We report a rare case of osteomyelitis due to Cryptococcus neoformans var. grubii in a non-immunosuppressed patient. The epidemiology, symptoms, diagnostics and treatment are discussed. The case illustrates the complexity of differential diagnosis of osteomyelitis.
Cryptococcosis is a disseminated infection in humans and is mainly caused by Cryptococcus neoformans. It is associated with HIV infections, causes estimated 180,000 deaths per year , and commonly affects the lung and central nervous system. Herein, we report a rare case of osteomyelitis due to Cryptococcus neoformans var. grubii in a non-immunosuppressed patient.
A 72-year-old woman was admitted to the orthopaedic clinic. She had a month-long history of complaint of pain and swelling on the right proximal tibia. Due to clinical presentation, the patient was pre-treated with ampicillin/sulbactam in outpatient clinical settings, where erysipelas was suspected. The physical examination revealed signs of an abscess measuring approximately 4 × 3 cm on the lower right leg area. The patient was afebrile with stable vital signs. In medical history by our patient, hypertension and hypothyroidism were recorded. There was a case of lupus erythematosus in her family history. According to laboratory reports, history of patient and clinical findings, there was no indication of a systemic infection or immunosuppression. The patient was originally from Morocco but has been living in Italy for 20 years. She spent the last 8 months in Morocco, before she came to Germany a month ago. She denied alcohol, tobacco and intravenous drug abuse. The initial laboratory findings revealed an increased C-reactive protein and gamma-GT. The sonography showed a pretibial abscess. Therefore, the patient was taken directly to surgery. Incision and drainage of the abscesses were performed, which included the debridement of 2 × 5 cm of the anterior tibial metaphysis. During the operation, a sample of tissue was taken for microbiologic and pathologic studies.
She was postoperatively treated with cefuroxime and clindamycin intravenously. Afterwards, magnetic resonance imaging with contrast (Fig. 1) was performed, indicating osteomyelitis of the tibia. Histology showed evidence of chronic granulation and acute inflammation. Microbiological Gram stain microscopy of homogenized tissue did not reveal any pathogens. After 3 days, microbiological cultures showed growth of yeast. Identification by MALDI-TOF revealed Cryptococcus neoformans. Lateral flow agglutination cryptococcal antigen test in serum was positive with a titre of 1:320. The results were completed by the reference laboratory. The identification of the species was verified based on urease production using Christensen agar, and melanin production using niger seed agar. The serotypes were determined by a PCR assay targeting the STR1 gen with appropriate controls for genotypes A, D, AD and B .
As a consequence of the diagnosis, a subsequent extended operation was performed. Because of the suspicion of a disseminated cryptococcosis, additional diagnostic was conducted. A CT scan of the thorax and abdomen demonstrated multiple lung consolidations. Ophthalmic and neurologic examinations revealed no pathological findings. There was no evidence of HIV, hepatitis, sarcoidosis, CD 4 lymphopenia, diabetes mellitus or corticosteroid use. In an interdisciplinary discussion between surgeons, internal medicine and microbiology specialists, the patient was diagnosed with nonmenigeal cryptococcal osteomyelitis with no known immunosuppression.
After the diagnosis, 300 mg daily liposomal amphotericin B was given intravenously for 2 weeks. Following that, the antifungal treatment was switched from amphotericin B to voriconazole, 200 mg two times per day. The patient was recommended to take voriconazole orally for at least 6 months. The patient returned to Italy, and the follow-up examination will occur there.
Cryptococcus is an encapsulated fungus that counts more than 30 species. Human disease is most commonly caused by two species, C. neoformans and C. gattii. C. neoformans is further subclassified into C. neoformans var. grubii and C. neoformans var. neoformans. C. neoformans is found worldwide and C. gattii in tropical and subtropical regions . Both species often occur in soil samples in areas close to hollow trees or frequented by birds. Yeast inhalation is the most common way of infection. Traumatic inoculation into tissue has been described .
Cryptococcosis occurs usually in immunocompromised and only seldom in immunocompetent patients. Risk factors are AIDS, glucocorticoids, organ transplantation, tuberculosis, liver disease and sarcoidosis . Typical clinical manifestations are meningoencephalitis and pneumonia. Less common sites of infection are the skin and the genitourinary tract. The skeletal system is infected in less than 10% of disseminated disease. The vertebrae are the most common sites of bone infection. The femur, tibia, rib and humerus can also be affected. In most cases, only one bone is infected . The reason for the skeletal cryptococcal infection is the hematogenous spread from a primary pulmonary source. Isolate osteomyelitis is rare. For this reason, the combination of a nonmeningeal cryptococcal osteomyelitis in an immune-competent patient is special. In a systematic review, including articles from 1977 to 2013, only 16 cases of cryptococcosis osteomyelitis without dissemination in immunocompetent patient were found.
The diagnosis of HIV-negative and non-transplant patients is often delayed because cryptococcosis is not concerned . Similar to nearly all reported cases, in our patient, a cryptococcal osteomyelitis was not expected. It consequently was initially treated as a bacterial infection. The symptoms of cryptococcal osteomyelitis are not specific. The patient often presents with swelling and pain of the soft tissue. Erythema, such as in this case, is rare . The radiologic examination shows osteolytic lesions with mild or absent periosteal reaction. In the laboratory findings, the inflammatory markers can be elevated. Normally, there are no specific signs for cryptococcosis in clinical routine. Nevertheless, cryptococcosis should be considered as a differential diagnosis for soft tissue complaints.
For further diagnosis, a cryptococcal antigen test should be performed. Diagnostic products for point-of-care testing are commercially available as lateral flow assays. These tests require less than 15 min hands-on time and have a high sensitivity from up to 98% in the plasma. A limitation can be the persistence of the cryptococcal antigen in patients with a prior episode of cryptococcosis. Further the cryptococcal antigen titre should not be used to monitor the therapy [9, 10].
For a definitive diagnosis, infected material is necessary. Punctate of the lesion, tissue and bone material are suitable samples for microbiologic diagnostic, and swabs are not recommended. Cryptococcus can be cultured on routine fungal and bacterial cultures. A microscopic examination can be done directly from the fresh material. On a typical Gram stain, Cryptococcus appears as oval-to-round cells. The sensitivity of the microscopy is under 86% and depends on the fungal burden [11, 12]. Additionally for identification, mass spectrometry or molecular methods can be used.
When the cryptococcal osteomyelitis is diagnosed, dissemination should be ruled out. Cryptococcosis often affects the central nervous system, so a spinal tap can be necessary. In this case, cerebrospinal fluid examination was disclaimed because the patient had no neurological signs such as headache, focal neuropathy or meningeal irritation. An ocular complication was ruled out by ophthalmic examination .
Due to the rarity of cryptococcal osteomyelitis in immune-competent patients, the therapy must be based on “Clinical Practice Guidelines for the Management of Cryptococcal Disease”  and the experiences of single case reports . Following these, an extended surgical debridement was executed. In addition, an antifungal therapy was inducted with liposomal amphotericin B for 14 days. A combination therapy consisting of amphotericin B and flucytosine, which would be in concordance with the recommendations for invasive cryptococcosis in HIV patients, was not chosen. The reasons are the following: first, the missing meningeal manifestation; second, the potential side effects of pancytopenia and nephrotoxicity; and third, the good general condition of the patient.
After clinical improvement, the patient was switched to oral voriconazole. Voriconazole was chosen due to the good tissue penetration and the high fluconazole minimal inhibitory concentration . This is important because stress-induced azole efflux pumps can lead to increased minimal inhibitory concentration in the patient .
In conclusion, although Cryptococcus neoformans infection in immunocompetent individuals is rare, it must be considered as a cause of osteomyelitis, especially in unclear cases. For achieving successful diagnosis and treatment, an interdisciplinary approach between specialists in surgery, internal medicine and microbiology is critical. A cryptococcal antigen test could be a screening tool in suspicious cases.
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Gehring, T., Kim, H., Schlabe, S. et al. Cryptococcal Osteomyelitis in an Immune-Competent Host: a Case Report. SN Compr. Clin. Med. 2, 232–234 (2020). https://doi.org/10.1007/s42399-019-00198-8
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