RESEARCH Hantavirus Pulmonary Syndrome,

hantavirus pulmonary syndrome (HPS) admitted to the Puerto Montt and Osorno Regional Hospitals, southern Chile, from 1997 to 2001, emphasizing epidemiologic, clinical , radiographic, treatment, and laboratory aspects. Hemorrhage was frequent (64%), and 48% of patients showed alterations in renal function. Ten patients died (40%). We identified three groups of patients, which included the following: 1) those with the least severe form who had prodromic symptoms without pulmonary involvement; 2) those with moderate illness who had interstitial pulmonary infiltrates, usually needed supplemental nasal oxygen , were hemodynamically stable, and had an APACHE II <12 (none of whom died); and 3) those with the severe form who required mechanical ventilation, frequently had hemodynamic instability (93%), experienced a high mortality rate (77%), and had an APACHE II >12. Mild forms of HPS also exist, which are poorly known; the symptoms could be confounded with those of other viral diseases, leading to underdiagnosis. H uman infection and disease caused by Hantavirus spp. were unknown in the Americas until May 1993 (1). Since then, hantavirus infection has been reported in the United States, Brazil, Paraguay, Bolivia, and Chile (2–5). A new species called Andes virus was isolated during an outbreak in Argentina, with a rodent reservoir of Oligoryzomys longicaudatus in rural Argentina and Chile (6). The most well-known clinical presentation of han-tavirus pulmonary syndrome (HPS) starts with an influen-zalike stage, with high fever, myalgia, asthenia, and after a prodromal period of 2 to 7 days, dyspnea, respiratory failure, and hemodynamic instability. Chest radiography shows rapidly progressing bilateral interstitial infiltrates, with an elevated hematocrit and thrombocytopenia. Other signs and symptoms have been reported, and in some case-patients, the disease may not progress beyond the prodromal stage or clinical symptoms may be completely absent (7). Asian and European forms of hantavirus disease consist of a group of febrile nephropathies known as hemorrhagic fever with renal syndrome (8), clinical features of which differ from the forms described in the Americas. This study describes some aspects of this emergent disease in a group of 25 patients with confirmed hantavirus infection, emphasizing clinical, radiographic, and laboratory aspects. Clinical chart information was recorded from of all patients with hantavirus pulmonary syndrome (HPS) admitted to the Osorno (n = 7) and Puerto Montt (n = 18) Hospitals from 1997 to 2001. All cases were confirmed by serologic tests performed at the virology laboratories of the Public Health Institute (Santiago) or Universidad …

We analyzed data from 25 consecutive patients with hantavirus pulmonary syndrome (HPS) admitted to the Puerto Montt and Osorno Regional Hospitals, southern Chile, from 1997 to 2001, emphasizing epidemiologic, clinical, radiographic, treatment, and laboratory aspects.Hemorrhage was frequent (64%), and 48% of patients showed alterations in renal function.Ten patients died (40%).We identified three groups of patients, which included the following: 1) those with the least severe form who had prodromic symptoms without pulmonary involvement; 2) those with moderate illness who had interstitial pulmonary infiltrates, usually needed supplemental nasal oxygen, were hemodynamically stable, and had an APACHE II <12 (none of whom died); and 3) those with the severe form who required mechanical ventilation, frequently had hemodynamic instability (93%), experienced a high mortality rate (77%), and had an APACHE II >12.Mild forms of HPS also exist, which are poorly known; the symptoms could be confounded with those of other viral diseases, leading to underdiagnosis.
H uman infection and disease caused by Hantavirus spp.were unknown in the Americas until May 1993 (1).Since then, hantavirus infection has been reported in the United States, Brazil, Paraguay, Bolivia, and Chile (2)(3)(4)(5).A new species called Andes virus was isolated during an outbreak in Argentina, with a rodent reservoir of Oligoryzomys longicaudatus in rural Argentina and Chile (6).
The most well-known clinical presentation of hantavirus pulmonary syndrome (HPS) starts with an influenzalike stage, with high fever, myalgia, asthenia, and after a prodromal period of 2 to 7 days, dyspnea, respiratory failure, and hemodynamic instability.Chest radiography shows rapidly progressing bilateral interstitial infiltrates, with an elevated hematocrit and thrombocytopenia.Other signs and symptoms have been reported, and in some case-patients, the disease may not progress beyond the prodromal stage or clinical symptoms may be completely absent (7).
Asian and European forms of hantavirus disease consist of a group of febrile nephropathies known as hemorrhagic fever with renal syndrome (8), clinical features of which differ from the forms described in the Americas.This study describes some aspects of this emergent disease in a group of 25 patients with confirmed hantavirus infection, emphasizing clinical, radiographic, and laboratory aspects.

Patient Population
Clinical chart information was recorded from of all patients with hantavirus pulmonary syndrome (HPS) admitted to the Osorno (n = 7) and Puerto Montt (n = 18) Hospitals from 1997 to 2001.All cases were confirmed by serologic tests performed at the virology laboratories of the Public Health Institute (Santiago) or Universidad Austral (Valdivia), with enzyme-linked immunoassay (ELISA) for immunoglobulin (Ig) M and IgG antibodies using Sin Nombre virus antigens provided by the Centers for Disease Control and Prevention, Atlanta, Georgia, USA.The Student t test was used to compare parametric variables, and chi square and Fisher exact test were used to compare discrete variables when necessary.A p value <0.05 was considered statistically significant.

Data Collection
The following data were recorded: age, sex, work type, residence, probable mechanism of infection, incubation period (only for those case-patients for whom precise information on the time of rodent exposure and onset of symptoms was available), medical history, and differential diagnosis.On admission, dyspnea, fever, anorexia, asthenia, headache, myalgia, chills, cough, abdominal pain, cyanosis, abnormal breathing sounds, hypotension (systolic blood pressure [SBP] <100), pulse rate, temperature, and respiratory frequency were recorded.A pseudoinfluenza course was understood to mean that the patients had a high fever, myalgia, headache, asthenia, and usually no rhinorrhea.
Clinical records noted any bleeding, alterations in renal or hepatic functions, alteration in consciousness, intensive care unit (ICU) admission, oxygen support, arterial oxygen tension (PaO 2 )/inspiratory oxygen fraction (FiO 2 ) (PAFI), administration of antibiotic drugs or corticosteroids, and mechanical ventilation (duration and time of connection).We defined a renal function abnormality according to American Thoracic Society (ATS) criteria with plasma creatinine values at the onset or during the course of the disease >1.2 mg/dL or blood urea nitrogen [BUN] >20 mg/dL (9), which are considered specific risk factors for death or a complicated course of community-acquired pneumonia.
Chest x-rays were analyzed, and the results were classified as an alveolar, interstitial, or mixed pattern, and the distribution of radiographic infiltrates as unilobar or multilobar, and unilateral or bilateral.The presence of pleural effusion was noted.In addition, we looked for an increase in the size of the opacity by >50% within 48 hours of admission because a rapid spreading of infiltrates shown by radiograph (which usually cannot be determined at the time of admission) indicates severe community-acquired pneumonia (9).
Laboratory tests at admission and during the course of the illness were recorded.
Methylprednisolone was administered (to 10 patients) according to a published protocol (10): 1,000 mg IV per day for 3 days, followed by 16 mg orally per day for 3 days, 8 mg per day for 3 days, and finally, 4 mg per day for 3 days.
An APACHE II severity score was calculated for every patient (11).For those admitted to the ICU, the score was calculated by using the data recorded at that time.For those patients not admitted to ICU, we used the worst parameters during hospitalization to find the worst APACHE.
Shock was defined as having a systolic blood pressure of <90 (which was not changed by fluid administration or required the use of vasoactive drugs), or as abnormalities in tissue perfusion shown by state of consciousness, oliguria, lactate acidosis, or both (12).Refractory shock was defined as shock lasting >1 hour with no response to volume resuscitation or pharmacologic therapy (13).We considered hemodynamic instability to have occurred when hypotension (SBP <100), fitting or not fitting the shock criteria, took place at any time during the clinical course.The length of hospital stay and the mortality rate were also evaluated.

Results
The data of 25 patients with confirmed cases of HPS were analyzed (17 men, 8 women, mean age 33.4 years, range 15-63 years).The infection was most commonly acquired through farm or timber work (40%), and 76% of the patients were rural residents.The incubation period, estimated in 14 cases, was 9.8 + 7.5 days (range 3-28 days).Symptom duration before admission was 5 + 1.8 days (range 2-10 days); 12 (48%) of 25 patients had requested previous medical care on one to four occasions before admission; and in 20 (80%) of 25 case-patients, a diagnosis other than HPS was initially suggested.
The results of laboratory tests at admission can be seen in Table 3; thrombocytopenia was indicated by a platelet count of <100,000 in 23 (92%) case-patients.The mean hematocrit values were 49.8 + 6.4, and three patients showed a value <45%.Twelve (48%) patients showed alterations in renal function, six (24%) exhibited a creatinine level >2.0, and one patient required hemodialysis.In 18 (72%) patients, liver function tests showed alterations, but only one patient had liver failure.
Hypotension at admission was observed in 12 (48%) of 25 patients, and 16 (60%) had hemodynamic instability (reaching 93% in the most severe group).Eight patients experienced refractory shock.In one patient, a Swan-Ganz catheter was used in a late stage of the infection, and the hemodynamic profile was consistent with septic shock, with low systemic venous resistence and high cardiac output.These conditions were also consistent with a case of nosocomial gram-negative sepsis; this was later demonstrated by blood culture.This case was the only one in which a bacterial overinfection was suspected and confirmed.
Radiographic changes exhibited at admission consisted of bilateral interstitial infiltrates in 14 patients (56%), alveolar infiltrates in 4 (16%), and mixed infiltrates in 5 (20%) patients.In two (8%) patients, the disease progressed without pulmonary infiltrates.The pulmonary infiltrates, when present, were bilateral and extended, involving 4 or 5 lobules in all cases.In seven (28%) patients, radiographic infiltrates were found to progress after 48 hours.Two patients showed pleural effusion.Samples from two patients with no pulmonary involvement underwent serologic tests because the patients lived in a rural region where previous cases had been found and because they had a clinical history of fever, myalgia, and malaise.One patient had thrombocytopenia (platelet count 53,000), and both had raised hematocrit values (50% and 46 %).
The mean PAFI at admission was 160 + 121 (range 40-508).Eight (32%) patients received oxygen either nasally or by mask, and in three (12%), supplemental oxygen was not required.Fifteen (60%) patients were admitted to the ICU, and 14 (56%) received mechanical ventilation early, 9 (64%) of 14 during the first 24 hours after admission, 4 before 48 hours, and 1 patient on day 3.The mean period of mechanical ventilation was 4 days (range 1-13 days).Ten (40%) patients died, seven before completing 1 day in the hospital, and one patient died later of septicemia caused by gram-negative bacteria.All patients who died showed diffuse and rapidly progressive interstitial pulmonary infiltrates, compatible with massive pulmonary edema, severe respiratory failure and refractory shock.Finally, electromechanical dissociation and asystolia were noted.
For the 15 patients admitted to the ICU, the mean APACHE II score was 18.3+8.7.No patient with APACHE II <12 died, and the mortality rate for the patients with APACHE II >12 was 77% (10/13) (p = 0.000).In the group of 10 case-patients who received methylprednisolone, 2 (20%) died, which contrasts with 8 (53%) deaths of 15 who did not receive this drug (p = 0.21).
We administered prednisolone to 10 patients; the decision to use it was made on admission for half of the casepatients and 2 to 4 days later for the remaining casepatients.One patient had hyperglycemia associated with the use of methylprednisolone.Nineteen (76 %) patients received antibiotic drugs, which were usually discontinued after confirmation of the viral cause.The variables with statistically significant differences between survivors versus nonsurvivors are shown in Table 4.Other variables associated with death were cyanosis (p = 0.005), renal function alteration (p = 0.001), shock (p = 0.000), ICU admission (p = 0.001), and mechanical ventilation (p = 0.001).Statistically significant differences were not observed for the following variables: hematocrit, platelet count, number of symptomatic days before admission, PaO 2 , leukocyte count, plasma sodium and potassium, bilirubin, glutamic-oxaloacetic transaminase (GOT) and glutamicpyruvic transaminase (GPT), type and number of bleeding episodes, alteration in consciousness, growth of 50% in radiographic images during the first 48 hours, and the use of methylprednisolone.
We identified three groups of case-patients.The first included two case-patients with only prodromic symptoms without pulmonary involvement.The second group (n = 9) consisted of patients who had a self-limited form of the disease, usually with different degrees of interstitial pul-monary infiltrates, who did not require intubation and received oxygen through noninvasive methods (including one case-patient who needed no oxygen), were hemodynamically stable, and had a low APACHE II (<12).The third group = 14) had severe forms of the disease with a high mortality rate (APACHE II >12), required intubation and mechanical ventilation, with hemodynamic instability in 13 (93%) and refractory shock in 8 (57%).Pulmonary infiltrates were usually alveolar.The mean hospital stay was 13.6 days + 24.7, ranging from hours for those patients who died quickly to 120 days in one patient with a peridural hematoma and severe secondary paraparesia as a consequence of a lumbar puncture.

Discussion
Our study confirms the existence of different clinical forms of hantavirus disease (7), including some without pulmonary involvement.A higher mortality rate was clearly associated with the most severe form (APACHE >12) of the disease, and death frequently occurred within the first  24 hours of hospital admission (70%).The main variables associated with death were APACHE II score, low PAFI, cyanosis, polypnea and tachycardia at admission, alterations in renal function, shock, and mechanical ventilation.The incubation period was estimated for 14 cases and ranged from 3 to 28 days (x = 9.8 + 7.5), which is consistent with other reports (7,14,15).The symptoms at admission were similar to those described in case-patients in the United States (16,17) and Chile (10,14).Fundamentally, the initial clinical presentation is similar to influenza without rhinorrhea, high fever, myalgia, headache, or asthenia, and often accompanied by abdominal symptoms such as pain, nausea, vomiting, and diarrhea.After a prodromal period of 2 to 7 days, respiratory symptoms appear with dyspnea, respiratory failure, and hemodynamic instability.Chest x-rays show bilateral interstitial infiltrates of different degrees of rapid progression.
Nevertheless, the infection can be manifested in other ways, and many cases do not go beyond the prodromal stage or elicit any symptoms.In January 1997, the first hantavirus serologic study was carried out in Chile; of 64 serum samples collected in a rural location, 7 were positive for specific Andes virus nucleoprotein IgG.These 64 samples represented almost the whole population living in the area of the first Chilean case-patient's residence.Thus nearly 10% of this rural population had had contact with the virus, although none of the provided a sample remembered a severe illness (7).
From 1995 to 2000, a total of 10 case-patients with mild forms of hantavirus disease were detected in Chile.The disease progressed in these case-patients without major pulmonary involvement, but the available information does not allow a close analysis of the clinical features of these cases, since most findings were from epidemiologic and serologic investigation (18).We found two casepatients who were admitted to the hospital because of a clinical course of fever, myalgia, and malaise, whose disease progressed with no pulmonary involvement as indicated by serial x-rays during their hospital stay.The diagnosis was suggested after considering the epidemiologic data (they lived in a rural area from which other cases had come) and suggestive laboratory test results: thrombocytopenia indicated by a platelet count of 53,000 in one and raised hematocrit value in both (50% and 46%).In these patients, the symptoms could have been confounded with a viral disease such as influenza and thereby been underdiagnosed because of the nonspecific character of the symptoms.In 80% of our case-patients, the initial diagnosis was incorrect, and 48% had received medical care on one to four occasions before hospital admission.By asking epidemiologically oriented questions in these endemic countries and regions, physicians may be able to make an earlier diagnosis of HPS.
In the series of patients described by Duchin et al. (16) in the United States, the early symptoms were similar to those described in the Asian and European forms of hantavirus disease known as hemorrhagic fever with renal syndrome.Nevertheless, no patient showed hemorrhages, renal involvement was minimal, and neither oliguria nor renal failure was observed in any case.The 1995 outbreak in Argentina was described as similar but details were not given (19).By contrast, the cases described in Chile are different, given the hemorrhagic manifestations observed.In Coyhaique (Chile), Tapia (10) saw petechiae in 38% (9/24), epistaxis in three pediatric patients and microhematuria in 16 patients (66.6%).In Region IX of Chile, Castillo (14,15) described a higher frequency of bleeding events (71% and 81%), including hematemesis, hemoptisis, epistaxis, and puncture site bleeding, similar to what we observed in 64% of the patients (Tables 1 and 2).In three patients of our series, a bleeding event was the reason for seeking healthcare.Thus, hemorrhagic manifestations appear to occur frequently in cases of hantavirus in Chile.
Concerning renal function, Tapia (10) observed raised creatinine of >1.5 in 7 of 24 cases, which did not correlate with the severity of clinical course.In this study, acute renal failure was considered a terminal phenomenon.Castillo reported two case-patients with acute renal failure; one required hemodialysis, and creatinine values were elevated (1.2-3.3 mg/dL) in 54% of the patients (14,15).In our series, 48% of the patients fulfilled the American Thoracic Society criteria for altered renal function (9), and the difference between the creatinine values of nonsurvivors and survivors measured at admission (p = 0.0003) was statistically significant.In 24%, creatinine values were >2.0, and one patient required hemodialysis.We believe that the use of common criteria to define renal failure in larger series can help estimate the changes in renal function, which seem to be more important than previously described and have a prognostic value.With regard to laboratory tests, raised hematocrit values and low platelet counts are exhibited by almost all patients at admission, and thus are important diagnostic elements, although they have no prognostic value.
Corticosteroids have the potential of modulating intrapulmonary inflammatory response by modifying the proinflammatory cytokine levels such as interleukin-1-β and tumor necrosis factor-∝ (TNF-∝), and have been used in the management of severe pulmonary disorders, with both an infective as well as a noninfective etiology such as miliary tuberculosis, Pneumocystis carinii pneumonia, vasculitides, and gastric acid aspiration (20).
In our study, 2 of 10 patients who received methylprednisolone (20%) died versus.8 of 15 (53%) in the group who did not receive this drug, although this difference was not statistically significant (p = 0.21).In larger series, a significant effect could perhaps be demonstrated.When the first cases were being diagnosed, however, we did not consider the use of corticosteroids; no protocol on how to use them existed, and most severely ill patients died very quickly and thus did not receive corticosteroids; their usage probably would not have changed the fatal course of the disease in this group, however.
The mortality rate in our series was directly related to the type of clinical presentation.In severe form, with APACHE II >12, mortality rate reached 77%, in contrast to those with a score <12, among whom no deaths were observed.From 1993 to July 2000, a total of 123 confirmed HPS cases were reported in Chile, 61 (49.6%) of which were fatal.This rate has decreased during the last 2 years, partly because of the improvement in diagnostic capacities and greater knowledge of the disease, which allows quicker identification and more effective treatment (18), but we think that this reduction also may be due to a dilution effect because more mild cases are found.
In our series, we distinguish three groups of patients.The first (n = 2), probably the least known, corresponds to patients with only prodromal symptoms, especially a pseudoinfluenza course with no pulmonary involvement, who are often not admitted to a hospital and are not recognized to have HPS.Correct diagnosis of these cases improves if one makes a good epidemiologic questionnaire.Groups 2 and 3 allow the patients to be classified according to clinical and radiologic criteria, severity, treatment, and prognosis.Use of uniform criteria is required to classify the patients infected by hantavirus with different clinical presentations, to thereby comparatively evaluate the mortality rate and the effectiveness of therapeutic measures.
Dr. Raúl Riquelme is a specialist in internal medicine and respiratory diseases and chief of the Department of Internal Medicine, Puerto Montt Regional Hospital, Puerto Montt, Chile.His main area of research has concerned community-acquired pneumonia.

Table 4 .
Variables with statically significant differences in survivors versus no survivors with hantavirus pulmonary syndrome a a SD, standard deviation; CI, confidence interval; PAFI, arterial oxygen tension/inspiratory oxygen fraction; SBP, standard blood pressure.