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Keywords:

  • Influenza virus;
  • kidney transplant;
  • liver transplant;
  • lung transplant;
  • organ transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Background: Solid organ transplant (SOT) recipients have been reported to be more susceptible to influenza virus. However, little is known about the clinical epidemiology and the implications of influenza viral infection among SOT recipients.

Methods: Cohort study of influenza viral infection in SOT recipients at the University of Pittsburgh Medical Center.

Results: Between November 1990 and April 2000, 30 cases of influenza were diagnosed in SOT recipients at our center, including influenza A (n = 22) and influenza B (n = 8). These included recipients of lung (n = 19), liver (n = 5) and kidney (n = 6) transplants. The incidence of influenza viral infection was 41.8 cases/1000 person years (PYs), 2.8 cases/1000 PYs and 4.3 cases/1000 PYs among lung, liver and renal transplant patients, respectively (p < 0.0001). Symptoms were reported in all patients and included malaise, myalgia/arthralgia, fever, cough, and shortness of breath. Secondary bacterial pneumonia occurred in five patients (17%). Other complications were seen in three SOT recipients (2 liver and 1 kidney) and included: myocarditis, myositis, and bronchiolitis obliterans. Biopsy of the transplanted organ was performed in 21 SOT recipients (18 lung, 1 liver and 2 kidney) at the time of influenza viral infection. Overall, 62% (13/21) showed variable degrees of acute allograft rejection, and included 61% (11/18) of lung, and 100% (2/2) of kidney transplant recipients.

Conclusions: Influenza infection is associated with significant morbidity in different groups of SOT recipients. Studies are needed to determine if yearly chemoprophylaxis with antiviral drugs might benefit this patient population.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Influenza is an acute, usually self-limited, febrile illness caused by infection with influenza A or B virus that occurs in outbreaks of variable severity almost every winter. Influenza virus causes severe disease in the elderly, particularly in patients with heart and lung diseases (1). Infection causing pneumonia, and in severe cases death, has been reported in immunosuppressed patients, particularly bone marrow transplant recipients and patients with leukemia (1–3).

Solid organ transplant (SOT) recipients also appear to be susceptible to influenza and are more likely to experience influenza-related complications (1). However, the majority of the reports of influenza in SOT recipients have been in kidney recipients (2–4). The population of SOT recipients is heterogeneous and it would be interesting to know if the findings reported in renal transplant recipients can be generalized to all SOT patients. We, like others, have recently reported cases of influenza virus infection in liver (5) and lung (6) transplant recipients. However, the small sample size of these reports has precluded an appropriate assessment of influenza virus infection and its implications in this patient population. The aim of this investigation was to assess the incidence, clinical characteristics and outcome of influenza virus infection in different groups of SOT recipients during 10 consecutive years.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patients and definitions

Solid organ transplant recipients were included in this report if a diagnosis of influenza virus infection was accomplished at the University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA between November 1990 and April 2000. The date of diagnosis of respiratory viral infection was defined as the date of the specimen obtained which yielded influenza virus. The definition of viral pneumonia included shortness of breath, cough, with or without fever in association with a new infiltrate on chest radiograph, and the detection of influenza virus in the absence of bacterial pathogens in sputum and/or bronchoalveolar lavage (BAL) specimens. Concurrent bacterial pneumonia was defined as consolidation on chest radiograph and bacterial isolation in sputum and/or BAL specimens. Naso-pharyngeal swabs/washes were not routinely done for diagnosis of respiratory viruses. Respiratory failure was defined as hypoxemia (PO2 < 60 mmHg) requiring mechanical ventilation.

Microbiology

All sputum and BAL fluids specimens underwent routine bacterial, fungal and viral cultures. Before 1999 the respiratory viruses were identified using conventional virus culture looking for cytopathic effect (CPE) or hemadsorption. For the last 2 years, specimens for detection of respiratory viruses were inoculated into shell vials containing a mixture of susceptible cell culture lines including mink lung cells and human adenocarcinoma cells A-549 (Diagnostic Hybrids, Inc., Athens, OH, USA). The shell vials were incubated and stained at 24 and 72 h by indirect fluorescent antibody staining technique with Bartels Viral Respiratory Screening and Identification Kit (Bartels, Inc, Issaquah, WA, USA) according to the manufacturer's protocol. Cells from positive shell vials were scraped and tested with antibodies for specific respiratory viruses including influenza.

Chart review

Medical records of the study patients were reviewed from the hospital's electronic information database Medical Archival Retrieval System. The admission history and physical examination were reviewed for the presence and duration of fever, malaise, myalgia/arthralgia, cough, and shortness of breath. Patients were assessed for the presence of respiratory failure requiring mechanical ventilation and development of pneumonia. Demographic data, dates of admission and discharge, dates of organ transplant operations, diagnostic procedures, and the outcome of present hospitalization were collected and tabulated. All chest radiographs were reviewed for the presence and location of lung infiltrates. Recorded microbiology data included the date, specimen site, and results of cultures of all specimens. Pathology data obtained included the date, specimen type, and results of tissue biopsy.

Statistical analysis

Continuous variables were presented as the mean standard deviation and categorical variables as proportions. The standard two-sample t-test was used to test differences between means, while difference in proportions were tested using Fisher's exact test.

The incidence of influenza viral infection in the different groups of SOT recipients was calculated by dividing the number of cases in each group by the corresponding total number of transplant recipients during the study period.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

During the 10-year interval from November 1990 to April 2000, 30 SOT recipients with confirmed influenza virus infection were diagnosed at the University of Pittsburgh Medical Center. These included 19 cases in 454 lung transplant recipients, 5 among 1728 liver transplant recipients, and 6 in 1387 renal transplants recipients. The incidence of influenza viral infection was 41.8 cases/1000 person years (PYs), 2.8 cases/1000 PYs and 4.3 cases/1000 PYs among lung, liver and renal transplant recipients, respectively (p < 0.0001). Viral isolates were recovered from respiratory specimens, which included bronchoalveolar lavage (n = 29) and sputum samples (n = 1). Influenza virus types isolated during the study period were A (n = 22) and B (n = 8). No other type of virus including adenovirus, rhinovirus, respiratory syncytial virus and/or cytomegalovirus was concomitantly isolated from respiratory secretions in any of the study patients. The distribution of cases of influenza A and B by months of the year during the study period is shown in Figure 1.

image

Figure 1. Number of influenza virus A and B infections in solid-organ transplant recipients by months of the year during a 10-year period (1990–2000).

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The demographic data, immunosuppressive treatment and clinical manifestations of the three groups of SOT recipients with influenza virus infection are summarized in Table 1. Influenza virus infections occurred more often in females than in males (male to female ratio 9/21). Among lung transplant recipients 11 cases were diagnosed in single and 8 in double lung transplant recipients. Symptoms lasted for a median of 6 days (range 1–14) before hospitalization. One of the lung transplant recipients received oseltamivir, an influenza neuraminidase inhibitor, with improvement in his clinical symptoms after 3 days of drug intake. Bacteria isolated by culture among the three lung transplant recipients with secondary bacterial pneumonia included Staphylococcus aureus (n = 2) and Nocardia asteroides (n = 1). All lung transplant recipients recovered from influenza viral infection. In liver transplant recipients one of the cases was nosocomial since the patient developed influenza viral infection 5 days after transplantation. Among liver recipients with community-acquired influenza, viral infection symptoms lasted for a median of 4 days (range 3–7) before hospitalization. Secondary bacterial pneumonia developed in two patients, and organisms isolated by culture in this group included Streptococcus pneumonia (n = 1) and Staphylococcus aureus (n = 1). Other associated influenza complications which were observed in two liver transplant patients included myocarditis (n = 1) and bronchiolitis obliterans (n = 1). These two patients had documented influenza vaccine 4 months before their disease. No direct mortality related to influenza occurred in liver transplant recipients.

Table 1. : Demographics and clinical manifestations of solid organ transplant recipients with influenza viral infection
DemographicsLung transplantLiver transplantKidney transplant
(n = 19)(n = 5)(n = 6)
Male/female 6/13 1/4 2/4
Median age (range)53 (26–66)50 (22–63)49 (35–68)
Caucasian17 (89%) 5 (100%) 5 (83%)
African American 2 (11%) 0 (0%) 0 (0%)
Asian 0 (0%) 0 (0%) 1 (17%)
Tacrolimus/prednisone 7 (37%) 5 (100%) 5 (83%)
Cyclosporine A/prednisone12 (63%) 0 (0%) 1 (17%)
Median time in months between TX and influenza34.5 (2–103)48 (1.5–108)38.6 (2–87)
Clinical manifestations
 Malaise 6 (32%) 5 (100%) 5 (83%)
 Myalgia/arthralgia 6 (32%) 2 (40%) 2 (33%)
 Viral pneumonia 5 (26%) 4 (80%) 5 (83%)
 Bacterial pneumonia 3 (16%) 2 (40%) 0 (0%)
 Need for respiratory support 0 (0%) 4 (80%) 2 (33%)

Among renal transplant recipients, the median duration of symptoms before hospital admission was 4 days (range 3–7). One renal transplant recipient developed severe generalized myositis during influenza viral infection, which was diagnosed by electromyography and muscle biopsy. This patient had received influenza vaccine early in the season. No influenza-related mortality occurred in the renal transplant group.

Biopsy of the transplanted organ was performed in a total of 21 SOT recipients at the time of influenza viral infection. These were lung (n = 18), liver (n = 1), and kidney (n = 2) recipients. Overall, 62% (13/21) showed variable degrees of acute allograft rejection, and included 61% (11/18) of lung, and 100% (2/2) of kidney transplant recipients. Review of the biopsy material and special stains on microscopy failed to show any viral inclusions in the transplanted organ.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Infection with influenza virus can result in a wide spectrum of clinical disease, ranging from asymptomatic infection to fulminant viral pneumonia. The influenza virus is recognized to cause severe infections in elderly patients with heart and lung disease (1). In some early reports on severe influenza epidemics, immunocompromised patients, particularly bone marrow transplant recipients, were described as being at higher risk for severe influenza complications (2, 7). However, besides the inconsistent data concerning renal transplant recipients, there is limited information on the clinical spectrum and implications of influenza virus infection among other SOT recipients.

Ljungman et al. (3), in a study of influenza A in 19 adult immunocompromised patients, described 12 cases in renal transplant recipients. All patients were receiving immunosuppressive therapy with cyclosporine A, azathioprine and prednisolone at the time of viral infection. One patient had received influenza vaccine earlier in the season. The most common symptom was fever with a median duration of 4 days. One patient was found to have viral pneumonia and another developed bronchitis. The remaining 10 patients recovered without complications. No data regarding their allograft status at the time of influenza infection was given. A second study (2) described three renal transplant recipients with influenza B viral infection. The most common symptoms in these patients were cough and fever. No data regarding influenza vaccine was reported, and none of the patients developed influenza-related complications.

In contrast with these early reports, the results of our study indicate that influenza virus infection is associated with significant morbidity in different groups of SOT recipients. This is illustrated by the high proportion of pulmonary and nonpulmonary complications in our study of SOT recipients as compared to reports of this viral infection in the general population (1). Several factors may predispose SOT recipients to infections with influenza virus. The most important one may be insufficient antibody levels against influenza virus. Protection against infection is afforded by the presence of substantial levels of antibody (8, 9). Although there is no exact correlation, serum hemagglutination-inhibiting (HI) antibodies titers of 1 : 40 or greater are associated with protection against infection in young people, while HI titers of 1 : 20 or 1 : 10 are associated with reduced protection (10). Furthermore, studies of HI antibody titer comparing SOT recipients with healthy subjects after influenza vaccine have consistently shown that a significantly lower proportion of SOT recipients developed protective HI antibody levels of 1 : 40 or greater (11–14). In addition, our analysis indicated a higher incidence of influenza infections among lung transplants recipients (41.8 cases/1000 PYs), as compared to liver and kidney transplant recipients. This may be the result of more aggressive respiratory surveillance of lung transplant recipients. On the other hand, this may also be explained by the fact that secretory antibodies in the respiratory tract are an important component of resistance against influenza viral infection (15, 16), a factor altered in lung transplant recipients. Indeed, data suggest that optimal protection occurs when both serum and secretory antibodies are present (17).

Influenza virus seems to be capable of activating immunological mechanism in the transplant organ, as evidenced by the high association rate with acute cellular rejection in our patients. These findings are in agreement with previous studies of kidney transplant recipients (18, 19), and a recent investigation (6) in lung transplant recipients that reported on development of acute allograft rejection and bronchiolitis obliterans after influenza viral infection. Perhaps the activation of immunological mechanism leading to allograft rejection by influenza virus is related to the production of ThI type alloreactive cytokines such as interleukin (IL)-1, tumor necrosis factor, IL-6 and IL-8 during viral replication. Indeed, a recent study (20) of adult patients experimentally infected with influenza A indicated that viral shedding was associated with increase in level of cytokines, such as IL-6 and IL-8. Thus, influenza viral infection might have a significant role in the function of the transplant organ.

The major focus of prevention has been influenza immunization in order to stimulate local and systemic antibodies. A number of trials have demonstrated the efficacy of influenza vaccine in the prevention of naturally occurring outbreaks of influenza (21, 22). Studies have suggested that vaccines reduced the frequency of severe influenza illness in both the young and the elderly (10, 22). However, our study suggests that this may not be the case for SOT recipients, as indicated by the patients who developed severe influenza despite vaccination. Indeed, some studies have documented that antibody responses to influenza vaccine decreased in all groups of SOT recipients (11–13). Therefore, we propose that other modalities of prevention against influenza should be considered in SOT recipients, such as chemoprophylaxis. Amantidine and rimantidine are related antiviral drugs, with similar mechanism of action, and are effective against influenza A only. They have an efficacy of about 75–90% and their protection may be additive to that of the influenza vaccine (23–25). However, data of the effectiveness of these drugs in SOT recipients are lacking. In relation to the new influenza neuraminidase inhibitors, zanamivir and oseltamivir, studies indicate that both drugs have a similar rate of effectiveness against influenza A and B viruses (26). In addition, recent (27, 28) reports have shown that the two drugs have had a similar rate of effectiveness in the prevention of illness. These studies did not include SOT recipients.

In summary, our findings indicated that influenza viral infection in SOT recipients is associated with significant morbidity and may affect the function of the transplant organ. Studies are needed to determine if prophylaxis with antiviral agents may in the future decrease influenza morbidity in SOT recipients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We thank Charles Rinaldo, Ph.D., Kirsten St. George, MAS, and the staff of the Clinical Virology Laboratory at the University of Pittsburgh Medical Center for providing their expert technical assistance for the identification of the type of influenza virus.

This work was presented in part at the 38th Annual Meeting of the Infectious Diseases Society of America held in New Orleans on 7–10 September 2000 (abstract# 583).

References

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  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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