A 63-year-old Caucasian male was referred from a local emergency centre as an outpatient with weight loss, chronic cough and blood-stained sputum. A chest radiograph done two weeks prior showed a round opacity in the posterior left lower lobe. This was treated as a bacterial pneumonia with oral levofloxacin with symptom progression prompting representation. The patient recalled that no previous travel history had been taken.
Background history included relapsed atrial fibrillation with a previous atrial ablation, on sotalol and rivaroxaban. Social history included distant cigarette use. Travel history included a work-related trip to the United Kingdom, as well as a trip to Angola six months prior, which included recreational cave-exploration activities. The patient had several months of chronic fatigue and headache, a non-productive cough and intermittent fever. This led to multiple primary care visits and repeated sputum testing for tuberculosis (TB) with negative results. More recent symptoms included unintentional weight loss of more than 10 kg and anorexia for 4 - 6 weeks, progressive chronic headaches without visual disturbance, 2 weeks of streaky haemoptysis and night sweats. No reported skin lesions, or urological or gastrointestinal symptoms.
The initial outpatient examination revealed an acutely unwell, afebrile, cachectic male patient. On general inspection, there was no clubbing, pallor or lymphadenopathy. Chest findings were unremarkable, except for a respiratory rate of 22 bpm (without hypoxia). On neurological examination, no nuchal rigidity or papilledema was present. The patient was admitted to the hospital from the outpatient clinic and isolated in the medical ward pending an infectious disease screen.
A repeat radiograph showed a well-defined mass in the posterior basal region of the left lower lobe. On biochemistry, the white cell count was elevated at 9.92 x 109 (3.9 - 9.8 x109) with a normal haemoglobin, and renal and liver function. Sputum for acid-fast bacilli and TB Gene Xpert was negative. Two HIV 4th generation ELISA tests were non-reactive.
Computed tomography (CT) showed a lobulated mass of 38 x 44x42 mm in the posterior basal segment of the left lower lobe, abutting the pleural space. Features included a hypodense lesion with necrotic areas and an inferior pleural-based nodule of 21 x 20x25 cm and no cavitation. Sub-centimetre pre-carinal lymph nodes of 5 x 7 mm and mild central bronchiectasis were noted. Imaging of the brain with a contrast CT was normal.
The presumptive diagnosis was that of a malignant lung mass with superimposed infection, however, pulmonary TB and atypical infections needed to be excluded.
The patient developed an in-hospital fever of 38.5  C and neck stiffness with severe headaches after 72 h in the hospital. The rest of the neurological examination, including fundoscopy, was normal. A repeat CT brain was normal, showing no evidence of raised intracranial pressure or a space-occupying lesion. A lumbar puncture (LP) was performed for cerebrospinal fluid (CSF) collection and empiric antimicrobial therapy was started with ceftriaxone pending the results. The opening pressure was 49 cmH2O.
Results of the lumbar puncture was total white cells = 560 cells/uL, polymorphs = 0 cells/uL, mononuclear cells = 560 cells/uL, total protein = 1115 mg/L (140 - 450 mg/L) and glucose = 2.7 mmol/L (2.2 - 3.9 mmol/L).
The following day, a fine needle aspiration biopsy (FNAB) was performed on the pulmonary lesion with rapid onsite cytology (ROSE). The pathologist detected numerous fungal yeasts with budding, which were strongly positive for mucin, and positive on PAS and Grocott stains, suggestive of Cryptococcus species.
Cryptococcal latex agglutination test (CLAT) was positive on serum and CSF. Microbiological culture of the lung mass, blood culture and CSF confirmed Cryptococcus gattii species and a diagnosis of disseminated cryptococcal disease was made.
The patient was commenced on induction amphotericin B (AmBd) and fluconazole 400 mg daily, in discussion with an infectious disease specialist from the nearest Tertiary centre.
The ophthalmological and urological assessment was normal. Subsequent fungal cultures detected Cryptococcus gattii species from the pulmonary lesion, the CSF and blood culture.
The patient experienced significant drug-related toxicities due to the AmBd, including renal failure up to 285 micromol/L (45 - 90 micromol/L), hypokalaemia and hypomagnesaemia) which was managed with aggressive fluid rehydration and intravenous (IV) electrolyte replacement.
During the induction phase, thrombophlebitis was managed initially with peripheral access and subsequently with central venous access. Intractable headaches occurred within the first 15 days, leading to near-daily LPs and opioid analgesia. Transfusion rigors were managed with IV paracetamol and a reduced rate of the AmBd and fluid rehydration. Ongoing monitoring for drug interactions between fluconazole and sotalol was continuous cardiac monitoring and measurement of QTc.
Ongoing intolerance by day seven, prompted a Section 21 application for Liposomal Amphoteracin B (LFAmB) and oral flucytosine (5-FC) with the South African Health Products Regulatory authority (SAHPRA). This application took nearly 10 days for approval, with an additional four days for the arrival of the LFAmB from the supplier.
The patient had completed approximately two weeks of interrupted Amphoteracin B and fluconazole therapy when the LFAmB was commenced.
The LFAmB was better tolerated by the patient, but there were ongoing problems with renal impairment, cholangitis and transfusion reactions, requiring discontinuation for up to 48 h at a time. The patient also experienced oesophagitis and vomiting, related to the pill burden of flucytosine at a dose of 6000 mg per day (12 tablets per day in divided doses every 6 h), which was managed with pantoprazole and metoclopramide. Recurrent anaemia required the transfusion of packed RBC every two weeks.
After a protracted hospital stay with treatment interruptions and treatment-related complications, the patient completed six weeks of induction therapy and was successfully discharged home. Treatment comprised of induction with AmBd+fluconazole and later LFAmB + 5-FC totalling six weeks.
Repeat Chest CT at the end of induction, demonstrated a reduction in the size of the pulmonary mass to 30 x 32x33 mm. The creatinine remained mildly elevated at 105 micromol/L (45 - 90 micromol/L), but all other biochemical parameters had returned to normal. All symptoms had resolved on discharge.
The consolidation phase of treatment was oral fluconazole 400 mg daily for 8 weeks, with a biochemical and clinical review every two weeks, followed by maintenance phase treatment of fluconazole 200 mg daily for 6 months, with a monthly review.
At the 6 & 12- month review, no relapse occurred and the CT chest only had a residual pulmonary nodule that will be followed annually.