SUMMARY. We report two cases of severe cytomegalovirus (CMV) primoinfection in seriously burned patients. The infection may have contributed to both patients’ fatal outcome. This underlines the importance of research in viral aetiology, especially with regard to CMV, when immunodeficient patients - as burn patients are - develop unexplained fever. We propose a monitoring and a prevention strategy for CMV in the most severely burned patients. The prevention strategy involves the use of skin allografts and blood products in seronegative patients. CMV infection should not be underestimated in severely burned patients.
Information on the epidemiology of cytomegalovirus (CMV) infections in burn patients is limited. Moreover, most published cases involved non-severely ill patients, with few consequences as regards vital prognosis.1-3 CMV may thus be underestimated in burns and misdiagnosed.
We report two cases of seriously burned patients admitted to the burn unit of Cochin Hospital, Paris, who developed symptomatic primary CMV infection, confirmed by evidence of CMV seroconversion. These cases are a reminder that severe CMV infections may develop in patients with serious burns. While the clinical background of these patients predisposed them to contracting CMV, the delayed diagnosis possibly contributed to the fatal outcome. Prevention of transmission of CMV to these vulnerable patients is essential, as highlighted in these cases.
The first patient was a 32-yr-old man with serious electrical third-degree burns in 28% of the body surface. Bilateral mid-thigh amputations were performed on day 1 of hospitalization, followed by right femoroiliac disarticulation on day 26. After amputation, the burned surface represented 8% of the body surface.
By day 5 in hospital, the patient had experienced several bacterial and fungal systemic infections, treated with various anti-infective drugs. On day 54, fever of more than 39 °C was noted, without any obvious effect on standard microbiological cultures and radiological investigations, including a magnetic resonance imaging investigation of the amputation stump. Despite pre-emptive antibiotherapy based on colonization, the fever persisted. Development of the fever was associated with moderate lymphocytosis (4.97 x 109/l; 4 x 109/l), cholestasis with rapid elevation of bilirubin (230 µmol/l; 3-17 µmol/l), and elevated procalcitonin (2.7 ng/l; 0.5 ng/l). A real-time quantitative CMV Taq Man-based PCR assay (ABI) was performed on serum drawn on hospital day 96, using an in-house assay adapted from Leruez-Ville et al.1 The CMV viral load was 500,000 copies/ml, consistent with a highly active CMV infection. CMV serology was then retrospectively performed on stored serum samples, and this evidenced seroconversion between hospital days 88 and 96. The results of hepatitis A, B, and C, of HIV 1 and 2, and of EBV serologies were negative. A fundus autofluorescence found no retinal localization and lung radiography was normal. The multiple blood transfusions required by the patient during hospitalization (in all, 53 red blood cell concentrates) were the only possible source of the infection that was identified.
Ganciclovir treatment was initiated. Despite antiviral medication, the patient rapidly deteriorated and died on hospital day 104.
A 52-yr-old woman was admitted after she sustained an 80% total body surface burn, including 37% third-degree, during a house fire. Several skin grafts were performed, including allografts (from 14 donors, including five CMV-positive donors) and multiple blood transfusions (a total of 35 red blood cell concentrates). On hospital day 61, only 7% of the body surface remained uncovered.
From hospital day 5, several bacterial infections were identified, but none was associated with haemodynamic deterioration and they all responded well to antibiotics.
On hospital day 62, a persistent fever of more than 39 °C developed, and again no focus of infection could be located. This fever was preceded by digestive symptoms such as vomiting, mild blood-stained diarrhoea, and abdominal meteorism. Hepatic biology showed a moderate cholestasis. On hospital day 65, an abdomen ultrasound scan was performed and dilated intra- and extrahepatic biliary tracts were noted, a picture compatible with CMV infection and a “thick sigmoid tract”. An endoscopic retrograde cholangiopancreatography was quickly performed and extensive antibiotherapy was started. At the same time, quantitative Taq Man-based (ABI) CMV PCR showed more than 1,000,000 copies/ml in the patient’s serum. Serology confirmed CMV seroconversion. Other viral serologies (hepatitis A, B, C; HIV 1 and 2) were negative. A fundus autofluorescence found no retinal inflammation due to CMV and a fibrocolonoscopy found no CMV colitis in the left part of the colon.
Forty-eight hours after initiation of Ganciclovir medication, the fever decreased and the digestive symptoms improved. However, after a few days, the patient suddenly died from a massive pulmonary embolism.
The presence of CMV infection in burn patients is considered rare, but according to some trials, the rate would appear to be nearly 20%.2-4 This type of infection may be underestimated in burn patients as it is paucisymptomatic.2,5,6 Because of the severe outcome of CMV infection in these patients, it is important to bear in mind the need to consider this infection as part of a systematic approach to the management of burn patients with persistent fever, especially if associated with digestive or hepatic symptoms or a general status of deterioration.
Among published trials, only a few have studied the mode of CMV transmission in seronegative patients. The use of CMV-positive allograft represents a risk.3,8,9 Blood products also constitute a contamination mode, even if the frequency has considerably decreased with leukocyte filtration.10 Our two patients - both CMV-negative when they entered the ward - were both transfused but only one received a skin allograft. Even if a link cannot be firmly proved in the first case, there is a high probability of an infection due to blood transfusion. In the second case, the two contamination modes are possible. This addresses the issue of the use of blood products and CMV-seropositive skin grafts in CMV-negative burn patients.
There is at present no recommendation about the detection and follow-up of CMV-seronegative patients. There is also no consensus on preventing CMV seroconversion in such potentially immunodeficient patients. Considering the possibility of seroconversion due to blood transfusion or skin graft, and the potential morbidity of this infection, the management of seriously burned CMV-negative patient needs to be discussed. First, a CMV serology should be systematically performed in the most serious patients entering the burns ward. In initially seronegative patients, a serological follow-up should be performed regularly during hospitalization. If a septic syndrome occurs without any obvious bacterial aetiology, CMV viraemia should be carried out. The use of CMV-negative blood products should prevent seroconversion - their use should be privileged after advice from the local blood product authorities and according to availability.10 In the same way, allografts from CMV-negative donors should be specifically requested when their use is indicated. The systematic search for CMV in grafts is not in fact currently a reliable enough method,8 while it should be preferentially performed with the virology laboratory’s collaboration. Lastly, besides seroconversion in initially seronegative patients, there is also the possibility of reactivation of the virus in primarily CMV-seropositive patients. It would appear logical to ask for CMV viraemia by PCR in every seriously burned patient developing a septic status of unexplained origin.
In conclusion, considering the lack of precise data on CMV infection in burn patients, we suggest that CMV serology should be part of the initial investigation on admission, and that CMV PCR in blood should be performed in the presence of any unexplained serious septic syndrome. Guidelines in the screening and follow-up of CMV-negative patients and in the use of blood products and skin allografts should be established in such patients.RÉSUMÉ. Deux cas sont présentés de primoinfection sévère par cytomegalovirus (CMV) chez des patients atteints de graves brûlures. Il est possible que cette infection ait joué un certain rôle dans leur décès, ce qui souligne l’importance de la recherche dans le secteur de l’étiologie virale, en particulier pour ce qui concerne le CMV, quand les patients immunodéficients, comme par exemple les patients brûlés, présentent une fièvre non expliquée. Les Auteurs proposent un monitorage et une stratégie de prévention du CMV chez les grands brûlés. Cette stratégie de prévention nécessite l’emploi d’allogreffes cutanées et de produits hématiques chez les patients séronégatifs. Il ne faut pas sous-estimer l’infection par CMV chez les patients atteints de brûlures sévères.