key: cord-0005631-5lqy1gjj authors: González, Y; Martino, R; Badell, I; Pardo, N; Sureda, A; Brunet, S; Sierra, J; Rabella, N title: Pulmonary enterovirus infections in stem cell transplant recipients date: 1999-02-26 journal: Bone Marrow Transplant DOI: 10.1038/sj.bmt.1701605 sha: a9134e8d2714c7dcc7b140376bfddb66faf7940c doc_id: 5631 cord_uid: 5lqy1gjj In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts. Pneumonia is a frequent infectious complication in patients with hematologic malignancies, particularly following stem cell transplantation (SCT). Most viral pneumonias in these patients have been traditionally associated with herpes viruses. In recent years, however, an increasing number of reports have shown the importance of upper and lower respiratory tract infections in SCT recipients and other immunocompromised hosts caused by community respiratory viruses, mainly respiratory syncytial virus, influenza A and B, parainfluenza, adenovirus and picornaviruses. [1] [2] [3] [4] [5] [6] The human picornaviruses (family Picornaviridae) which cause respiratory infections include rhinoviruses and enteroviruses, which in turn are classified into polioviruses, coxsackieviruses A and B, echoviruses and enterovirus 68-71. Infections by non-polio enteroviruses have rarely been reported in SCT recipients. Herein, we describe the presentation and clinical course of four highly immunocompromised SCT recipients with an acute respiratory illness who had enterovirus isolated from the bronchoalveolar lavage (BAL). One hundred and forty-four patients with hematologic malignancies received an allogeneic SCT and 414 patients received an autologous SCT between January 1990 and November 1997 at our institution. During this period, 190 BAL were performed in SCT recipients with an acute lower respiratory illness. All specimens were submitted for virological studies including antigen detection of respiratory viruses and tissue culture inoculation for cytomegalovirus, herpes simplex virus, enteroviruses and conventional respiratory viruses. An enterovirus was isolated as the sole pathogen in the BAL from four patients, whose characteristics are summarized in Table 1 . A 6-year-old male underwent an autologous bone marrow transplant (ABMT) for acute lymphocytic leukemia (ALL) in second complete remission (CR). The leukemia relapsed 9 months post-ABMT, and he received salvage chemotherapy with ICE (idarubicin, standard-dose cytarabine and etoposide). On day 20 of chemotherapy, neutropenic fever developed and empiric treatment with ceftazidime and amikacin was begun. Fever persisted and on day 24 he developed a nonproductive cough with a normal chest Xray, and on subsequent days vancomycin and liposomal amphotericin B were added. The patient did not defervesce and by day 33 his chest X-ray showed an alveolar infiltrate in the left upper lobe. A BAL was performed which grew only a non-polio enterovirus. Following neutrophil recovery the fever abated and the respiratory symptoms slowly improved. A 52-year-old male underwent an allogeneic peripheral blood SCT (PBSCT) from an HLA-identical sister for mantle cell lymphoma in refractory relapse. The post-PBSCT course was uneventful, but the disease recurred in blastic phase on day +106. Cyclosporine (CsA) was discontinued and salvage chemotherapy with ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) was given, followed by infusion of PBSC from the same donor. Twenty-five days after the second ESHAP he developed grade II acute GVHD, with complete response to steroids plus CsA. On day 50 after the second ESHAP he developed fever and a nonproductive cough. Chest X-ray showed a bilateral alveolar infiltrate, and empiric treatment with imipenem was begun. Within 48 h (day 52) fever persisted with respiratory deterioration, liposomal amphotericin B was added and a BAL was performed. On day 58 the patient developed overt respiratory failure and i.v. steroids plus ganciclovir were added. The BAL was reported positive for a non-polio enterovirus. Despite aggressive supportive management, the patient's respiratory status further worsened and he died on day 64. Consent for a postmortem study was not given. A 13-year-old male received an ABMT for ALL in second CR. The disease recurred 3 months after SCT and salvage chemotherapy with ICE was given. On day 23 of chemotherapy he developed neutropenic fever and was treated with ceftazidime plus amikacin for Escherichia coli bacteremia. Fever persisted over the following days with no further positive blood cultures, and within 2 days he developed respiratory symptoms with a right lower lobe alveolar infiltrate on chest X-ray. Liposomal amphotericin B was added and a first BAL was performed. Two days later he required intubation with mechanical ventilation and a second BAL was performed. Both BALs were later reported positive for a non-polio enterovirus. The patient died 2 days later with multi-organ failure and post-mortem examination revealed diffuse pulmonary lesions consistent with adult respiratory distress syndrome (ARDS). A 5-year-old male underwent a syngeneic BMT for ALL in second CR. The disease recurred within 6 months, and after achieving a third CR he underwent an unrelated cord blood transplant 9 months from the first BMT. CsA and steroids were given as GVHD prophylaxis. On day +18, grade I acute GVHD appeared with complete response to an increase in the dose of i.v. steroids. On day +37 he developed recurrent neutropenic fever which was treated with ceftazidime plus amikacin. Blood culture yielded Pseudomonas aeruginosa and viridans streptococci. The patient was on prophylactic liposomal amphotericin B and vancomycin was added on day +39. That same day bilateral alveolar infiltrates were first noted and the patient developed frank respiratory failure within 24 h, requiring intubation with mechanical ventilation; a BAL was performed which was later reported positive for a non-polio enterovirus. Despite aggressive supportive management the patient died 6 days later from multi-organ failure. Postmortem examination revealed only pulmonary changes consistent with ARDS. Enteroviruses are frequent human pathogens. In immunocompetent hosts their main clinical presentations are a common cold-like or flu-like syndrome and they may often be asymptomatic. Mild respiratory symptoms usually predominate. Additionally, enteroviruses are a leading cause of viral meningitis in children and myocarditis in all age groups. Enteroviruses spread from person to person. The usual mode of transmission is fecal-oral and studies of respiratory infection induced by certain types of enteroviruses in adult volunteers have shown that intranasal or aerosol administration more effectively induces respiratory infection. 7 Isolation of enteroviruses requires cellular cultures. Once identified, serotyping is cumbersome since more than 68 serotypes have been described to date and only reference laboratories can type all known serotypes. These difficulties may explain why enteroviral diagnostic techniques are unavailable on a routine basis in most microbiology laboratories and why these viruses have rarely been reported as causing infections in immunocompromised hosts. New highly sensitive PCR-based methods are being developed, but at present these diagnostic techniques are available only in research laboratories. 8 There have been few previous reports describing enterovirus infections in immunocompromised cancer patients in general and SCT recipients in particular. Two BMT recipients had an enterovirus (non-polio enterovirus in one and echovirus 11 in another) isolated from various organs in the setting of fatal pericarditis and pneumonitis. 9, 10 In a prospective study of infectious gastroenteritis in BMT recipients, a coxsackievirus was isolated in the stools of four patients, all of whom died from this complication; 11 these same investigators reported an epidemic of coxsackie A1 gastroenteritis affecting seven patients with six fatalities. 12 Surprisingly, there have been no other reports of lower gastrointestinal infections by these viruses, and in immunocompetent hosts enteroviruses do not produce gastroenteritis. There have also been only few reports of acute lower respiratory tract infections by picornaviruses in hematopoietic SCT recipients, with most cases leading to severe respiratory failure and death. However, 90% of the isolates were rhinoviruses and only 10% were due to non-polio enteroviruses. 3, 4 Some enteroviral pneumonias appear to be preceded by upper respiratory tract symptoms, but this sequence of events is not as apparent as with other community respiratory viruses such as rhinoviruses, parainfluenza viruses or respiratory syncytial virus. 4 As with other viral pneumonias, the exact implication of the isolation of an enterovirus from BAL and the fatal pulmonary infection is sometimes unclear, since post-mortem studies may be unavailable, show non-specific findings, or another pathogen (usually fungal or bacterial) may be identified. In our cases, however, only one patient (UPN 811) had concomitant infections which could otherwise explain the development of ARDS, namely Pseudomonas aeruginosa and viridans streptococci bacteremia. In conclusion, the clinical course of these four patients reflects the severity of this complication. Enterovirus infection may be an additional cause of pneumonia in severely immunocompromised hosts. Larger patient series will be required to confirm this observation and to identify possible epidemiologic or clinical features. Respiratory virus infection in immunocompromised patients Community respiratory virus infections among hospitalized adult bone marrow transplant recipients Respiratory viral infections in immunocompetent and immunocompromised persons Community respiratory virus infections in immunocompromised patients with cancer Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience Community respiratory virus infections following stem cell transplant Human Enterovirus Infections PCR-based strategies for the detection of human enteroviruses Prolonged enteroviral infection in a patient who developed pericarditis and heart failure after bone marrow transplatation Disseminated echovirus infection complicating bone marrow transplatation Infectious gastroenteritis in bone marrow transplant recipients Outbreak of coxsackie A1 gastroenteritis: a complication of bone marrow transplantation