A male in his fifties with history of insulin-dependent diabetes and deceased donor kidney transplant, presented with acute on chronic ascending paralysis. He received his transplant 7 months prior to admission with alemtuzumab induction. Cytomegalovirus (CMV) status was high risk with the patient being CMV negative and the donor being CMV positive. His maintenance immune suppression was primarily tacrolimus, mycophenolate mofetil, and prednisone 5 mg and consistently had CMV viremia (mid-2s log IU/mL) with wild-type genotype on recent testing.

Three months prior to admission he had Klebsiella graft pyelonephritis complicated by native mitral valve endocarditis, and he was treated with 6 weeks of oral ciprofloxacin. After this admission he developed lumbar back pain and mild weakness in his feet and lower legs.

Six weeks prior to admission he was admitted for malaise, was found on imaging to have a right lower lobe focal opacity, and was treated for 7 days initially with piperacillin/tazobactam and then amoxicillin/clavulanate.

Four weeks prior to admission he was admitted for bilateral lower extremity weakness. MRI of the lumbar and thoracic spine with and without gadolinium was negative though severely limited by motion. Weakness was thought due to deconditioning due to his multiple hospitalizations. CT scan of his chest showed non-calcified nodularity mostly in the upper lobes and right hilar and subcarinal lymphadenopathy with 1 cm right lower lobe opacity. He was treated with piperacillin/tazobactam for pneumonia for 10 days and follow-up chest imaging was recommended.

One week prior to admission he was transitioned from tacrolimus and mycophenolate mofetil to belatacept for maintenance immune suppression. Several days prior to admission he noticed it became much more challenging to walk; while previously he had been able to ambulate with a walker, he was unable to get out of bed and it was now difficult to feel below his knees. He developed a productive cough. When he informed his transplant doctors, he was asked to come into the emergency room. In the emergency room he had a foley catheter placed for urinary retention and his bladder was still distended after decompression.

Insulin dependent diabetes- recent Hemoglobin A1c: 8

Deceased Donor Kidney transplant 7 months prior to admission, CMV D+/R-

Deep vein thrombosis and pulmonary embolism

Surgeries: AV fistula; Kidney transplant

No known allergies

Atovaquone 1,500 mg daily

Enoxaparin

Insulin long acting and with meals

Prednisone 5 mg daily

Belatacept

Valganciclovir 450 mg BID

The patient was not in acute distress and vital signs were within normal limits: Temperature 37.6°C, heart rates 95 beats per minute, blood pressure 126/88, respirations 18 per minute and oxygen saturation 95% on room air. His cranial nerves were intact as was the sensation and strength in his arms. His hip flexion was reduced to 4/5 bilateral, knee flexion extension was 3/5 and ankle flexion/extension was 0/5. Patella and Achilles tendons were areflexic. He had decreased sensation to pinprick and vibration below the knees and decreased perianal sensation. His examination was otherwise normal.

Relevant laboratory findings include a white blood cell count of 3.4 x1000/µL (reference 4.0-10.0 x 1000/µL) with absolute lymphocyte of 0.3 (1.0-4.0 x 1000/µL), and 12% immature bands (0-10%). Hemoglobin was 9.8 (12.0-18.0 g/dL) and platelets were normal. Blood urea nitrogen was 32 (6-20 mg/dL) and creatinine had increased from baseline of 1.96 to 2.75 (0.40-1.30 mg/dL). Recent flow cytometry showed a CD4 count of 8/µL (466-1608/µL) and CD19 count of 2/µL (101-525/µL). His CMV serum PCR has fallen from 2.46 log IU/mL the previous week to less than 2.14 log IU/mL. Pre-transplant labs were notable for HTLV IgG being positive. HIV screening was negative prior to transplantation. Recent interferon gamma release assay was indeterminate. Remainder of routine labs were normal.

Lumbar puncture showed turbid, xanthochromic fluid. No opening pressure was recorded. Cell count was 1,290 nucleated cells/µL (<6 cells/µL), 39 red blood cells/µL (0 cells/µL), glucose 31 mg/dL (40-70 mg/dL) , protein 1,196 mg/dL (15.0 -45.0 mg/dL) and adenosine deaminase 9.7 U/L (<7.0 U/L).

Figure 1. CT scan of chest. Stable consolidation of the right lower lobe with surrounding ground glass with a focal cavitation in the right lower lobe consolidation and subcarinal and paraesophageal lymphadenopathy

Figure 2A. MRI of spine with gadolinium. Intramedullary peripherally enhancing lesion seen in the spinal cord from T12 to L1

Figure 2B. Expansion of the conus and obliteration of the surrounding subarachnoid space

Figure 2C. Cauda equina nerve roots are clumped most prominently at the L1-L3 level without nerve root enhancement

Figure 3. MRI of brain with gadolinium. Ring-enhancing lesions of the supra and infra-tentorial brain parenchyma, splenium of the corpus callosum, left caudate nucleus, brain stem and right cerebellum the largest being 1.5 cm. Supratentorial lesions shown.

Figure 4. Gram stain of brain biopsy. Beaded, branching gram positive rods

In solid organ transplant recipients, the differential diagnosis for pulmonary-brain syndromes encompasses a wide variety of pathogens. Pulmonary-brain syndromes begin with the colonization or infection of the respiratory track with subsequent dissemination to the central nervous system. Besides Nocardia, other potential pathogens are tuberculosis, Pseudomonas, Aspergillus, Mucormycosis spp., dimorphic fungi, Cryptococcus, and Toxoplasma(1, 2). This patient prior to admission also had CMV viremia. CMV of the central nervous system can rarely present with a syndrome of transverse myelitis with CSF demonstrating pleocytosis with neutrophilic predominance, high-protein and hypoglycorrhachia on lumbar puncture—though the cell count is not typically as high as seen in this case(3). Most cases of CMV myelitis have been documented in the HIV/AIDS literature as opposed to the transplant literature. Finally, thought this patient had positive HTLV-1 IgG prior to transplant and he had slowly progressive weakness and back pain, he otherwise does not meet the clinical presentation of tropical spastic paraparesis of hyperreflexia and clonus(4).

He had received alemtuzumab, which is a recombinant humanized monoclonal immunoglobulin G1 that targets CD52 surface antigen, present on 95% of B and T cells as well as macrophages, mature and immature dendritic cells(5). Alemtuzumab causes prolonged and profound immune suppression, including mature B cell, CD4+ T cell and Th17 cell depletion(6, 7). Alemtuzumab has been associated with an increased risk of CMV viremia and disseminated fungal infection compared with basiliximab or anti-thymocyte globulin(8). It has also been associated with autoimmunity, most often Grave’s disease—though this is most often seen in the multiple sclerosis literature(9). Alemtuzumab is used often in younger patients with a lower predicted risk for rejection.

Nocardia in solid organ transplant recipients most often affects the lungs. On imaging Nocardia presents as nodules in about 70% of patients though it can also present as a cavitation (30%), consolidation (40%), pleural effusion (25%) or interstitial involvement (12%)(10). Disseminated infection is the next most common manifestation. Nocardia also has a propensity for the central nervous system and skin(10). The species of Nocardia can assist with empiric antibiotic choice as antibiotic sensitivities can take weeks to return. Nocardia farcinica may be resistant to third-generation cephalosporins and minocycline, variably resistant to imipenem and 0.5-6% of isolates resistant to the mainstay of Nocardia therapy, which is trimethoprim-sulfamethoxazole(11). A two or three-drug regimen is recommended initially for central nervous system disease and continued for at least 12 months with clinical and radiographic monitoring for at least 1 year after completion of therapy to detect late relapses(11).

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11. Sorrell TC, Mitchell DH, Iredell JR, Chen SC. Nocardia species. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. : Elsevier; 2015.

ID week Fellows' Day 2021 - oral presentation This case was contributed by: Dr. Lauren Pischel, Dr. Eric Elliot, Dr. Marwan Azar and Dr. Jeffry Topal

Yale School of Medicine

The case was originally presented at ID Week 2021, a joint effort of Infectious Diseases Society of America (IDSA), HIV Medical Association, Pediatric Infectious Diseases Society (PIDS), and the Society for Healthcare Epidemiology of America (SHEA), during an interactive session on Fellows' Day. Copyright Infectious Disease Society of America (IDSA), 2021. Used with permission.

Case #21005: A male in his fifties with history of insulin-dependent diabetes and deceased donor kidney transplant, presented with acute on chronic ascending paralysis. [Internet]. Partners Infectious Disease Images. Available from: http://www.idimages.org/idreview/case/caseid=593.

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