PARAINFLUENZA VIRUS TYPE 4: CASE REPORT AND REVIEW OF THE LITERATURE

Parainfluenza viruses (PIV) are a common cause of respiratory illness in children. Four types have been identified, numbered 1 through 4. 1 PIV types 1 to 3 account for the majority of respiratory disease. However, in clinical series when virus isolation was attempted, PIV4 has accounted for between 1 and 11% of all PIV-related illness. 2–6 We present the case of a child with severe pulmonary infection attributed to PIV4 and discuss the known spectrum of disease related to this virus. Case report. A 15.5-month-old Native American female toddler was hospitalized in Reno, NV, in January, 1998, with fever, cough, somnolence and respiratory distress. During the previous 3 weeks she had had a persistent mild upper respiratory tract infection (URTI), and during the week before admission she took amoxicillin for acute otitis media. During the 24 h before admission, the patient had fever, cough and decreased activity and was taken to the emergency department because of increasing shortness of breath. Past medical history was unremarkable with no previous hospitalizations, surgery or injuries. Development was normal. Immunizations were up to date. Family history was noncontributory. On examination the child had subcostal, intercostal and supraclavicular retractions. Vital signs on presentation were temperature 38.5°C, respiratory rate 60 breaths/min, heart rate 190 beats/min and blood pressure 118/56 mm Hg. Tympanic membranes demonstrated no light reflex but were otherwise normal, and there was no conjunctivitis, pharyngitis or meningismus. Cardiac examination was normal and chest auscultation revealed diffuse symmetric rales. There was no rash and the remainder of the examination was unremarkable. The initial complete blood count showed a total white blood cell count of 19 × 10 9 cells/l (82% segmented neutrophils, no band forms); platelets, hemoglobin, electrolytes, blood urea nitrogen and creatinine were normal. A chest radiograph showed bilateral diffuse interstitial infiltrates. Blood culture, obtained before initiating antimicrobial therapy, had no growth. Therapy was started with intravenous cefotaxime, supplemental oxygen and aerosolized albuterol. During the next 12 h fever persisted, and she developed acute respiratory distress syndrome and shock necessitating mechanical ventilation and inotropic support. An echocardiogram revealed a fractional shortening of 11% with mitral valve and pulmonic valve regurgitation. Central venous pressure was 15 cm H2O. Digoxin and furosemide were begun. During the ensuing 3 days the patient developed progressive multiorgan dysfunction manifested as hepatic failure, prerenal azotemia and disseminated intravascular coagulation. The child had a focal seizure of her right arm and the right side of her mouth. A computed tomography scan of the central nervous system revealed no intracranial abnormalities. The patient was transferred without incident to a tertiary care facility on Hospital Day 4. Intravenous immunoglobulin was given (2 g/kg). Echocardiography was unremarkable with a normal fractional shortening and normal ejection fraction. Cerebrospinal fluid obtained by lumbar puncture was normal. The patient’s multiorgan dysfunction improved; however, she remained comatose. On Hospital Day 5 several erythematous, nonblanching papules developed on the left upper arm. On Hospital Day 7 anisocoria was noted, and the left pupil did not react to light. Computed tomographic scan revealed evidence of severe hypoxic-ischemic encephalopathy with diffuse loss of differentiation of the gray-white matter border. The family elected to withdraw intensive support, and the patient was transported to a facility closer to home to continue supportive care. An extensive retrospective diagnostic evaluation was performed in consultation with the California Unexplained Deaths and Critical Illness (UNEX) Project, a multisite, population-based surveillance effort aimed at early recognition of new and difficult-to-diagnose infectious agents. 7 Serology performed through UNEX excluded 11 possible infectious agents for the child’s illness: cytomegalovirus;Mycoplasma pneumoniae; PIV1 to 3; adenovirus;Chlamydia spp.; influenza virus types A and B; respiratory syncytial virus; hantavirus; Rocky Mountain spotted fever;Ehrlichia chafeensis; human granulocytic ehrlichiosis; and typhus. IgM directed against PIV4 was detected in serum taken on Hospital Day 4 using enzyme immunoassay and indirect immunofluorescent assay. 8 For both assays the patient’ serum was Marsorb G-treated (MarDx, Carlsbad, CA) to remove IgG. Discussion. The parainfluenza viruses, family Paramyxoviridae, cause a substantial amount of respiratory illness, especially in children. PIV4 was first isolated in 1958 and although two subtypes exist, types 4A and 4B, their clinical syndromes are indistinguishable. 3 Previously isolation of PIV by culture was more difficult than for other parainfluenza viruses because of lack of a rapid detection method and a late, weak hemadsorption. Only recently has an immunofluorescence method been described for detecting PIV4 in tissue culture. 5 An early inoculation study of healthy volunteers confirmed that PIV4 causes a mild upper respiratory tract infection in adults. 9 In the Tecumseh study of respiratory illness, a cohort of parents and their children were followed for 72 months. Viral cultures of respiratory secretions were done if members of the cohort had respiratory symptoms. 4 Parainfluenza viruses were isolated in 98 of the 2392 specimens (4.1%): 7 were PIV4; and 6 of these were subtype A. The majority of PIV4 infections occurred in children <2 years of age. For the patients in the Tecumseh study, information about clinical signs and symptoms specifically attributable to PIV4 is not available. A few clinical series describing the spectrum of illness associated with PIV4 have been published (Table 1). An early report evaluated the spectrum of disease associated with PIV4 isolates in England among inpatients and outpatients. 10 Of 18 isolates one-half were identified in children younger than 3 years. Of 16 cases in which clinical information was available, most had bronchitis or bronchopneumonia. Other associated syndromes included URTI, convulsion and pleural effusion. One patient each had syndromes clinically indistinguishable from rubella, erythema infectiosum and roseola infantum. A single patient, identified because of contact with another patient, had an asymptomatic infection. A seroprevalence study for both the A and B strains found that the majority of infections occur in children between 3 and 5 years old and that >50% of English children were seropositive by 5 years of age.Table 1: Summary of parainfluenza type 4 reportsIn a study of hospitalized children in England, 2 16 of 151 (10.6%) parainfluenza virus infections were attributable to type 4. The spectrum of disease ranged from mild URTI in the majority to more severe lower respiratory tract illnesses. Febrile seizures occurred in 44% of children. Croup, which accounted for 56% of all PIV-associated illness, was diagnosed in only one patient with PIV4 infection. Death occurred in a 14-month patient with cretinism and recurrent lower respiratory tract infections who had bronchiolitis; PIV4 was isolated from both the nasopharynx on admission and the left lung on autopsy. In 1993 a series of children from Montreal, Canada, who had PIV4 isolated from respiratory secretions was reported. 5 Isolates were identified from cultured virus with the useof a PIV4-specific monoclonal antibody. In this report 10 isolates of PIV4 (4%) were detected in the 252 respiratory virus cultures done during a 56-month period. The average age of the patients was 29.7 months; 8 of these patients were younger than 20 months. Three infants had paroxysmal cough as the sole manifestation of PIV4 infection and a 5-week-old presented with apnea. Five of the patients had lower respiratory tract infections, 4 with frank consolidation on chest radiograph. One 6-year-old girl had an upper respiratory tract infection with headache and vomiting and developed an unsteady gait and a short generalized seizure not associated with fever. A lumbar puncture showed mild lymphocyte pleocytosis, and PIV4 was isolated from the nasopharynx but not from the cerebrospinal fluid. After infection with PIV4 four of the patients had recurrent pulmonary disease manifested as bronchiolitis, bronchospasm or pneumonia. From Houston, TX, Lindquist et al. 3 reported 13 patients diagnosed during a 6-year period, 10 inpatients and 3 outpatients. The majority had an underlying illness, including infection with HIV, reactive airway disease, congenital heart disease, prematurity and chronic granulomatous disease. The 10 hospitalized patients in this report all had lower respiratory tract infection with apnea, bronchiolitis or pneumonia. Three patients had other respiratory viruses isolated: a 4-month-old with concomitant infection with influenza A and B, an 11-month-old with respiratory syncytial virus and adenovirus and an 18-month-old with respiratory syncytial virus. Two of the outpatients, both infected with HIV, had upper respiratory tract infection as the sole manifestation of PIV4 infection. The third outpatient was a 13-year-old with juvenile rheumatoid arthritis who developed meningismus. PIV4 was isolated from the cerebrospinal fluid of this patient, although there was no evidence of inflammation in the fluid. Recently Laurichesse et al. 6 published a large epidemiologic study of PIV infections in England and Wales. PIV4 was identified by virus isolation, direct immunofluorescence or complement fixation test serology and accounted for 88 of the 8221 PIV laboratory reports (1.1%) to the Public Health Laboratory Service. PIV4 infection was diagnosed most frequently between October and January and least frequently between April and August, a seasonal pattern similar to those of PIV1 and PIV2. The majority of patients with PIV4 were <1 year of age. For 22 patients clinical information was available; the majority had bronchiolitis. The patient presented in this report had PIV4 infection identified by IgM serology by two methods. Her initial presentation consisted of a prolonged prodrome of URTI followed by a lower respiratory tract infection resembling bronchiolitis. Her condition rapidly progressed to severe hypotension, multiorgan system failure and massive hypoxic ischemic encephalopathy resulting in a persistent vegetative state. To our knowledge this is the first case of a severe viral sepsis syndrome caused to PIV4 in a previously well child. Special tests are necessary to diagnose infection with PIV4. The identification of culture isolates requires a specific monoclonal antibody that is commercially available. 5 However, rapid diagnostic tests are unavailable given that there is currently no commercial method for direct detection in clinical specimens. The IgM evaluation used to diagnose this patient is a research tool not generally available; public health surveillance, such as the type performed by the UNEX, may be an important way to delineate the spectrum of this difficult-to-diagnose virus. Acknowledgments. KAS was partially supported by National Research Service Award 5 T32 GM07546 from the National Institutes of Health. DJP was supported by the California Emerging Infections Program, Oakland, CA. We thank Peggy S. Weintrub, M.D., for review of the manuscript.

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