Influenza Pneumonia in Lung Transplant Recipients

5 Similowski T, Mehiri S, Attali V, et al. Comparison of magnetic and electrical phrenic nerve stimulation in assessment of phrenic nerve conduction time. J Appl Physiol 1997; 82:1190 –1199 6 Hamnegard CH, Wragg S, Kyroussis D, et al. Mouth pressure in response to magnetic stimulation of the phrenic nerves. Thorax 1995; 50:620 – 624 7 Attali V, Mehiri S, Straus C, et al. Influence of neck muscles on mouth pressure response to cervical magnetic stimulation. Am J Respir Crit Care Med 1997; 156:509 –514 8 Stevens WM, Burdon JG, Clemens LE, et al. The “shrinking lungs syndrome”: an infrequently recognised feature of systemic lupus erythematosus. Aust N Z J Med 1990; 20:67–70 9 Luo YM, Polkey MI, Johnson LC, et al. Diaphragm EMG measured by cervical magnetic and electrical phrenic nerve stimulation. J Appl Physiol 1998; 85:2089 –2099 10 Zifko U, Remtulla H, Power K, et al. Transcortical and cervical magnetic stimulation with recording of the diaphragm. Muscle Nerve 1996; 19:614 – 620 11 Millette TJ, Subramony SH, Wee AS, et al. Systemic lupus erythematosus presenting with recurrent acute demyelinating polyneuropathy. Eur Neurol 1986; 25:397– 402 12 White JE, Bullock RE, Hudgson P, et al. Phrenic neuropathy in association with diabetes. Diabet Med 1992; 9:954 –956

after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis. (CHEST 2001; 119:1277–1280) Key words: allograft rejection; bronchiolitis obliterans syndrome; influenza; lung transplantation; obliterative bronchiolitis Abbreviations: BMT ⫽ bone marrow transplant; BOS ⫽ bronchiolitis obliterans syndrome; CMV ⫽ cytomegalovirus; OB ⫽ obliterative bronchiolitis

viruses are increasingly recognized to cause R espiratory morbidity and mortality in the community. Influenza

viruses, in particular, are among the most important seasonal respiratory pathogens. During the winter months, up to 10% of all patient visits to physicians are due to influenza-like illnesses.1 In addition, influenza may cause 10,000 to 40,000 deaths and ⬎ 150,000 hospitalizations annually, especially in patients with preexisting medical conditions.2

For editorial comment see page 997

Influenza Pneumonia in Lung Transplant Recipients* Clinical Features and Association With Bronchiolitis Obliterans Syndrome Stavros Garantziotis, MD; David N. Howell, MD, PhD; H. Page McAdams, MD; R. Duane Davis, MD, FCCP; Nancy G. Henshaw, PhD; and Scott M. Palmer, MD, MHS

Influenza-related illness has been described in immunocompromised persons, including solid-organ and bone marrow transplant (BMT) recipients.3–5 Between 6% and 29% of all acute respiratory infections in BMT patients are caused by influenza viruses.3,4 The incidence and significance of influenza infection after lung transplantation, however, remains unknown. In this article, we provide the first detailed description of the clinical presentation, radiographic features, histologic findings, and clinical outcomes of influenza pneumonia in three lung transplant recipients.

Case 1 Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients *From the Departments of Medicine, Division of Pulmonary and Critical Care Medicine (Drs. Garantziotis and Palmer), Pathology (Drs. Howell and Henshaw), Radiology (Dr. McAdams), and Surgery (Dr. Davis), Duke University Medical Center, Durham, NC. Manuscript received May 18, 2000; revision accepted September 1, 2000. Correspondence to: Scott M. Palmer, MD, MHS, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Box 3876, Bell Building, Duke University Medical Center, Durham, NC 27710; e-mail: [email protected]

A 53-year-old African-American woman had received a bilateral lung transplant in October 1997 for end-stage sarcoidosis. Although she experienced a complicated posttransplant course characterized by severe reperfusion injury, she was discharged from the hospital with acceptable pulmonary function (FEV1 of 1.60 L or 60% predicted). The patient did well, with no episodes of allograft rejection or infection, and remained free from bronchiolitis obliterans syndrome (BOS). In April 1999, she presented with increasing shortness of breath, cough productive of yellow sputum, fatigue, and weakness. She was afebrile. Physical examination revealed diffuse rhonchi and wheezes throughout both lung fields, with decreased breath sounds at the right lung base. Chest radiography revealed homogeneous rightlower-lobe consolidation with small associated pleural effusion (Fig 1). She received 3 weeks of antibiotic treatment (ceftazidime and ciprofloxacin) without improvement. Therefore, bronchoscopy was performed and the results revealed bilateral mucopurulent secretions without endobronchial lesions. Transbronchial biopsy was not performed because of hypoxemia during the procedure. Immunofluorescence staining of the lavage fluid returned positive for influenza A virus. Culture findings were negative for viruses, fungi, and bacteria. She was treated with a 2-week course of amantadine. Although the patient’s clinical condition and radiographic findings improved by discharge, her CHEST / 119 / 4 / APRIL, 2001

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Case 3

Figure 1. Influenza A pneumonia in 53-year-old woman after bilateral lung transplantation for sarcoidosis. A posteroanterior chest radiograph shows homogeneous consolidation and volume loss in the right lower lobe, a small right pleural effusion, and heterogeneous opacity in the left lower lobe.

pulmonary function remained reduced at subsequent follow-up visits. Over the next 6 months, the patient experienced a progressive decline in pulmonary function with increasing hypoxemia, and she ultimately died in October 1999. Autopsy revealed evidence of severe obliterative bronchiolitis (OB).

A 38-year-old white woman had received a left single lung transplant in August 1998 for end-stage emphysema secondary to ␣1-antitrypsin deficiency. She had an excellent functional outcome (FEV1 of 1.60 L or 49% predicted) and had multiple surveillance biopsy findings negative for infection or rejection. In December 1999, the patient presented to the clinic with a 2-day history of fever (temperature up to 40°C), nausea, and emesis. She denied having respiratory symptoms. Chest radiography demonstrated perihilar heterogeneous opacities in the transplanted lung (Fig 2). She was treated initially with ganciclovir, ceftriaxone, and clindamycin for possible aspiration or CMV pneumonia. Due to increased lethargy and hypotension, she was transferred to the ICU. There she underwent bronchoscopy, and the lavage fluid results were positive for influenza A on immunofluorescence stain and viral culture. Other cultures and stains for respiratory viruses, bacteria, and fungi were negative. Histologic analysis showed acute patchy pneumonitis without evidence of rejection (Fig 3, top). She was started on zanamivir and continued on the other antibiotics. She developed some bronchospasm with zanamivir, which was alleviated by bronchodilator treatment. The patient improved clinically and was discharged home after 9 days. Nasal wash examination prior to discharge showed no evidence of influenza. Three months after influenza infection, the patient returned with a significant decline in pulmonary function (FEV1 0.88 of L or 27% predicted). Bronchoscopy with biopsy at that time revealed mild (grade A2) rejection (Fig 3, bottom). Despite augmented immunosuppression and histologic resolution of acute rejection, the patient has experienced a clinical course consistent with progressive BOS.

Discussion Influenza is increasingly recognized to cause significant morbidity and mortality in the community, especially

Case 2 A 40-year-old white man had received a heart-lung transplant in May 1998 for Eisenmenger’s syndrome secondary to a singleoutlet ventricle. His early posttransplantation course was complicated by acute lung allograft rejection in May and June of 1998, and cytomegalovirus (CMV) pneumonitis in September 1998. His pulmonary function remained excellent (FEV1 of 4.05 L or 91% predicted), and results of surveillance biopsies of the heart showed no rejection. He presented to the transplant clinic in March 1999 with a 2-day history of sore throat, abdominal pain, and diarrhea. His lungs were clear to auscultation. Arterial blood gas measurements on room air revealed moderate hypoxemia and metabolic acidosis. Further laboratory studies showed acute renal insufficiency, and leukocytosis with bandemia. Chest radiography showed bibasilar heterogeneous and linear opacities. The patient was started on IV piperacillin/tazobactam and ganciclovir for possible bacterial or CMV pneumonia. Bronchoscopy showed erythematous and edematous airways without secretions. The lavage fluid was positive for influenza B on immunofluorescence. Viral, fungal, and bacterial culture findings were negative. Histologic analysis demonstrated mild bronchial inflammation but no allograft rejection. With continued supportive care, including gentle hydration, the patient’s symptoms, acidosis, and renal insufficiency improved significantly. Two months later, the patient’s pulmonary function was significantly worse than his baseline level (FEV1 2.39 L or 54% predicted). Transbronchial biopsy at that time revealed minimal (grade A1) lung allograft rejection. Despite augmented immunosuppression, the patient has experienced a progressive decline in pulmonary function consistent with BOS. 1278

Figure 2. Influenza A pneumonia in 38-year-old woman after left single lung transplant for emphysema. An anteroposterior chest radiograph shows heterogeneous perihilar opacities in left lung. Selected Reports

Figure 3. Micrographs of the biopsy tissue from Case 3. Top: Biopsy specimen taken at the time of influenza infection, showing patchy acute pneumonitis. A cluster of neutrophils within an alveolar space near the center of the micrograph is shown at higher magnification in the insert (bar in main figure ⫽ 100 ␮m; bar in inset ⫽ 10 ␮m). Bottom: Biopsy taken shortly after influenza infection, showing grade A2 rejection. A conspicuous collar of mononuclear inflammatory cells (arrowheads) surrounds a small vessel (bar ⫽ 100 ␮m) [periodic acid-Schiff, original ⫻ 250; inset, original ⫻ 625].

among pediatric patients and the elderly. In addition, influenza infection has been well described in BMT recipients. In a large prospective study4 of BMT patients over two winter seasons, influenza virus was isolated from 6% of patients (12 of 217) with acute respiratory illness. Pneumonia developed in 75% of patients with influenza isolated, and 33% ultimately died of progressive pneumonia.4 Similarly, influenza has been described as a devastating infection in pediatric solid-organ transplant recipients, with mortality rates ⬎ 20%.5 In contrast, influenza infection has been described infrequently in adult recipients of solid-organ transplants, including recipients of lung allografts. In fact, in our previous article6 on community respiratory viral infections in adult lung transplant recipients, no cases of influenza infection were observed. Similarly, at another center, among 1,820

BAL samples obtained from 137 lung transplant recipients over a 6-year period, influenza virus was isolated only twice.7 In this article, we provide the first detailed description of influenza infection among lung transplant recipients. In normal hosts, influenza infection is characterized by the sudden onset of fever, chills, rigors, headache, malaise, myalgia, and dry cough.8 Features of infection vary among different age groups, with GI symptoms more common in children, but systemic complaints such as malaise and chills more common in adults and elderly patients. In contrast, in our population of adult lung transplant recipients, GI symptoms predominated in two of three patients. In normal hosts, symptoms of influenza infection often improve within 3 to 5 days.8 Primary viral pneumonia can develop, however, especially in elderly and immunocompromised patients. Secondary infections with bacterial pathogens are also common, usually with Streptococcus pneumoniae or Staphylococcus aureus. All three lung transplant recipients had new findings on chest radiographs at time of presentation. The radiographic findings were nonspecific and ranged from subtle heterogeneous and linear opacities to homogeneous lobar consolidation. Although bacterial superinfection could explain the radiographic findings, the presence of influenza alone on BAL cultures in all three patients favors primary influenza pneumonia. Little is known about the histologic changes in influenza pneumonia. The existing reports from the literature are derived from autopsies in patients who succumbed to the pneumonia, and are therefore are not likely representative of patients earlier in the course of disease. Autopsy reports describe acute inflammation with a strong component of diffuse alveolar damage.9 In the two patients in our series who underwent a transbronchial biopsy, there was evidence of acute pneumonitis, but no diffuse alveolar damage. Because histologic findings are nonspecific, screening BAL fluid for respiratory viral pathogens is essential. Newer direct fluorescent antibody techniques, as were employed in our patients, permit a more rapid identification of specific respiratory viral pathogens as compared to the traditional cell culture methods. In addition, the sensitivity of rapid direct fluorescent antibody techniques proved superior in our series, as the culture finding was positive in only one patient. Importantly, all three of our patients experienced progressive BOS that began shortly after the influenza infection. BOS is generally thought to represent a manifestation of chronic lung allograft rejection and correlates with the histologic development of OB. Autopsy confirmed the presence of OB in one of our patients. Follow-up biopsies in the other two patients demonstrated late acute allograft rejection. The association is especially striking in the two patients who developed BOS with no prior history of acute rejection or CMV infection, both of which have been identified as major risk factors for BOS.10 Because of the timing of BOS and influenza infection in these three patients, it is interesting to speculate that viral infection contributed to the development of BOS. A plausible hypothesis is that stimulation of cellular immunity in response to viral infection results in enhanced recognition of allogeneic tissue leading to acute and/or chronic allograft rejection. A direct cytopathic effect of the CHEST / 119 / 4 / APRIL, 2001

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respiratory viruses on the bronchial and alveolar epithelium, however, cannot be excluded. Consistent with our observations in these patients, a seasonal onset of BOS has been described in lung transplant recipients, implicating a possible role for seasonal viral pathogens in the etiology of this condition.11 Similarly, we have previously described a high rate of BOS in patients who survived infection with respiratory syncytial virus, adenovirus, or parainfluenza virus.6 In addition, OB was recently noted to have developed in a pediatric lung transplant recipient shortly after recovery from influenza pneumonia.12 Given the potential relationship between influenza infection and rejection, additional emphasis on prevention of infection may be warranted. Numerous studies in nonimmunocompromised patients have demonstrated that annual vaccination with inactivated influenza vaccine leads to a reduction in influenza-related hospitalizations and deaths.8,13 The role of vaccination in solid-organ transplant recipients, however, is controversial because of conflicting data about antibody responses to influenza vaccination.14,15 Therefore, serologic testing for antibody development and booster vaccination may be indicated. In addition, aggressive vaccination of all close contacts and household members also should be considered to decrease the risks of infection in transplant recipients. Finally, several drugs, including amantadine, rimantadine, and the newer neuraminidase inhibitors, zanamivir and oseltamivir, appear effective in the prevention of infection in normal hosts.8,16 Further research is needed to determine the efficacy of these agents in transplant recipients. In summary, we report three cases of influenza pneumonia in lung transplant recipients. The initial presentation did not always involve the respiratory tract but included predominant GI symptoms in two of three patients. New radiographic opacities consistent with viral pneumonia were seen in all cases, and histologic findings revealed acute pneumonitis. Because the signs and symptoms of infection tend to be nonspecific, a high clinical suspicion for influenza infection is required and appropriate tests need to be pursued in order to make a definitive diagnosis. Significant morbidity resulted from acute infection, with all patients requiring hospitalization. More importantly, a striking association was observed between influenza infection and the subsequent development of BOS in each patient. Further research, thus, is needed to determine if influenza infection directly or indirectly contributes to the development of acute and/or chronic rejection in lung transplant recipients.

References 1 Anonymous. Update: influenza activity, United States 1999 – 2000 season. MMWR Morb Mortal Wkly Rep 2000; 49:53–57 2 Barker WH. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970 –1978. Am J Public Health 1986; 76:761–765 3 Whimbley E, Eling LS, Couch RB, et al. Influenza A virus isolation among hospitalized adult bone marrow transplant recipients. Bone Marrow Transplant 1994; 13:437– 440 4 Whimbley E, Champlin RE, Couch RB, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22:778 –782 1280

5 Apalsch AM, Green M, Ledesma-Medina J, et al. Parainfluenza and influenza virus infections in pediatric organ transplant recipients. Clin Infect Dis 1995; 20:394 –399 6 Palmer SM Jr, Henshaw NG, Howell DN, et al. Community respiratory viral infections in adult lung transplant recipients. Chest 1998; 113:944 –950 7 Holt ND, Gould FK, Taylor CE, et al. Incidence and significance of noncytomegalovirus viral respiratory infection after adult lung transplantation. J Heart Lung Transplant 1997; 16:416 – 419 8 Cox NJ, Subbarao K. Influenza. Lancet 1999; 354:1277–1282 9 Ljungman P, Andersson J, Aschan J, et al. Influenza A in immunocompromised patients. Clin Infect Dis 1993; 17:244 – 247 10 Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; 155:789 – 818 11 Hohlfeld J, Niedermeyer J, Hamm H, et al. Seasonal onset of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15:888 – 894 12 Faul JL, Akindipe OA, Berry GJ, et al. Influenza pneumonia in a pediatric lung transplant recipient. Transpl Int 2000; 13:79 – 81 13 Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995; 333:889 – 893 14 Dengler TJ, Strnad N, Buhring I, et al. Differential immune response to influenza and pneumococcal vaccination in immunosuppressed patients after heart transplantation. Transplantation 1998; 66:1340 –1347 15 Blumberg EA, Albano C, Pruett T, et al. The immunogenicity of influenza virus vaccine in solid organ transplant recipients. Clin Infect Dis 1996; 22:295–302 16 Campion K, Silagy C, Keene O, et al. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998; 352:1877–1881

Continuous Calcium Chloride Infusion for Massive Nifedipine Overdose* Yui-Ming Lam, MB; Hung-Fat Tse, MD; Chu-Pak Lau, MD, FCCP

A 37-year-old woman presented with persistent hypotension and noncardiogenic pulmonary edema after massive nifedipine overdose. Judicious use of continuous and prolonged high-dose IV calcium infusion was administered to provide sustained increases in serum ionic calcium level (approximately 2 mmol/L) and was able to improve the hemodynamic status without any major adverse reaction. (CHEST 2001; 119:1280 –1282) *From the Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. Manuscript received May 30, 2000; revision accepted August 31, 2000. Correspondence to: Hung-Fat Tse, MD, Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China; e-mail: [email protected] Selected Reports