Cryptococcosis is a life-threatening fungal infection that affects immunocompromised patients, causing predominantly meningoencephalitis and pneumonia. Lymph node involvement is rare and its identification may not be obvious. We report the case of a patient recently diagnosed with AIDS and previously treated for cryptococcal meningitis who developed multifocal cryptococcal disease despite antifungal treatment, expressed as cervical and mediastinal lymphadenitis and constitutional symptoms. The difficulty of the diagnosis was based on the fact that cryptococcal meningitis was resolved after treatment, and the new manifestations were more typical of other conditions such as tuberculosis and malignancy. Final diagnosis was established after fine-needle aspiration cytology of a lymph node with Cryptococcus identification. Such cases may be difficult to manage, and the possibility of clinical relapse versus cryptococcal immune reconstitution inflammatory syndrome is discussed. Induction therapy was restarted and maintained for a longer period, and the total duration was based on clinical response.
- drugs: infectious diseases
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Cryptococcus neoformans is a yeast-like fungus with an important pathogenic role in patients with impaired immunity, such as HIV-infected patients with CD4+ T cell count under 200×106 cells/L.1 Cryptococcal infection is acquired by inhalation of aerosolised infectious particles, frequently found in soils contaminated with avian excreta, causing primarily pulmonary involvement.1 The fungus can then disseminate, showing a marked preference for the central nervous system (CNS). Thus, the spectrum of the disease caused by Cryptococcus species consists predominantly of meningoencephalitis and pneumonia, but cryptococcosis can affect any tissue or organ.1 Although there have been several case reports of cryptococcal lymphadenitis,2–6 lymph node involvement by Cryptococcus is not a common manifestation in patients with AIDS.7
A 46-year-old man, having been admitted with Pneumocystis jirovecii pneumonia (PCP), was diagnosed with HIV-1 infection. CD4+ T cell count at diagnosis was 185×106 cells/L and HIV viral load was over 2 million copies/mL. He was treated with trimethoprim/sulfamethoxazole for 21 days, and then started on secondary PCP prophylaxis and antiretroviral therapy (ART) with abacavir/lamivudine and dolutegravir. He was also kept on steroid therapy, started after the diagnosis of PCP.
One week after discharge, he presented to the outpatient clinic complaining of a recent onset of fever, night sweats, prostration and persistent holocranial headache. He was hospitalised to undergo further study. Blood tests showed a haemoglobin of 109 g/L with normal leucocyte and platelet counts, and an increased C reactive protein (173 mg/L). Chest and abdominal CT revealed multiple mediastinal adenopathy forming a conglomerate mass on the right hilus, a ground-glass pattern on the right superior lobe parenchyma and a discrete hepatosplenomegaly.
Tuberculous lymphadenitis was suspected, so the patient was started on antimycobacterial therapy on the first day of hospitalisation. During the first week, the patient was still febrile and presented worsening of headache and emergence of slight behavioural changes, such as depression, anxiety and disinhibition.
Mycobacteria tests on sputum, bronchoalveolar lavage (BAL) and blood samples were negative. Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus and herpes simplex virus serologies were also negative.
Brain MRI showed small focal lesions on the left white matter. A lumbar puncture (LP) was performed, revealing an increased opening pressure (41 cmH2O). Cerebrospinal fluid (CSF) analysis revealed pleocytosis (108 cells/µL with 54% lymphocytes), and cryptococcal antigen was detected in both serum and CSF samples. CSF cultures were positive for C. neoformans.
The patient was started on antifungal treatment with amphotericin B and flucytosine for 2 weeks, as induction regimen. Clinical response was favourable, with resolution of fever and neurological symptoms. LP was repeated, showing normal intracranial pressure and a negative culture of CSF.
After 2 weeks, the patient was discharged with a prescription of fluconazole 400 mg daily consolidation regimen. As there was no evidence of mycobacterial infection, antituberculosis drugs were stopped.
One month after discharge, the patient started noticing progressive neck swelling and presented new onset of fever, night sweats, malaise, fatigue, anorexia and unintentional weight loss. When he presented to the outpatient clinic, he had had these complaints for the previous 2 weeks.
On examination, the patient was febrile (39°C). Head and neck palpation revealed a right supraclavicular mass with 5 cm of major axis, which was firm, tender and painful. There were no oedema or exudates on oropharynx examination and no skin lesions. Lung, cardiovascular, abdominal and neurological assessments were unremarkable.
Initial laboratory work-up showed a haemoglobin of 116 g/L, a white cell count of 11.8×109/L with 68% neutrophils and 20% lymphocytes, and an elevation of C reactive protein (211 mg/L) and sedimentation rate (108 mm/hour). Platelet count, creatinine and liver enzymes were normal.
CT scan of the neck and chest revealed prominent bilateral cervical and mediastinal lymphadenopathy, forming two conglomerate masses: one on the right supraclavicular region with 52×37 mm and another one on the right hilum region with 43×26 mm. There were also scattered micronodules and a diffuse interstitial thickening in both lungs.
Brain MRI showed new focal nodular lesions, bilateral, located on the frontal and temporal lobes (figure 1).
A puncture of the cervical conglomerate was performed for cytological examination. Bronchoscopy revealed two endobronchial lesions (figure 2A,B) which were biopsied, and a BAL was performed.
Microbiology studies of all bronchial and lymph node materials were negative (including Gram staining, fluorescent microscopy and cultures for bacteria and mycobacteria).
Fine-needle aspiration cytology (FNAC) of the cervical lymph node showed a polymorphonuclear infiltrate with numerous spherical yeast cells. When seen with H&E stains, these organisms were surrounded by halos, a characteristic appearance given by the thick polysaccharide capsule (figure 3A). The numerous fungal cells were strongly coloured with Grocott’s methenamine silver stain, some showing narrow-based budding (figure 3B). These morphology features were consistent with Cryptococcus spp.
Cytological examination of the BAL showed a neutrophilic infiltrate. Histological evaluation of the endobronchial lesions showed areas of squamous metaplasia involved by fibrinoleukocyte exudate with several yeast cells with the same features as seen in FNAC. There was no evidence of neoplastic involvement. Serum cryptococcal antigen was positive.
Our patient had a recent diagnosis of AIDS and a history of two hospitalisations due to opportunistic infections: PCP and cryptococcal meningitis. On this second episode the patient had already a mediastinal conglomerate, the aetiology of which was not clarified. The recent onset of constitutional symptoms and lymph nodes enlargement raised the suspicion of an infectious cause (such as tuberculous lymphadenitis) or a lymphoproliferative process.
After investigation, the patient was diagnosed with multifocal cryptococcal disease, with antigenaemia, CNS, lymph nodes and pulmonary involvement. There were no signs of malignancy or mycobacterial infection. This was an unexpected conclusion in a patient who was thought to be under antifungal treatment. Paradoxical immune reconstitution inflammatory syndrome (IRIS) was considered. However, after identification of multifocal cryptococcal disease, the patient admitted he had not complied with consolidation therapy.
Our patient was started on antifungal treatment with liposomal amphotericin B (4 mg/kg per day intravenously) and flucytosine (100 mg/kg per day orally in four divided doses). As there was clinical relapse with disseminated disease, induction therapy was prolonged until there was sustained evidence of reduction of lymph nodes size and resolution of fever and neurological involvement. Thus, he completed 6 weeks of induction therapy with amphotericin and flucytosine, followed by 12 weeks of consolidation therapy with fluconazole 800 mg daily. After this period, a maintenance regimen with fluconazole 200 mg daily was initiated and is ongoing. The patient was also kept under ART with abacavir/lamivudine and dolutegravir and secondary prophylaxis of PCP with trimethoprim/sulfamethoxazole.
Outcome and follow-up
After restarting induction therapy, the patient showed slow but progressive improvement of systemic symptoms, with complete defervescence after 4 weeks. During the fifth week of induction therapy, brain MRI, LP, and neck and chest CT scan were performed. The MRI showed regression of most focal brain lesions, with some residual hyperintensities in the frontal location. There was a normal opening pressure on LP, and CSF search for cryptococcal antigen and cultures were negative. CT scan showed a reduction in lymphadenopathy size by half and, in the pulmonary parenchyma, a resolution of the interstitial infiltrate with residual micronodules. The patient was discharged after 6 weeks, showing good compliance with consolidation and maintenance regimens.
At his 2-month follow-up, he had returned to work, regained his weight, had no symptoms and the cervical mass was under 10 mm of major axis. Chest CT also revealed a faded and smaller mediastinal conglomerate. HIV viral load was under 35 copies/mL and CD4+ T cell count was 618×106 cells/L.
Lymphadenopathy is a common finding in HIV-infected patients, and can be a presenting feature in around 35% of patients with AIDS.8 Causes may include persistent generalised lymphadenopathy, lymphoid malignancies and opportunistic infections, depending on the stage of the disease. All these entities can be efficiently diagnosed by aspiration study of the lymph nodes.8
Here we report the case of a patient with recent diagnosis of AIDS who presented onset of cryptococcal meningitis 1 week after initiating ART. This episode may be considered in the context of cryptococcal IRIS (C-IRIS).
C-IRIS is mediated by recovery of Cryptococcus-specific immune responses driven by ART, resulting in exaggerated inflammatory host reaction. There are two distinct modes of presentation: ‘paradoxical C-IRIS’, presenting as worsening or recurrence of treated cryptococcal disease; and ‘ART-associated cryptococcosis’, in which patients develop new clinical cryptococcosis after ART initiation.9 In the latter, it is difficult to differentiate between ‘unmasking’ C-IRIS (caused by restoration of specific immune responses) and progression of occult cryptococcosis in the context of persisting immunodeficiency.
In the first episode of cryptococcal meningitis, our patient met the criteria for ART-associated C-IRIS, the treatment of which involves antifungal therapy and control of raised intracranial pressure. There is no consistent evidence of the benefit of steroids in C-IRIS, but a short course may be considered in case of marked deterioration or development of life-threatening complications.9 10 Our patient presented a favourable response to these measures and was later discharged under consolidation therapy.
After 1 month, he comes to medical attention with cervical and mediastinal lymphadenopathy and constitutional symptoms. As lymph node involvement is not a common manifestation of cryptococcosis and the patient had shown a favourable initial response to antifungal treatment, the new clinical features were initially thought to be in the context of a tuberculous lymphadenitis or a lymphoproliferative disease. However, investigational work-up led to the diagnosis of a multifocal cryptococcal disease with CNS, lymph nodes and pulmonary involvement.
Aspiration puncture of an involved lymph node was a key resource in establishing the diagnosis. In fact, FNAC is a first-line diagnostic tool for lymph node lesions in patients with HIV, and it provides a safe, quick and inexpensive identification of the cause of lymphadenitis.7 8 11
Pulmonary involvement was investigated based on CT findings, since the patient had no respiratory symptoms. Pulmonary cryptococcosis frequently follows an indolent course; the majority of cases do not come to clinical attention and many of them are discovered incidentally.1
Our patient presented clinical deterioration with multifocal disease, following initial clinical response to antifungal therapy. This could be understood as a continuum of C-IRIS manifestations, now as a paradoxical event. However, it was found that he did not comply with consolidation antifungal therapy, which constitutes an alternative explanation for clinical deterioration.9 Tissue identification of cryptococcal cells is also more likely to indicate a microbiological relapse.9 12
Regardless of whether one is able to confirm or exclude the diagnosis of C-IRIS, optimisation of antifungal therapy should take priority.9 10 Considering the possibility of a relapsed cryptococcal infection, induction therapy was reinstituted and kept for a longer course, according to current guidelines (4–10 weeks).10 13 After the induction phase, salvage consolidation therapy should be maintained for 10–12 weeks.13
In this case, we chose to guide induction therapy length according to clinical evolution, so it was maintained for a total of 6 weeks, until there was a sustained reduction of lymph nodes size and resolution of fever and of CNS involvement. Our patient then underwent consolidation therapy for a total of 12 weeks, with no signs of new relapse. He is now under maintenance therapy, which will be continued until he completes a total of 12 months of antifungal treatment, as long as HIV viral load remains undetectable and CD4+ T cell count above 100×106 cells/L.
Persistent generalised lymphadenopathy is a common finding in HIV-infected patients, and work-up should look beyond tuberculosis and malignancies as these are the most frequent causes.
FNAC is a first-line diagnostic technique for lymphadenopathy investigation in HIV-infected patients, and is a safe, quick and cost-effective procedure and successfully identifies most opportunistic infections.
Lymphadenitis is a rare manifestation of Cryptococcus infection, indicating a multifocal and potentially life-threatening disease.
Relapse of cryptococcal infection may be difficult to distinguish from paradoxical C-IRIS, but the presence of positive cultures favours the first diagnosis.
Relapse may occur due to non-compliance with consolidation or maintenance antifungal regimens and, in such cases, induction therapy should be restarted and maintained for a longer period (4–10 weeks), followed by 10–12 weeks of consolidation treatment.
We would like to thank Dr Ana Isabel Silva, Dr Ana Margarida Ferreira and Dr Fernando Pardal from the Department of Pathology, Hospital de Braga, for their contribution in providing the cytological images.
Contributors IME is the first author and contributed to the case study and conception of the manuscript. FSP, CT and CA contributed to the case study and critical review. CA supervised the writing critically. All authors have made significant contributions to this manuscript. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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