Adenoviral Infections in Bone Marrow Transplanted Adult Patients: A Review of the 44 Cases Reported in the Last 25 Years

Adenoviral infections in immunocompromised individuals may be life-threatening conditions. The aim of this review is to document all the reported cases of adenoviral infection is patients having undergone bone marrow transplantation (BMT). A comprehensive literature search of the databases Pubmed, Science Direct, and Google Scholar was conducted to identify all the case reports of adenoviral infections in BMT patients. A total of 30 articles with 44 patients were included. The most common underlying condition was acute lymphocytic leukemia (23%) followed by acute myeloid leukemia (18%). The most common site of infection was disseminated (50%), followed by liver infection (8%) and hemorrhagic cystitis (8%). Cidofovir was administered in 40.9% of the cases, and death was reported in 34.4% of them. Ribavirin was administered as monotherapy in 15.9% of patients, with a mortality rate of 57.1%. We found that the antiviral drug option had no statistically significant effect on the mortality rate (p=0.242). Also, the absence of graft-versus-host disease (GVHD) was not associated with an improved outcome (p=0.523). There was, however, a statistically significant difference in the outcome based on the site of infection (p=0.005), with a higher rate of mortality in the disseminated and gastrointestinal cases. To the best of our knowledge, this is the first review documenting all the cases of adenoviral infections in BMT patients. Future randomized studies are needed to validate the results of the present study.


Introduction And Background
Adenoviruses are common pathogens that cause a wide range of illnesses and symptoms. They are extremely widespread and their seropositivity among children younger than four years old has been reported as high as 80% [1][2][3]. In the vast majority of immunocompetent hosts, adenoviral infections are self-limited and fatal cases are rare [4][5]. However, adenoviral infection in immunocompromised individuals, including patients having undergone bone marrow transplantation (BMT), maybe a life-threatening condition.
The most common sites of adenoviral infections include the respiratory tract, gastrointestinal tract, and urinary tract. Disseminated adenoviral infections can also occur, mainly in stem cells transplanted recipients and rarely in healthy hosts, and are associated with high mortality rates [2,6]. The diagnosis of a disseminated adenoviral infection is established when two or more sites are affected or when the virus is isolated from the blood. In some studies, moderate to severe graft-versus-host disease (GVHD) has been referred to as a risk factor for severe manifestations of adenoviral infections in BMT patients [6][7][8][9][10]. The efficacy of antiviral therapeutic strategies against adenoviral infection is still debatable and no specific therapy is strongly recommended.
The aim of the present review is to document all the reported cases of adenoviral infections in BMT patients. Data including the underlying hematologic disorder, the site of infection, the presence or absence of GVHD, the antiviral drug treatment, and the outcome of the cases are also recorded and statistically analyzed.

Review Methods
We performed a comprehensive electronic search of the PubMed, Science Direct, and Google Scholar electronic databases to identify all the reported cases of adenoviral infections in BMT patients from their   1  2  3  4   5  6  7  4  5 inception up to October 2021. The search terms used were as follows: "Bone Marrow Transplantation", "Adenovirus", "Adenoviral Infection". Exclusion criteria were: (1) reports of pediatric population, (2) the presence of HIV infection, (3) other causes of immunodeficiency. Conference abstracts were not included. Any duplicates or obviously irrelevant studies were also excluded.
A dedicated data extraction form was developed for recording all relevant details, involving publication details (author(s) and year of publication), number of patients, patients' age, underlying hematologic condition, site of infection, the presence or absence of GVHF, the antiviral drug option, and the outcome.
The data were entered into an Excel sheet (Microsoft Corporation, Redmond, WA) and were analyzed using the Statistical Program for Social Sciences (SPSS) 21.0 (IBM Corporation, Armonk, NY). The graphs were created using GraphPad Prism software version 9.0 (GraphPad Software, La Jolla, CA). Categorical variables were expressed as frequencies and percentages. Continuous variables were given as mean (range). The data were analyzed using contingency tables. The chi-square test of independence was used to determine whether there was an association between the categorical variables. A p-value of less than 0.05 was considered statistically significant.
Taking into account that this study is a review of published articles, neither ethics approval nor informed consent was needed.

Results
A total of 30 articles, with 44 patients, published from 1996 to 2020 were included (   The most common antiviral drug used was cidofovir in 18 of the cases (40.9%), either as monotherapy (8/44) or combined with intravenous immunoglobulin (IVIG) (10/44) and death was reported in 34.4% of them. In particular, there was a 62.8% mortality rate in the monotherapy group and a 37.5% mortality rate in the combined treatment group. Other treatment options included ribavirin (7/44, 15.9%), ganciclovir (4/44, 9%), and IVIG administered intravenously (2/44, 4.5%). The mortality rate in the patients treated with ribavirin was 57.1% and in patients treated with ganciclovir 25%. There was no statistically significant difference in the outcome with respect to the antiviral treatment used (x 2 =11.52, df=9, p=0.242) (Figure 1). There were six patients who received no antiviral treatment and the outcome was death for all of them. In six patients, the therapeutic strategy was not mentioned.  Adenoviruses may infect a variety of systems such as the respiratory, gastrointestinal, or urinary tract. Adenoviral infections account for 1% to 7% of respiratory tract infections, and typical symptoms include fever, pharyngitis, tonsillitis, cough, and a sore throat. Patients with adenoviral gastrointestinal tract infections usually present with symptoms such as gastroenteritis, vomiting, and diarrhea. Adenoviral urinary tract infections typically cause symptoms such as dysuria and hematuria, which might rarely lead to hemorrhagic cystitis. Finally, ocular adenoviral infection manifestations include epidemic keratoconjunctivitis, pharyngoconjunctival, fever, and nonspecific conjunctivitis. Nosocomial transmissions via environmental contamination, like ophthalmic instruments or eyedrops, have also been reported [41][42][43].
Adenoviral infections in immunocompromised individuals are serious conditions and their fatality rates may be as high as 60% to 80%. Disseminated infections are common among immunocompromised patients and multiorgan failure is a well-known complication. Persistent adenoviral infections can be manifested as pneumonia, renal failure, hepatitis, hemorrhagic cystitis, or encephalitis. In BMT patients, adenoviral infection is the third most common viral infection after human herpes simplex virus and cytomegalovirus [6][7]. Adenoviral infections that occur within the first 30 days to 90 days after transplantation are often a result of recent exposure while adenoviral infections that occur within 90 days or more are usually a result of adenoviral reactivation [8][9]. It has been reported that moderate to severe GVHD is a risk factor for severe manifestations of adenoviral infections in BMT patients [6][7][8][9][10]. Other risk factors reported are severe T-cell depletion and human leukocyte antigen (HLA) mismatch [44][45][46][47][48].
Immunocompetent hosts usually do not require specific therapy, and they produce neutralizing antiviral antibodies within two weeks from the infection. This, however, does not apply to immunocompromised patients. Unfortunately, there are no specific guidelines for the treatment of adenoviral infections in BMT patients. Treatment options include various antiviral drugs, such as ribavirin and cidofovir, or immunoglobulin. Those drugs have been shown to reduce the viral load and are associated with improved outcomes.
This is a review of 44 reported cases of adenoviral infections in adult patients with hematological diseases having undergone BMT. The present study indicated that the prognosis of adenoviral infections in BMT patients does not correlate with the underlying hematologic disorder or the antiviral treatment used. The prognosis, however, is poor in patients that do not receive any antiviral treatment at all. We found that the site of infection is the most important prognostic factor in those infections. Disseminated and hepatic forms are associated with the worst prognosis.
The present study had some limitations. The evidence obtained comes only from case reports. Future prospective randomized studies are needed to validate the results of the present study. There is a limited number of cases reported in the literature, and the absence of statistical significance may be related to this. Finally, in many of the studies, the presence or absence of GVHD and the antiviral treatment used are not reported, and this could have altered the results. Unfortunately, despite our efforts, we were not able to retrieve this information.

Conclusions
Adenoviral infections are extremely common and with a wide spectrum of clinical manifestations. The present study is a review of all the cases of adenoviral infections in BMT patients reported in the literature.
To the best of our knowledge, this is the first study documenting these cases and analyzing them in order to draw conclusions.
Based on our findings, adenoviral infections represent serious conditions in patients having undergone BMT and are associated with high mortality rates. The disseminated and hepatic infections are the most serious and with the worst outcomes. However, we found no correlation between the type of underlying condition or the presence of GVHD and mortality rates. There are no formal guidelines regarding the treatment of adenoviral infections in BMT patients, however, cidofovir and ribavirin are the most commonly employed by clinicians. We found no statistically significant differences with respect to the antiviral treatment used, but this could be related to the limited number of cases. It should be emphasized that the patients that did not receive any antiviral treatment had the worst outcomes. Taking into account the severity of those infections in this group of patients and the lack of formal guidelines for their treatment, future prospective randomized studies are necessary.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.