Case Report
A Rare Case of Pulmonary Cryptococcosis in an Immunocompetent Patient
https://doi.org/10.21203/rs.3.rs-4682418/v1
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Pulmonary cryptococcosis is an uncommon invasive fungal infection of the lungs seen in immunocompromised individuals but increasingly reported among the immunocompetent. We report on a rare case of pulmonary cryptococcosis in the immune component host highlighting the unique clinical and radiological presentation.
Cryptococcosis is an opportunistic invasive systemic fungal infection predominantly diagnosed in immunocompromised individuals such as those with Acquired Immunodeficiency Syndrome (AIDS), hematological/lymphoproliferative malignancies and patients on immunosuppressive therapy e.g. post-transplant cases. Other at-risk individuals are patients with uncontrolled diabetes and cancer patients on chemotherapy. The infection is however being increasingly diagnosed among immunocompetent individuals, usually with a varied clinical and radiological presentation making diagnosis difficult in the majority of cases (1, 2).
Although transmission of the infection is via inhalation of cryptococcal spores making the lungs the primary site of infection, dissemination to other parts of the body such as the meninges, brain, skin and lymph nodes commonly occurs, often with clinically silent or no obvious pulmonary lesions (3). Spread to the meninges is most predominant, making cryptococcal meningitis the commonest clinical form of the infection particularly in the immunocompromised (4). However, among the immunocompetent, isolated pulmonary cryptococcal infection tends to be more prevalent and this is known as pulmonary cryptococcosis, which may disseminate to other sites in the body when disease is advanced (1, 5). In a study by Zhang Y et al, more than half of all pulmonary cryptococcosis cases diagnosed were in immunocompetent hosts (6). Similarly, several other studies have demonstrated the high occurrence of pulmonary cryptococcosis among immune competent individuals compared to immunocompromised patients (7, 8).
Although there has been few documented cases of pulmonary cryptococcosis among HIV-positive patients in sub-Saharan Africa, there has been no clear documentation of the disease among immunocompetent individuals in the sub-region as well as in Ghana (9, 10). We therefore present this unique case of pulmonary cryptococcosis in an immunocompetent patient, highlighting the clinical and radiological characteristics of the disease as well as the diagnostic challenges faced, with the aim of creating awareness.
A 19-year-old female was referred to the TB clinic of a tertiary hospital with about 3 weeks history of shortness of breath and a total left “whiteout” on a chest radiograph suspected to be a massive left pleural effusion (Fig. 1). She had a 5-month history of cough, productive of scanty clear sputum with associated night sweats and minimal weight loss. A chest tube passed at the district hospital where she initially reported, less than 50 mls of a gelatinous clear aspirate was drained from the pleural space over a week. The tube was subsequently removed, and patient referred as a case of geneXpert negative pulmonary TB. Patient reported a past medical history of seizure disorder diagnosed at the district hospital about 7-months prior to the onset of the chronic cough which had been controlled on oral Carbamazepine 200mg daily, although she had defaulted on treatment for some months. She was a secondary school student and lived in a rural community with her parents who were peasant farmers.
At presentation, we found a chronically-ill looking young lady, mildly dyspneic at rest but had no pallor, fever or peripheral lymphadenopathy. Chest auscultation was suggestive of left hemithorax consolidation. The chest Computed Tomography (CT-scan) requested showed replacement of the left lung by a large complex heterogeneously enhancing mass with hypoenhancing areas suggestive of cystic change or necrosis. The lesion caused complete compression of the left main bronchus and partially encased the pulmonary trunk and thoracic aorta (Fig. 2). Oesophageal compression by the mass was also evident. A second 4 mm solitary pulmonary nodule was noted in the apex of the right lung as were multiple enlarged supraclavicular, paratracheal, sub-carinal, and left hilar lymph nodes. Left lung malignant tumor with possible metastasis to the contralateral lung and mediastinal lymph nodes was strongly suspected. Percutaneous lung biopsy was done but histology was inconclusive due to inadequate tissue obtained. The pathologist however commented on the possible presence of cryptococcus but could not distinguished that from an artifact in the absence of specials stains and thus recommended repeat biopsy. Treating clinicians interpreting this as possible superimposed fungal infection, initiated oral fluconazole 200mg daily and arranged for repeat biopsy on out-patient basis due to insistence by her parents for discharge.
Patient unfortunately defaulted on the biopsy appointment and returned to clinic about five months later with symptoms of dysphagia to solids, focal seizures of the left upper limb and presence of huge lumps on her left chest wall. She was fully conscious but looked cachexic (weight had dropped from 52kg at initial visit to 36kg), pale and moderately dyspnoeic at rest but had no fever. There were firm-to-hard, non-tender left anterior, lateral, and posterior chest wall masses with the largest measuring 15 x 25cm (Figs. 3a, b & 4a) with no differential warmth. An ulcer discharging a gelatinous fluid at the old chest tube insertion site was noted (Fig. 4a) and the spleen was palpated 5cm below the costal margin. The suspicion of primary lung cancer with brain and contralateral lung metastasis was maintained and repeat percutaneous lung biopsy performed. Histology revealed alveoli with areas of luminal foamy histiocytes and round to oval encapsulated yeasts with thin cell walls and narrow-based budding consistent with presence of Cryptococcus (Fig. 7). On Periodic Acid Schiff (PAS) and Gomori Methenamine Silver (GMS) stains (Fig. 5), yeast cells were highlighted. No malignant cells were noted. Abdominal ultrasound confirmed splenomegaly (15.8cm) with nonspecific multiple cystic and tubular lesions in the spleen and a diffusely enlarged liver (18cm).
Diagnosis of pulmonary cryptococcosis with a giant cryptococcoma in the left lung and a small cryptococcal granuloma in the right lung was secured. Though we were unable to get a brain CT-scan due to financial constraints, dissemination to the brain in a form of a cerebral cortex granuloma was strongly suspected based on the focal seizures as well as dissemination to the spleen and mediastinal lymph nodes. Serum CRAG testing was not immediately accessible, and a lumbar puncture was not done due to the huge posterior chest wall masses and its attendant difficulty with positioning. A 2-week induction phase was initiated with Amphotericin B deoxycholate 1mg/kg on day 1, then 1.5mg/kg daily for 2 weeks. Whiles on amphotericin therapy, she developed severe hypokalemia and hyponatremia that required correction and severe anemia requiring blood transfusion. Upon successful completion of induction phase, high-dose fluconazole 400mg twice daily was initiated for the consolidation phase. There was progressive reduction in the size of the chest wall masses based on periodic chest circumference measurements (Fig. 4b) with improved symptoms of cough and dysphagia. Focal seizures were controlled on oral Levitiracetam.
Patient was successfully discharged after 64 days on admission and scheduled for review within 2 weeks. The decision was to refer to thoracic surgeons if reduction in size of cryptococcoma was not significant on the anti-fungal therapy. Patient however defaulted clinic review again for unclear reasons and a follow-up call to parents’ revealed patient had passed away at home about 6 weeks post-discharge following an acute episode of breathlessness after a large meal.
Pulmonary cryptococcosis, though rare, has been shown to occur more in the immunocompetent in whom the presentation tends to be atypical, and diagnosis delayed as most cases are asymptomatic and only identified as incidental lung nodules (6, 7, 8). Where symptoms do occur they are mild and non-specific which may include cough, chest pain, weight loss, fever or hemoptysis. The extent and severity of cryptococcal infection has been shown to be dependent on the level of immunity and this underpins why the disease is predominantly localized to the lungs in immunocompetent patients as opposed to rapid dissemination from the lungs to the brain/meninges in the immunocompromised host with no or insignificant lung lesions (7). In the current review, the patient similarly had a chronic cough but only sought medical help when she began experiencing shortness of breath. We however suspect on hindsight, that the earlier diagnosis of the seizure disorder months prior to the onset of the chronic cough could have been the first evidence of the disease in this young lady. This portrays how pulmonary disease in the immunocompetent could remain hidden for years and manifesting with symptoms of dissemination. As similarly reported by Suwatanapongched et al, 67% of the immunocompetent patients diagnosed with pulmonary cryptococcosis already had disease dissemination to the CNS attributed to delayed diagnosis, allowing for disease advancement (11).
Radiologically, pulmonary cryptococcosis in the immunocompetent typically presents with solitary nodules/masses averagely 0.5–52 mm in size, mostly peripheral in the upper to middle lung zones, hence commonly misdiagnosed as lung cancer when solitary (5, 6). On the contrary, some reports have shown that the size of cryptococcal nodules/masses could vary widely ranging from 1cm to 15cm in its widest diameter (11). The cryptococcal mass in our patient was huge invading and outgrowing the left thoracic cage with multiple areas of cystic changes. Mitsuoka and Kanazawa similarly reported a case of a giant cryptococcoma characterized by cystic areas with chest wall invasion noted on the CT-scan (12). The rare presence of mediastinal and hilar lymph node enlargement as well as compression of vascular structures within the mediastinal, which our patient had, are considered atypical in pulmonary cryptococcosis and represent features of an aggressive disease (11, 13). The rapid growth of the cryptococcal mass in our patient with significant invasion of the chest wall within 5-months from the initial CT is another evidence of the rarely aggressive nature of pulmonary cryptococcosis as opposed to its known indolent nature. It may appear that the presence of these hypoenhancing cystic or necrotic changes within the tumor facilitates the enormous growth in size.
Diagnosis of cryptococcosis usually begins with the high index of suspicion in an immunocompromised patient particularly in HIV. The infection in an immunocompetent patient is hardly suspected resulting in extremely delayed diagnosis as evident in the current case report in which the disease was not even considered as a differential. The diagnosis is however secured via biopsy of suspicious lung nodules and histopathological presence of cryptococcus. Newer non-invasive diagnostic tests such as serum cryptococcal antigen (CRAG) has a high sensitivity in diagnosing disseminated infections but has very little diagnostic role in cases of isolated pulmonary cryptococcosis with majority testing negative except those with advanced/disseminated disease (7). Current guidelines therefore recommend mandatory serum CRAG testing in immunocompetent patients with cryptococcomas for early detection of the typical occult CNS dissemination. This ensures appropriate treatment with IV amphotericin B instead of the recommended oral anti-fungal in the case of isolated pulmonary cryptococcosis (14). Had there been a high index of suspicion at the initial presentation of this young girl, serum CRAG testing could have unmasked the disease despite the inconclusive histopathology findings and averted the need for repeat biopsy.
As per current guidelines, anti-fungal therapy which has been shown to be effective, is the recommended first line therapy for all cases of pulmonary cryptococcosis with surgical intervention vaguely reserved for cases with poor response to initial anti-fungal therapy (13, 14). In accordance with guidelines, our case was started on anti-fungal treatment and appreciable response was evident with reduction in size of chest wall masses as shown in Fig. 4b. There was also significant symptom improvement particularly with dysphagia. However, with patients’ death post-discharge, we suspect she may have aspirated judging from the event surrounding her death. Could this have been a result of significant intrathoracic pressure or raised intracranial pressure from a further increase in the cryptococcoma in the lung or brain respectively? Though there was objective improvement in the disease prior to her discharge, the patient may have defaulted therapy considering the erratic clinical course encountered. In the case report by Anandpara and team, the patient similarly had a cryptococcoma, significant mediastinal infiltration with compression of vascular structures but outcome on anti-fungal treatment was positive. Perhaps the large mass size in our case and the possible CNS dissemination, (known to be associated with poor prognosis), could have been the differing factor (15). In a case presented by Haddad et al, undiagnostic bronchoscopy led to an exploratory thoracotomy and lobectomy after which histology confirmed Cryptococcus and post-lobectomy adjuvant anti-fungal treatment based on antigenaemia yielded a positive outcome (16). Similarly, Mitsuoka and Kanazawa observed a favorable response to anti-fungal therapy only after a diagnostic minimally invasive thoracotomy with drainage of discolored fluid from the invading cryptococcoma (12). With above favorable reports above, we also pondered on whether an early surgical intervention in combination with anti-fungal therapy could have improved patient outcome.
With this first documentation in our setting, pulmonary cryptococcosis should be considered as a differential in cases of lung mass/masses particularly when no clear risk factors for lung malignancy exists. Serum CRAG testing and early involvement of thoracic surgeons should be encouraged in suspected pulmonary cryptococcoma as this has the potential of improving mortality.
Acknowledgements
The authors thank Dr Yayra Klinogo, Dr. Sylvester K Owusu Amoako, Dr Baatso for their help with retrieval of patient clinical data
Additional Information
Consent: Written informed consent was obtained from the parent of the patient for publication including images and pictures therein. Conflict of Interest: Authors have no conflicts of interest to declare. Funding: No funding was obtained by any of the authors in favor of this publication.
No competing interests reported.
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