1. ¹University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA
2. ²Infectious Disease, Baltimore, MD, USA
3. ³Pathology, Baltimore, MD, USA

Infection-related mortality after stem cell transplantation is related to patient age, immunological status, duration of neutropenia, comorbid medical conditions and perhaps more importantly, the ability to rapidly identify the pathogen and institute timely appropriate antibiotics. Here, we describe a case that highlights an unusual infection with a very high case-fatality rate, in which early recognition and treatment is critical.

A 73-year-old Caucasian male with multiple myeloma received autologous SCT after BCNU and melphalan. After 5 years, he developed secondary myelodysplastic syndrome/AML associated with an isochromosome 17q. Despite advanced age, with an excellent performance status and no comorbid illnesses, he received an allograft from his HLA-matched sister. Conditioning included busulfan 3.2 mg/kg/day i.v. for 4 days followed by cyclophosphamide at 75 mg/m²/day. A total of 4.08 10⁶ G-CSF-mobilized CD34 cells/kg were infused. GVHD prophylaxis was tacrolimus and methotrexate. Antimicrobial prophylaxis included voricanozole, acyclovir and gatifloxacin. On day+5, G-CSF at 5 g/kg/day was started.

He was asymptomatic until day+8 when he developed perianal discomfort and mild hemorrhoidal bleeding. No thrombotic occlusion or perianal abscess was noted. On the morning of day+9, the patient complained of restless legs and pain in both calves, which did not improve with mild walking exercise or gentle massage. Towards noon on the same day, he became extremely anxious and uncomfortable because of persistent pain in his legs, particularly in both calves. No swelling, inflammation or crepitus was noted. Repeat physical examination in the afternoon revealed tenderness of thighs, calves and lower abdomen, with tense abdominal distension and diminished bowel sounds. There was no obvious discoloration or crepitus on exam. Aztreonam and amikacin were started for Gram negative coverage because of a history of allergy to cefepime and beta-lactam antibiotics. Hematocrit was 23, down from 25 earlier that morning. Creatinine phosphokinase and LDH were normal. Urine culture was positive for Stenotrophomonas maltophilia. Blood cultures remained negative.

The patient developed fever, persistent muscle pain not relieved by intravenous morphine sulfate, hypotension and respiratory distress necessitating transfer early next morning to intensive care. Vancomycin was added empirically. Blood cultures were still negative. He became progressively more hypotensive and underwent elective intubation. Arterial blood, gas after intubation showed acidosis. He was also started on vasopressors and Imipenem in place of aztreonam. Blood chemistry analysis could not be performed because three different blood samples sent to the laboratory were all hemolyzed. Serum in the blood specimen containers was red in color, suggesting gross intravascular hemolysis. He expired at day+10.

Autopsy showed an aplastic marrow with no evidence of leukemia. There was a small pocket of gas in the region of the mediport device in the right pectoralis major. There was extensive intracardiac bacterial growth but without inflammatory cells. Both lungs also showed multiple foci of bacteria without any inflammatory cells. The liver showed extensive colonization with a Gram-positive bacillus with pockets of gas production (Figure 1). The gastrointestinal system was remarkable for normal well-preserved serosal and mucosal surfaces. The right kidney showed arteriolonephrosclerosis and bacterial overgrowth throughout the kidney. The spleen showed prominent autolysis and bacterial overgrowth with loss of white pulp and congestion of red pulp (Figure 2). Post-mortem blood and skeletal muscle cultures were positive for Clostridium perfringens (CP).

Figure 1.

Liver biopsy showing abundant Gram-positive rods seen at high magnification (40 10 power field).

Full figure and legend (71K)

Figure 2.

Splenic tissue infiltrated diffusely by CP organisms seen at intermediate magnification (10 10 power field).

Full figure and legend (78K)

The patient died less than 24 h after reporting the first symptom of restless legs and muscle pain. Of note, blood cultures drawn 1 day prior to death were negative, but post-mortem blood culture grew CP. Thus, it is likely that he was not infected when the pre-mortem culture was drawn.

CP is usually isolated from tissue infection and bacteremia that occurs after a trauma.¹ It causes rapidly progressive muscle necrosis with acute inflammation in the absence of polymorphonuclear cell infiltration. Indeed, no inflammatory cells and neutrophil infiltration were observed in our autopsy materials (see figures). CP infection can be associated with systemic toxicity and hemolysis. The fulminant course of the infection and features of extensive tissue necrosis are related to release of bacterial toxins at the infection site.² The -toxin has been associated with gas gangrene, hemolysis, muscle necrosis and increased vascular permeability.^{3, 4} CP can cause soft tissue infections like myonecrosis (gas gangrene) and intra-abdominal infections (peritonitis, abscess, wound infections).

The entry site of this infection remains speculative in our case. Spontaneous or nontraumatic myonecrosis or distant 'metastatic' spread can occur after mucositis or typhlitis in neutropenic patients causing circulation of Clostridia and implantation in tissues that are able to support their growth.⁵ It is possible that CP might have entered his blood stream from a microperforation in the gastrointestinal tract and then seeded the liver and skeletal muscles. The right chest mediport could be another site of entry in view of gas formation over his pectoralis muscle.

CP has been reported as a complication of pooled platelet transfusion.⁶ It is unlikely that the stem cell product was contaminated since the incubation period of CP is less than 4 days and frequently less than 24 h. Although he had no documented transfusion reaction or fever prior to developing initial muscular symptoms, bacteria might have been introduced through platelet transfusion. He had received platelet and packed red cell transfusions on two consecutive days just prior to the initial symptoms of muscle pain. Neither platelet nor red cell bags were cultured because no immediate reaction was observed during or after transfusions.

In immunocompetent patients, the first sign of infection is usually severe pain at the site and edema and tenderness of the involved muscle with hemorrhagic bullae. Presence of gas is seen later in the disease course and can be recognized by palpation, X-ray or CT scan.⁷ Signs of intravascular hemolysis including hemoglobinuria are seen in patients with CP bacteremia.^{7, 8} In the end stage, hypotension, renal failure and metabolic acidosis can ensue before death.¹ Of note, we also observed excessive hemolysis in three sequential blood samples. Rapid hemolysis is an important key finding, which should alert clinicians about the possibility of CP septicemia.

The post-mortem report revealed hepatic necrosis with intrahepatic gas formation. Liver biopsy culture did not show bacterial growth, but the Gram stain revealed Gram-positive bacilli consistent with CP. Interestingly, myonecrosis and CP were noted in the pectoralis major muscle overlying the mediport site, suggesting that this may be the site of entry. Other autopsy findings included hemopericardium, hemothorax and hemoperitoneum. Extensive capillary damage due to CP sepsis might also have contributed to the extensive bleeding, which may explain his hypotension.

Although CP infection has been reported after autologous bone marrow transplantation,⁷ this is the first case occurring in an allograft recipient. Bodey et al published a 12-year experience of 136 patients of clostridial bacteremia in cancer patients with 58% overall survival. However, mortality was 100% if patients had acute hemolysis, gas gangrene and diffuse spreading cellulitis.⁵ CP septicemia and associated complications were reported in leukemia^{9, 10} and Hodgkin's lymphoma.⁸ Management includes aggressive surgical debridement of all necrotic tissue in conjunction with antibiotics such as penicillin and clindamycin. Alternative antibiotics include chloramphenicol, metronidazole and imipenem.

CP sepsis is a rare but highly fatal infection in SCT recipients. Myonecrosis with possible Clostridia infection should be considered in transplant recipients with severe unexplained myalgia. Clindamycin should be instituted early in suspected cases, even in the absence of fever pending culture and other laboratory results. We believe that this important observation will increase the awareness of this complication. Early suspicion and timely institution of aggressive treatment may alter the clinical course of infection and save some patients.