Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome

First admission

A male, 30-year-old drug addicted patient in OST was admitted to the local hospital. He was hepatitis C positive and had a history of hospitalisations for skin infection. At admittance, he was in a poor general condition with nausea, vomiting, abdominal pain and muscle aches. Physical examination revealed a diffusely tender abdomen and poor dental status. Laboratory investigations disclosed non-specific inflammatory signs with an increased erythrocyte sedimentation rate (83 mm/h) and C-reactive protein (CRP, 90 mg/L), severe normocytic anaemia with a haemoglobin of 7.8 g/dL and renal insufficiency (serum creatinine 133 μmol/L, estimated glomerular filtration rate 60.1 mL/min/1.73m²) with microalbuminuria. Blood cultures were negative. Radiological examinations of the thorax and abdomen showed splenomegaly and a pancreatic cyst, but otherwise no radiologic signs of infection, malignancy or kidney pathology. His CRP and serum creatinine levels fell spontaneously, and he left the hospital against the doctor’s advice after four days.

Second admission

Two months later, the patient fractured his right clavicle. After a two-week delay, he was admitted to hospital with a fever and a swollen and erythematous clavicular region. His general condition and nutritional status had worsened, nausea and vomiting persisted and anaemia and renal insufficiency had relapsed. Blood cultures were positive for Staphylococcus aureus, and antibiotic treatment against suspected osteomyelitis was initiated. Magnetic resonance imaging (MRI) of the clavicular region and the upper arm showed mottled signal changes with a high signal intensity in the lateral clavicle, the humeral bone and the acromion (Figure 1a). The diagnoses considered at this time were osteomyelitis or malignancy. Biopsies from the fractured bone, bone marrow and gastric mucosa were performed in the work-up of this complex symptomatology.

Figure 1. Radiological and biopsy findings.

(a) MRI (T2-blade-sag-FS) of the right humerus showing mottled signal changes. (b) Clavicular bone (H&E): The marrow space is infiltrated by histiocytes with bluish transparent bubbles. (c) Bone marrow (H&E): Massive infiltration of histiocytes and scarce remaining hematopoietic tissue. (d) Gastric mucosa (H&E): Infiltration of vacuolated histiocytes in an extended lamina propria. All scale-bars 50 μm.

Biopsy findings

The biopsies all showed similar infiltrates of histiocytes with a cytoplasm extended by vacuoles of different sizes (Figure 1b–d) and eccentrically located nuclei.

Biopsies from the fractured bone revealed reactive changes with ongoing fibrosis. The fibrotic tissue contained the multivacuolated histiocytes as singular cells, small groups or sheets of cells (Figure 1b). The bone marrow biopsy showed massive histiocytic infiltrates (Figure 1c). There was reduced fat cell content, and there was almost no visible hematopoietic tissue. The gastric biopsy showed antrum mucosa with elongated gastric pits and aggregates of multivacuolated histiocytes in both the superficial and deep lamina propria (Figure 1d). A gastric biopsy taken two years previously was re-examined. It showed the same histiocytic infiltrates; however, the findings did not lead to the correct diagnosis at the time.

In the hematoxylin and eosin (H&E) stain, the vacuoles had distinct membranes and a bluish, transparent looking content. Vacuole content did not stain in the periodic acid Schiff (PAS), Prussian blue or Alcian blue stain. The cells were positive for CD68/PGM1 confirming the histiocytic nature (Figure 2a). The vacuoles stained red in Congo red stain and black in the periodic acid methenamine silver (PASM) stain (Figure 2b and c). The vacuoles did not show birefringence in Congo red stain or other stains.

Figure 2. Staining properties.

All micrographs are from the same bone marrow biopsy. (a) CD 68/PGM1: The vacuolated cells are CD68-positive histiocytes. (b): Congo red stain: Vacuole content stains faintly red. (b) PASM: Vacuole content stains grey or black. All scale bars 50 μm.

Interpretation

The microscopic appearance of the vacuolated histiocytes and the histochemical staining properties were consistent with PVP deposition.^12,13 At that time, several of the OSDs marketed in Norway contained PVP.⁴ Our patient had injected both buprenorphine tablets and methadone syrup regularly over several years. The buprenorphine tablets contained PVP K30 (MW 44–54 kDa). The specific methadone syrup he had been injecting contained large amounts of PVP K90 (MW 1 000–1 500 kDa).¹⁴ While much of the PVP K30 is expected to be excreted within weeks, PVP K90 will not be excreted and consequently accumulates in the body.⁶ It is therefore plausible that injections of the PVP K90-containing methadone syrup were the cause of the PVP-deposition disease in this patient. Based on the history of this patient and other similar cases,^15,16 the European Medicines Agency suspended this methadone syrup in 2014.¹⁴

Further development

After the diagnosis was made, the patient’s health gradually declined, in part due to his poor self-care and underlying chronic drug addiction. There is no specific treatment for PVP deposition disease. His persistent anaemia was treated with regular blood transfusions and erythropoietin-stimulating agents with limited effect. He had short episodes of mild thrombocytopenia and leukocytopenia, and, in general, his leukocyte response to infection was weak. The kidney failure was managed by supportive treatment, and serum creatinine levels fluctuated between 150 and 450 μmol/L.

Within the first year of the diagnosis, the patient suffered a left sided pathological femoral neck fracture with impaired fracture healing, complicated by chronic osteomyelitis. In the right hip, he developed severe bone destruction of the acetabulum with dislocation of the femoral head and a subsequent femoral neck fracture (Figure 3a). MRI scans of both hips and the pelvis (not shown) revealed the same changes as those detected in the shoulder region. Biopsies from the greater trochanter region showed extensive histiocytic infiltrates (Figure 3b). Surgical treatments were unsuccessful. Henceforth his mobility deteriorated to such a degree that he needed a wheelchair and required daily activity support and care in a palliative care centre. Furthermore, he developed endocrine pancreas insufficiency with insulin-dependent diabetes mellitus. He had a gradual weight loss of 22 kg during four years despite adequate food intake. Malabsorption due to exocrine pancreas insufficiency was suspected, but supplementation of pancreas enzymes had little effect on the weight loss.

Figure 3. Pathological fractures and bone destruction: radiological and biopsy findings.

(a) Pelvic radiograph. Left hip: The hip prosthesis has been removed due to loosening and replaced by a Girdlestone hip. Right hip: Extensive lytic and sclerotic changes in the proximal femur and acetabulum leading to medial dislocation of the femoral head. (b) Biopsy from the right greater trochanter (H&E): The marrow space is filled with histiocytes with the bluish vacuoles characteristic of PVP-deposition. The bone trabecula has empty lacunar spaces and contains a bluish material. Scale bar 50 μm.

Five years after the diagnosis of PVP deposition disease, the patient died, impaired by multi-organ failure and advanced cachexia with a body mass index below 15 kg/m².

Autopsy

The autopsy concluded that the immediate cause of death was multi organ failure due to PVP deposition disease, which in turn was a consequence of the patient’s illicit substance abuse. The following organs and tissues were sampled during the autopsy: the pericardium and myocardium, the pleura and lungs, kidneys, liver, pancreas, gastric mucosa, adrenal glands, peritoneum and abdominal adipose tissue, the spleen, lymph nodes, and femoral bone and bone marrow. Microscopically, we observed PVP-deposition in all sampled organs and tissues (Figure 4). The PVP-containing histiocytes were partly scattered in the interstitium, e.g. in the myocardium (Figure 4a), and partly organised like larger, nodular lesions, e.g. in the pleura (Figure 4b). Peri- and intra-neural distribution was seen in several organs including the heart. However, there were no clinical, echocardiographic or electocardiographic evidence of impaired cardiac output or arrhythmias prior to his death. Autopsy findings corresponded well with the clinically observed pancreas and kidney insufficiency. There was little preserved exocrine and endocrine pancreas parenchyma. The pancreatic tissue was dominated by dense fibrosis interspersed by heavy infiltrations of histiocytes (Figure 4c). The kidney showed moderate to severe interstitial fibrosis and tubular atrophy, and only minor glomerular changes. There were infiltrates of PVP-containing histiocytes in the interstitium, mostly in atrophic areas (Figure 4d). In glomeruli, we observed a slightly increased number of histiocytes and occasional PVP-containing vacuoles. There were no amyloid depositions or signs of other renal diseases. The autopsy revealed no evidence of infection besides minor foci of acute inflammation in the pancreas.

Figure 4. Autopsy findings (H&E).

Infiltrates of histiocytes with the bluish vacuoles characteristic of PVP in all organs. (a) Myocardium: Interstitial fibrosis and histiocytic infiltrates. Scale bar 50 μm. (b) Pleura: Nodular lesion composed of fibrotic tissue and histiocytes. We found similar lesions in the pericardium and peritoneum. These were macroscopically visible. Scale bar 200 μm. (c) Pancreas: Pronounced fibrosis with histiocytic infiltrates. Poorly preserved ductal structures. Scale bar 50 μm. (d) Kidney: Cortical tissue showing interstitial fibrosis, tubular atrophy, and an infiltrate of histiocytes in the extended interstitium. Scale bar 50 μm.