary Material 1: Supplementary figure 1. Timeline of diagnostic workup and treatment during admission with COVID-19, N. farcinica , C. dubliniensis infections and probable invasive aspergillosis.
Supplementary Material 2: Supplementary Figure 2. Summary illustration of diagnostic steps and how they guided treatment decisions.
Acknowledgements
We would like to thank the patient and his family for giving consent to publish this case report and clinical imaging.
Abbreviations
Species
Immunoglobulin A
Computed Tomography
European Organisation for Research and Treatment of Cancer
Polymerase chain reaction
Cycle threshold
Magnetic Resonance Imaging
Intravenously
Matrix assisted laser desorption/ionisation time-of-flight analyser
Authors’ contributions
LV wrote the clinical case presentation section and contributed to part of the discussion. LV also provided the description of the radiological images in Figs. 2–4. LV edited and finalized the manuscript.
EH wrote the background section, part of the discussion and the abstract and focused on the microbiological challenges of this case. EH also provided the summary figures (Fig. 1 and supplementary Figs. 1 and 2).
HN and DV contributed to the writing process of the manuscript, offering valuable feedback and insights into the microbiological management. They both reviewed the manuscript.
IV treated the patient and provided critical insights into the clinical details and management. IV also reviewed the manuscript.
All mentioned authors reviewed the final manuscript.
Funding
The authors declare that there was no funding involved.
Availability of data and materials
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
The patient’s relatives gave their written consent to publish this case report with involved clinical images, after the patient passed away.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
Supplementary Materials
Supplementary Material 1: Supplementary figure 1. Timeline of diagnostic workup and treatment during admission with COVID-19, N. farcinica , C. dubliniensis infections and probable invasive aspergillosis.
Supplementary Material 2: Supplementary Figure 2. Summary illustration of diagnostic steps and how they guided treatment decisions.
Data Availability Statement
No datasets were generated or analysed during the current study.