Introduction

Cryptococcosis is a fungal infection caused by Cryptococcus species. Cryptococcosis mainly occurs in immunosuppressed patients and is one of the AIDS-defining diseases in HIV-infected individuals. Other predisposing conditions include immunosuppressive medication, malignancy, organ transplantation, chronic organ disease (liver, lung, kidney), diabetes mellitus and sarcoidosis. Cryptococcosis is rarely diagnosed in people without any underlying disease [1, 2].

The most common human-pathogenic species is Cryptococcus neoformans, which is distributed worldwide and is mainly found in bird faeces [3]. Infection with C. neoformans is likely caused by inhalation of basidiospores form or small, poorly encapsulated yeasts. Since the basidiospores have small polysaccharide capsules, they can probably be deposited in the respiratory tract [4].

The most common manifestations of cryptococcal infection are meningoencephalitis, as well as pulmonary or cutaneous forms [5,6,7]. Especially in immunocompromised patients, the infection may become disseminated. Symptoms of meningoencephalitis include headache, fever and disturbance of consciousness. Common symptoms of pulmonary infection are productive cough, haemoptysis, dyspnoea, chest pain, fever, night sweats and weight loss [8,9,10].

There are several diagnostic tools to detect cryptococcosis. Serum tests for cryptococcal antigen, using latex agglutination and enzyme immunoassay techniques, have a high sensitivity [11]. The yeasts can be visualised in direct microscopic examination using a methenamine silver stain, Fontana-Masson stain or periodic acid–Schiff reaction. The polysaccharide capsule of the cryptococci can be recognised by light microscopy using an India ink stain [12, 13]. The diagnosis can be confirmed by detection in fungal culture.

The radiological features of pulmonary cryptococcosis are non-specific, including basal pulmonary nodules, lobar infiltrates, hilar and mediastinal lymphadenopathy, and pleural effusions [14,15,16].

Since the clinical and radiological findings in cryptococcosis are not highly specific, there is a risk of misdiagnosis. There have been cases where cryptococcosis and other fungal diseases have been misdiagnosed as tuberculosis [17]. Rare fungal infections such as cryptococcosis should always be considered or excluded in the differential diagnosis of tuberculosis.

Cryptococcal infection is treated with various antifungal drugs such as amphotericin B, flucytosine and fluconazole. The therapeutic regime and duration of treatment depend on the immune status and on the severity of infection. In meningoencephalitis and disseminated infections, a combined induction therapy with amphotericin B and flucytosine for 2 weeks is recommended [18]. Subsequently, consolidation and maintenance therapy with fluconazole is continued for 12 months [18, 19].

Cryptococcal infections are reported in pregnant and postpartum women [20, 21]. However, there are only limited statistical data to draw any evidential conclusions about the incidence of the disease in association with pregnancy. During pregnancy, amphotericin B should be used for the treatment of cryptococcosis. Flucytosine and fluconazole are contraindicated for use in the first trimester due to teratogenicity [18].

Knowledge about cryptococcosis in pregnant and postpartum women is based on case reports, official data on the epidemiology are not available. Especially in Europe and in HIV-negative individuals, cryptococcosis is a rare disease. For this reason, we would like to share this unusual case of a HIV-negative postpartum woman who was diagnosed with cryptococcosis.

Case report

A 20-year-old female patient consulted an emergency department due to recurrent fever, night sweats, weight loss and nausea. The patient had no history of previous illnesses, chronic diseases, home medication or allergies. The symptoms began approximately 2 weeks after the woman gave birth to her first child via an emergent caesarean section. Due to a wound healing disorder of the section scar, several antibiotic therapies were initiated, which did not have any effect on the patient’s condition. Physical examination revealed mild, painless enlargement of the cervical lymph nodes. Physical examination of the heart, lungs, skin and abdomen was without abnormalities.

Laboratory chemistry showed undulating elevated inflammatory parameters (CRP up to > 200 mg/l, reference < 5 mg/l), as well as hypochromic microcytic anaemia (haemoglobin 6.7 g/dl, reference 12–16 g/dl) assumed to be due to iron deficiency. In addition, there was a moderate elevation of liver enzymes (ALT 71 U/l; reference 0–34 U/l, AST 40 U/l; reference 0–31 U/l).

The growth of Crytococcus neoformans was detected in two pairs of blood cultures. The patient was subsequently admitted to hospital for further diagnostic clarification. Serum cryptococcal antigen was negative. Repeated control blood cultures 6 days after initiation of antifungal therapy remained sterile.

Computed tomography of the thorax showed extensive bihilar, mediastinal and supraclavicular lymphadenopathy (Fig. 1). A supraclavicular lymph node was extirpated to rule out lymphoma.

Fig. 1
figure 1

Axial computed tomography scan showed pulmonary hilar (a) and cervical (b) lymphadenopathy (highlighted by the white arrows)

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Histology of the lymph node revealed epithelioid cell granulomatous lymphadenitis with included pathogenic structures, consistent with the clinical diagnosis of Cryptococcus neoformans infection (Fig. 2).

Fig. 2
figure 2

Pathological examination demonstrated lymphadenitis with encapsulated, round-shape yeasts (black arrows), which is consistent with the diagnosis of cryptococcosis. a Haematoxylin and eosin (H&E) stain, b periodic acid–schiff (PAS) stain

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For further diagnostics, a bronchoscopy with bronchoalveolar lavage and transbronchial lymph node biopsy was performed. An infection with Mycobacterium tuberculosis was ruled out by microscopy and PCR testing.

The HIV serology was repeatedly negative. There was no evidence of malignant haematological disease found in the bone marrow aspirate. Cerebral involvement of cryptococcosis was ruled out by lumbar puncture (negative cryptococcal antigen and negative PCR testing in the cerebrospinal fluid) and cerebral MRI (Fig. 3).

Fig. 3
figure 3

There was no evidence of meningitis or other pathological findings in the cerebral magnetic resonance imaging

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In summary, we diagnosed pulmonary cryptococcosis with bloodstream infection in an immunocompetent postpartum patient. A timeline of the examinations and treatment is summarised in Fig. 4.

Fig. 4
figure 4

Timeline of the examinations and therapy. lAMB Liposomal amphotericin B. CT Computed tomography

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The Cryptococcus neoformans strain isolated from the blood cultures was tested for its susceptibility to various antimycotics. Table 1 shows the results of the resistance testing.

Table 1 Resistance testing of the isolated C. neoformans strain
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Antifungal therapy with fluconazole (800 mg i.v. once a day) was initiated. However, daily episodes of fever remained, and the inflammatory parameters increased. A combined therapy with amphotericin B (3 mg/kg) was intended. Unfortunately, the patient developed an anaphylactic reaction with dyspnoea, tachycardia and nausea during the first application of liposomal amphotericin B.

Rotation of azole therapy to isavuconazole did not result in clinical improvement. Due to the patient’s worsening general condition, combined antifungal therapy was required.

Consequently, we decided to desensitise the patient to liposomal amphotericin B according to a protocol based on Shadur et al. [22]. The different solutions with increasing concentrations were prepared by the hospital pharmacy (Table 2). Desensitisation was performed under ICU surveillance and the patient had no immediate adverse effects.

Table 2 Application protocol desensitisation Ambisome® (liposomal amphotericin B, lAMB)
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About the third day of therapy with liposomal amphotericin B, the patient developed nausea, emesis and severe hypokalaemia.

Prior to initiation of the therapy, potassium (4.4 mmol/l, reference 3.8–5.0 mmol/l) and creatinine (0.7 mg/dl, reference 0.6–1 mg/dl) were within a normal range. Potassium levels were continuously monitored and substituted, but even with high-dose intravenous substitution via central venous catheter, the hypokalaemia persisted.

Due to these side effects, the therapy with amphotericin B was stopped after one week. Antifungal therapy was continued with isavuconazole (200 mg/d).

In follow-up examinations, the patient’s clinical condition improved and therapy with isavuconazole is continued with good tolerability. We intend to continue the maintenance therapy for 6 to 12 months, depending on the clinical course.

Discussion

Cryptococcemia is rare and mostly occurs in immunocompromised patients. The prognosis depends on timely and appropriate antifungal therapy and the immune status of the patient [23].

The negative cryptococcal serology (latex cryptococcus antigen detection system) in our case is unusual as the sensitivity and specificity of serological tests are very high [24]. In our patient, we would expect a high antigen load due to fungemia and extensive infection. False negative test results may be due to a very high cryptococcal antigen load, a phenomenon known as prozone effect [25].

The management of cryptococcemia is analogous to the treatment of meningoencephalitis or disseminated cryptococcosis [18]. We avoided additional flucytosine administration due to the known adverse events, such as bone marrow suppression, hepatotoxicity or enterocolitis [26].

The knowledge of cryptococcosis in pregnant women and infections in the postpartum period is based on case reports. There are case reports from all over the world (USA, Uganda, Morocco, Dominican Republic) of cryptococcosis in immunocompetent pregnant women [27, 28], although a higher incidence of infection in HIV-positive pregnant and postpartum women has been published [20, 21].

The modulation of the immune system during pregnancy and the postpartum period may lead to an increased susceptibility to infections. During pregnancy, an adaptation of the maternal immune system occurs. Hormonal changes have been shown to influence the immune cell function [29, 30]. There is also evidence of altered T cell function during pregnancy [31]. These mechanisms could lead to an increased predisposition to infection, especially in the third trimester and the postpartum period. In our patient’s case, there were no irregularities in the lymphocyte proliferation status as an indication of impaired T cell activity.

Similar to the present case, courses of infection with exacerbation of symptoms in the last trimester or postpartum have been reported [20, 32]. An immune reconstitution inflammatory syndrome (IRIS) should be considered in HIV-positive individuals and due to impaired T cell function postpartum, as it has been reported postpartum as well as in fungal infections [30, 33, 34]. There is no specific therapy of IRIS. Corticosteroids should only be considered if there are signs of an increased intracranial pressure [18]. No specific diagnostic tools are available to differentiate IRIS from persistent infection.

In other case reports, persistent clinical symptoms led to a change in antifungal therapy [28]. We tested the Cryptococcus neoformans strain isolated in the blood cultures for its susceptibility to various antimycotics. Resistance testing suggested increased susceptibility to isavuconazole. For this reason, we decided to change the therapy from fluconazole to isavuconazole, although there are no recommendations for this regime [18]. The presumed failure of antifungal therapy could also be explained by the immunological changes mentioned above.

We were furthermore able to document a successful desensitisation to liposomal amphotericin B. To our knowledge, only a few cases of desensitisation to amphotericin B have been described [22, 35]. A standardised protocol is not available.

In summary, we present an unusual case of an HIV-negative patient with postpartum pulmonary cryptococcosis and cryptococcemia. Cryptococcosis should be considered as a rare differential diagnosis in pregnant and postpartum women, even in the absence of immunosuppression. In case of allergic reaction to amphotericin B, desensitisation is a possibility to establish an adequate therapy.