A 67-year-old man was evaluated at the emergency department because of fever (up to 38,9  C), general fatigue, rhinorrhea and dyspnea for four days, without cough, thoracic pain or sore throat.
The patient had a history of severe chronic obstructive pulmonary disease (COPD) for which he underwent a bilateral lung transplantation eleven years ago. He also suffered from mild obstructive sleep apnea syndrome, type 2 diabetes mellitus and chronic renal insufficiency, with an estimated glomerular filtration rate (eGFR) of 30 mL/min/1,73m2. The patient's therapy consisted of azathioprine, everolimus and methylprednisolone, as well as thrice weekly azithromycin and twice weekly dapsone to prevent Pneumocystis jirovecii (PJP) infection. Other medications included spironolactone, bumetanide, bisoprolol, atorvastatin, enalapril, moxonidine, prazosin, omeprazole, trazodone, zolpidem, gliclazide, magnesium, calcium and vitamin D.
On physical examination, he appeared mildly ill, without fever. Oxygen saturation was 96% while breathing ambient air. Pulmonary auscultation revealed normal breath sounds and clinical examination was otherwise normal. Blood analysis showed mildly elevated inflammatory markers (C-reactive protein (CRP) 57.8 mg/L), stable chronic renal insufficiency (serum creatinine 2.49 mg/dL with an eGFR of 26 mL/min/1,73m2) and normal liver function. Chest radiography showed no abnormalities. A mild infectious bronchitis was diagnosed, moxifloxacin was initiated and the patient was admitted to the respiratory department.
Two days after admission the patient developed high fever (39,1  C). Oxygen saturation was 93% while breathing ambient air. Clinical examination and pulmonary auscultation were normal. Blood cultures were taken and moxifloxacin was switched to piperacillin-tazobactam. Over the next four days the patient continued to develop daily fever. Blood cultures remained negative. Nevertheless, meropenem was started instead of piperacillin-tazobactam and a further work-up was performed.
Chest computed tomography (CT) scan revealed bilateral ground glass opacities scattered over both lung fields (Fig. 1). Everolimus was discontinued and replaced by tacrolimus, due to concerns of possible pulmonary toxicity. Transbronchial biopsies (TBB) revealed mild (grade A2B0) acute cellular rejection, which was treated with high-dose intravenous corticosteroids followed by tapering. Bronchoalveolar lavage (BAL) fluid showed a concurrent positive PJP polymerase chain reaction (PCR) despite adequate prophylaxis. Because of the patient's underlying chronic renal failure primaquine and clindamycin were administered as first choice for PJP treatment, instead of trimethoprim-sulfamethoxazole.
Soon after starting treatment fever disappeared and the patient's dyspnea improved significantly. Inflammatory markers returned to normal. Four days after initiation of therapy, however, dyspnea at rest reappeared. Oxygen saturation on pulse oximetry was 87% while breathing ambient air and chest auscultation revealed normal heart and breath sounds. The patient appeared mildly cyanotic, without signs of respiratory distress. Arterial blood gas analysis showed a pH of 7.49, a pO2 of 80.3 mmHg, a pCO2 of 29.5 mmHg, a bicarbonate of 22.4 mmol/L and a methemoglobin of 13.0%. Chest radiography did not show any new findings. A diagnosis of methemoglobinemia was made and a conservative approach was chosen. Supplemental oxygen through nasal cannula (2 L/min) was initiated. Three days later the patient appeared in moderate respiratory distress and seemed more cyanotic. Chest auscultation was clear, oxygen saturation on pulse oximetry was 86% with supplemental oxygen (3 L/min) and respiratory rate was 22 per minute. Repeated arterial blood gas analysis showed a dark brown color (Fig. 2), a pO2 of 100 mmHg, a pCO2 of 35.6 mmHg and a methemoglobin of 33.7%.
Treatment with primaquine was discontinued and replaced by trimethoprim-sulfamethoxazole, despite the reduced eGFR. Oxygen flow rate was increased to 5 L per minute through nasal cannula. The next day, however, the patient continued to experience moderate respiratory distress and methemoglobinemia had even increased to 36.0%. We preferred not to treat with methylene blue due to concerns of possible serotonin syndrome, since the patient was also taking trazodone once daily. Ascorbic acid intravenously at a dose of 1 g four times daily was administered. Over the next days, the patient's shortness of breath disappeared completely, oxygen saturation on pulse oximetry improved and the patient's skin color and methemoglobin levels returned to normal (Fig. 3). The patient recovered completely and was eventually discharged from the hospital after 35 days, without need for supplemental oxygen.
CT of the lungs showing widespread scattered ground glass opacities.