Viral infections in immunocompromised patients

The number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is steadily increasing, and the outcome of this intervention is largely dependent on how well complications in the form of severe infections can be adequately diagnosed and controlled. Adenoviruses (AdV) have emerged as important causes of morbidity and mortality in these patients. Early diagnosis of the infection by detection of viral DNA may improve the prognosis.

In paper I we evaluated a surveillance strategy for detection of AdV DNA by real-time PCR in a prospective study of hematological allo-HSCT recipients. In parallel with a routine cytomegalovirus surveillance program, plasma samples from 97 recipients were analyzed by quantitative PCR for detection of AdV DNA. A total of 5% of the patients had detectable AdV DNA in plasma. Only one patient had high titers and none developed AdV disease. Bone marrow as a source of stem cells and myelodysplastic syndrome as the indication for transplantation were independently associated with higher risk of acquiring AdV infection.

We concluded that the strategy did not have a significant effect on the clinical outcome in our material, but given the sometimes high incidence of AdV infection and disease in other settings, we do not dismiss the idea of surveillance.

With a somewhat different approach to improve the clinical care for patients undergoing immunosuppressive treatment, we investigated the etiology to febrile neutropenia. Chemotherapy-induced neutropenia is one of the major side effects of the treatment of maligancies, and the risk of infection is increased by the severity and duration of neutropenia. The empiric administration of broad spectrum antibiotics has substantially decreased the mortality rate of patients with febrile neutropenia, but in only approximately one-third or fewer of the fever episodes, bacterial infection is documented. It is likely that other pathogens, such as viruses, play an important role as etiological agents, and an overuse of antibiotics could be anticipated.

Therefore, in paper II and paper IV we investigated the presence of common viral infections and febrile neutropenia in children with cancer as well as adult patients with hematological disorders. A broad range of respiratory viruses in nasopharyngeal aspirate (NPA) and viruses commonly reactivated in allo-HSCT recipients were sought for. With human rhinovirus (HRV) being the predominant virus, we found an viral agent in half of the cases in the pediatric cohort. Of these, 25% co-occurred with a bacterial finding. Virus detcted in blood was a rare event. In the adult population, we detected a viral pathogen in 42% of the episodes of febrile neutropenia. This should be compared to 13% in afebrile neutropenic patients that were included as controls. In both groups, approximately half of the viruses were detected in blood. The predominant respiratory virus was HRV, whereas BK virus was the commonest finding in blood. In one-third of the virus-positive cases, a bacterial infection was documented. We furthermore found NPA being superior to a flocked nasal swab for collection of respiratory specimens (paper III).

We concluded that the prevalence of viruses was high in neutropenic patients with fever, and it was higher than for neutropenic patients without fever. It is plausible that a number of the patients with febrile neutropenia suffer from viral infections, and are thus not helped by antibiotics. Unfortunately, the presence of virus could not function as a predictor for non-bacterial infection. The findings, however, warrants further research related to the earlier achievements with aim to identify patients where continuous empiric antibiotic treatment could be avoided.

List of scientific papers

I. Öhrmalm L*, Lindblom A*, Omar H, Norbeck O, Gustafson I, Lewensohn-Fuchs I, Johansson JE, Brune M, Ljungman P, Broliden K. Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: incidence and outcome. Bone Marrow Transplant. 2010 Apr 19. *Equal contribution.
https://doi.org/10.1038/bmt.2010.86

II. Lindblom A, Bhadri V, Söderhäll S, Öhrmalm L, Wong M, Norbeck O, Lindau C, Rotzén-Ostlund M, Allander T, Catchpoole D, Dalla-Pozza L, Broliden K, Tolfvenstam T. Respiratory viruses, a common microbiological finding in neutropenic children with fever. J Clin Virol. 2010 Mar;47(3):234-7. Epub 2010 Jan 6
https://doi.org/10.1016/j.jcv.2009.11.026

III. Öhrmalm L, Wong M, Rotzen-Ostlund M, Norbeck O, Broliden K, Tolfvenstam T. Flocked nasal swab versus nasopharyngeal aspirate for detection of respiratory tract viruses in immunocompromised adults: a matched comparative study. BMC Infect Dis. 2010 Nov 26;10(1):340. [Epub ahead of print]
https://doi.org/10.1186/1471-2334-10-340

IV. Lars Öhrmalm, Michelle Wong, Carl Aust, Per Ljungman, Oscar Norbeck, Kristina Broliden, Thomas Tolfvenstam. Virus association to fever in adult neutropenic patients with hematological disorders: a cross-sectional study. [Manuscript]