Mycophenolate mofetil/prednisone/sirolimus

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

A woman [age not stated] developed recurrent Clostridioides Difficile infection, recurrent allograft pyelonephritis, Herpes simplex virus associated oral ulcers and oesophagitis, severe Q fever pneumonia, severe Q fever endocarditis and acute respiratory distress syndrome following immunosuppressive treatment with prednisone, mycophenolate mofetil and sirolimus [routes, dosages and durations of treatments to reactions onsets and outcomes not stated].

The woman had end-stage renal disease secondary to type 1 diabetes mellitus. She had undergone a deceased donor renal transplantation in 2004. Since the transplant, she had been maintained on immunosuppressive regimen comprising sirolimus, mycophenolate mofetil and prednisone. She had numerous infectious complications over the years comprising recurrent allograft pyelonephritis, recurrent Clostridioides difficile infections and herpes simplex virus associated oral ulcers and oesophagitis. She lived in a rural farm area and was also in contact with the animals like dogs, cows, horses and donkeys. At the age of 59 years, she presented with a 1-day history of dry cough and fatigue, which had started suddenly and was associated with post‐tussive emesis. She also had fever, chills, malaise, myalgias, headaches, nausea and vomiting. She then developed shortness of breath and confusion. She was found to be febrile and severely hypoxic. She required 40 liters of oxygen via heated high flow nasal cannula. Physical examination was significant for bibasilar mild inspiratory crackles, diffuse bilateral expiratory wheezing and tachypnoea. She was empirically treated with vancomycin, cefepime, azithromycin, cotrimoxazole [trimethoprim‐sulfamethoxazole] and isavuconazole. A chest x‐ray showed patchy multifocal opacities. A CT scan of the chest demonstrated extensive bilateral centrilobular nodules, consolidation and ground‐glass opacities, all more pronounced in the lower lobes. Plasma cytomegalovirus and Epstein‐Barr virus PCR, respiratory viral PCR, Legionella urine antigen, Streptococcus pneumoniae urine antigen, serum Aspergillus galactomannan, serum Coccidioides serology, serum Blastomyces serology, urine Histoplasma antigen, serum Cryptococcus antigen, Hantavirus serology and blood cultures were found to be negative. The HIV‐1/2 antibody was negative on a previous occasion. A bronchoscopy showed erythematous and edematous airways with mucus plugs. Bronchoalveolar lavage bacterial, fungal, and acid‐fast bacilli cultures were found to be negative, Pneumocystis jiroveci direct fluorescent antibody stain was negative (at which point TMP‐SMX was stopped), Aspergillus galactomannan was negative, and cytology was negative for malignant cells. A transthoracic echocardiogram (TTE) revealed a normal ejection fraction and no valvular abnormalities. Pneumocystis jiroveci direct fluorescent antibody stain was found to be negative and cotrimoxazole was stopped. Aspergillus galactomannan was negative, and cytology was negative for malignant cells. A transthoracic echocardiogram (TTE) revealed a normal ejection fraction and no valvular abnormalities. Over the next 5 days, her oxygen requirements increased and meropenem was added to the antibiotic regimen. Her condition continued to deteriorate and ultimately required intubation for mechanical ventilation. Her chest X ray showed worsening bilateral pulmonary infiltrates, consistent with acute respiratory distress syndrome.

The woman's therapy with sirolimus was stopped and methylprednisolone was started emperically. She was then found to have acute Q fever as she had positive Q fever serologies. Her antibiotics were changed to doxycycline for 2 weeks for acute Q fever, and methylprednisolone was stopped. A repeat TTE at that time showed mild aortic sclerosis with trace aortic regurgitation. Doxycycline was replaced by minocycline on day 9 of therapy to minimise the risk of erosive esophagitis. An esophagogastroduodenoscopy (EGD) showed Herpes simplex virus type 1, for which aciclovir was added and ultimately transitioned to valaciclovir upon discharge. Additionally, her immunosuppressive regimen was also modified, in which, only sirolimus was replaced by tacrolimus, but prednisone and mycophenolate mofetil were continued. Despite having acute kidney injury, her graft function had returned to baseline at discharge. One month later, she was readmitted to the hospital for recurrent allograft pyelonephritis and Q fever serologies were found to be positive. A repeat TTE showed mild aortic sclerosis without stenosis, without aortic regurgitation, and no valvular vegetations. Due to the thickened aortic valve, there was concern for evolving Q fever endocarditis, so she was restarted on doxycycline with the addition of hydroxychloroquine. She underwent a transesophageal echocardiogram (TEE) which showed aortic sclerosis with trace aortic regurgitation and no valvular vegetations. The Q fever serologies were repeated and even after 2 months, the Q fever serologies were unchanged except for negative phase II IgM titer. She was asked to continue dual therapy for minimum of 18 months.