Chronic graft versus host disease (cGVHD) manifesting as parotitis after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is artificially divided into acute and chronic forms depending on its date of onset. Although there may be a continuum of clinical findings, chronic GVHD can affect numerous organs that are not typically affected by acute GVHD. Chronic GVHD involving the salivary glands and/or lacrymal glands which clinically manifests as xerophthalmia and/or xerostomia similar to Sjogren’s syndrome occurs commonly after hematopoietic cells transplantation, particularly with transplants utilizing mobilized peripheral blood stem cells. However, de novo chronic GVHD manifesting as parotitis and submandibular lymphadenopathy is underrepresented in the literature. Here we describe a patient with severe aplastic anemia who received an allogeneic hematopoietic cell transplant that developed recurrent parotitis and submandibular lymphadenopathy more than 8 months following the procedure which may have been a manifestation of chronic GVHD.

The patient is a 37-year-old Nepalese female who developed RBC and platelet transfusion dependent pancytopenia in 2003. A bone marrow biopsy was consistent with a diagnosis of severe aplastic anemia (SAA) and she received treatment in her homeland with prednisone and cyclosporine for more than 2 years without response. She presented to the NHLBI in 2006 where a diagnosis of SAA was confirmed. She received a trial of cyclosporine and horse ATG without response and subsequently underwent a T-cell replete G-CSF mobilized peripheral blood stem cell transplant from her HLA identical sibling on 21 March 2007 following conditioning with fludarabine, cyclophosphamide, and horse ATG.

¹ She received cyclosporine and mini-dose methotrexate as GVHD prophylaxis. Neutrophil engraftment occurred on day +20 and by day +30 short-tandem repeat based PCR studies revealed she had achieved 100% donor chimerism in myeloid and T-cell lineages. On day +85 she developed acute GVHD of the GI tract associated with watery diarrhea which resolved completely with corticosteroid therapy. On day +219 she developed new onset thrombocytopenia possibly related to chronic GVHD which prompted treatment with mycophenolate mofetil (an evaluation for platelet auto-antibodies was not pursued). On day +263 the patient was admitted to the hospital for evaluation of multiple new symptoms including symmetric, diffuse swelling of the neck and cheeks, facial edema, fever, a nonproductive cough and was noted to have increased blood eosinophils (18.2% with an absolute eosinophil count of 1.966 K cells/μl). Her medications on admission included cyclosporine, mycophenolate mofetil, valtrex, atovaquone, amlodipine, magnesium, and lamivudine. She had no prior history of mumps or sick contact exposure.

A neck CT showed diffuse soft tissue edema of the face and enlargement of both submandibular and parotid glands with no discrete focal abnormalities within the parenchyma of these glands (Figure 1). There was no neck lymphadenopathy. Lab tests revealed a white blood cell count of 16 k /μL, a hemoglobin of 10.9 gm/dL, platelets of 91 k/μL, with a differential showing an absolute neutrophil count of 8.0 k/μL, with eosinophils increased at 28% (absolute eosinophil count elevated at 4.1 k/μl). Her LDH, liver function studies and electrolyte panel all were within normal limits although her CRP was slightly elevated at 1.83 mg/dL.

Figure 1.

Panel A: substantial swelling of the parotid glands;

Panel B: marked decrease in swelling 3 days following the initiation of prednisone.

An ANA and ENA (Anti-SSA/B) were negative and serum amylase, lipase, and IgG levels were all found to be within normal ranges.

An extensive infectious disease workup including blood, respiratory, stool and urine cultures for multiple different bacterial, viral, and parasitic pathogens returned negative (which included: urine/saliva mumps viral culture; respiratory viral culture and rapid detection for Influenza A, RSV, HSV; throat culture for Hemolytic group A strep; stool C-diff toxin; stool EIA or PCR for Norovirus, rotavirus, adenovirus and Giardia). Sequential PCR analysis of blood samples for EBV and CMV as well as acute and convalescent viral titers for mumps obtained on admission and roughly 1, 2, and 3 weeks after the onset of symptoms ruled out a viral etiology to her symptoms.

A flexible sigmoidoscopy with biopsy obtained on day +267 showed crypt injury and dropout associated with focal mucosal erosion without granulomas, viral inclusions and parasitic organisms. Some rare crypts showed cryptitis with a neutrophilic infiltrate and rare apoptotic cells suggestive of GVHD. The inflammatory infiltrate in the lamina showed numerous plasma cells. Special stains for fungi, acid-fast bacilli and immunohistochemistry for CMV all returned negative.

Her fever, diarrhea, face/neck swelling and eosinophilia improved quickly following the initiation of 20mgs of daily prednisone (figure 1). A prednisone taper was initiated and she was discharged on day +272. Two days following the discontinuation of prednisone, her fever, facial/parotid swelling and eosinophilia recurred in association with an erythematous scaly skin rash involving the face, arms and upper torso. Biopsy of the skin showed irregular acanthosis, compact hyperkeratosis, hypergranulosis, and numerous apoptotic/necrotic/dyskeratotic keratinocytes along the basal layer, typical for chronic lichenoid GVHD which would be classified and staged as chronic skin GVHD with lichen planus like features with a skin score of 2 according to the NIH consensus for cGVHD staging .² A core needle biopsy of the parotid gland was deferred due to the potential to cause injury to the facial nerve. She was reinstituted on another course of low-dose prednisone (20mgs/day) and again had a quick improvement in her parotid/neck swelling and gradual resolution of her chronic skin GVHD.

During both episodes, the patient never developed any oral ulcerations and denied symptoms of dry eyes or mouth. Her steroids were tapered slowly without recurrence of facial swelling or skin GVHD although she did develop bronchiolitis obliterans symptoms (BOS) on Day +325 associated with a small decline in FEV1 necessitating an increase in her prednisone dose.

In conclusion, this patient had a clinical presentation of parotid/submandibular swelling occurring in association with chronic skin GVHD in the context of a negative infectious disease work-up. Although a core needle biopsy of the parotid gland would be required to make a definite diagnosis of GVHD-induced parotitis, the risk of facial nerve damage precluded its use. The resolution of all her symptoms with corticosteroid therapy including biopsy proven GI GVHD and chronic skin GVHD that was temporally related to her other symptoms raises the possibility that her parotitis and submandibular adenopathy were manifestations of chronic GVHD.